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  • Topographic effects
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  • 1
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    Baroclinic flow around planetary islands in a double gyre : a mechanism for cross-gyre flow (2010)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2010. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 40 (2010): 1075-1086, doi:10.1175/2009JPO4375.1.
    Description: A quasigeostrophic, two-layer model is used to study the baroclinic circulation around a thin, meridionally elongated island. The flow is driven by either buoyancy forcing or wind stress, each of whose structure would produce an antisymmetric double-gyre flow. The ocean bottom is flat. When the island partially straddles the intergyre boundary, fluid from one gyre is forced to flow into the other. The amount of the intergyre flow depends on the island constant, that is, the value of the geostrophic streamfunction on the island in each layer. That constant is calculated in a manner similar to earlier studies and is determined by the average, along the meridional length of the island, of the interior Sverdrup solution just to the east of the island. Explicit solutions are given for both buoyancy and wind-driven flows. The presence of an island of nonzero width requires the determination of the baroclinic streamfunction on the basin’s eastern boundary. The value of the boundary term is proportional to the island’s area. This adds a generally small additional baroclinic intergyre flow. In all cases, the intergyre flow produced by the island is not related to topographic steering of the flow but rather the pressure anomaly on the island as manifested by the barotropic and baroclinic island constants. The vertical structure of the flow around the island is a function of the parameterization of the vertical mixing in the problem and, in particular, the degree to which long baroclinic Rossby waves can traverse the basin before becoming thermally damped.
    Description: This research was supported in part by NSF Grant OCE 0451086.
    Keywords: Gyres ; Baroclinic flows ; Topographic effects ; Streamfunction ; Orographic effects
    Repository Name: Woods Hole Open Access Server
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  • 2
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    Shelf circulation and cross-shelf transport out of a bay driven by eddies from an open-ocean current. Part I : interaction between a barotropic vortex and a steplike topography (2011)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2011. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 41 (2011): 889–910, doi:10.1175/2010JPO4496.1.
    Description: This paper examines interaction between a barotropic point vortex and a steplike topography with a bay-shaped shelf. The interaction is governed by two mechanisms: propagation of topographic Rossby waves and advection by the forcing vortex. Topographic waves are supported by the potential vorticity (PV) jump across the topography and propagate along the step only in one direction, having higher PV on the right. Near one side boundary of the bay, which is in the wave propagation direction and has a narrow shelf, waves are blocked by the boundary, inducing strong out-of-bay transport in the form of detached crests. The wave–boundary interaction as well as out-of-bay transport is strengthened as the minimum shelf width is decreased. The two control mechanisms are related differently in anticyclone- and cyclone-induced interactions. In anticyclone-induced interactions, the PV front deformations are moved in opposite directions by the point vortex and topographic waves; a topographic cyclone forms out of the balance between the two opposing mechanisms and is advected by the forcing vortex into the deep ocean. In cyclone-induced interactions, the PV front deformations are moved in the same direction by the two mechanisms; a topographic cyclone forms out of the wave–boundary interaction but is confined to the coast. Therefore, anticyclonic vortices are more capable of driving water off the topography. The anticyclone-induced transport is enhanced for smaller vortex–step distance or smaller topography when the vortex advection is relatively strong compared to the wave propagation mechanism.
    Description: Y. Zhang acknowledges the support of theMIT-WHOI Joint Programin Physical Oceanography, NSF OCE-9901654 and OCE-0451086. J. Pedlosky acknowledges the support of NSF OCE- 9901654 and OCE-0451086.
    Keywords: Transport ; Eddies ; Barotropic flow ; Topographic effects ; Vortices ; Currents ; Potential vorticity ; Rossby waves
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  • 3
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    On the effective capacity of the dense-water reservoir for the Nordic Seas overflow : some effects of topography and wind stress (2013)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2013. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 43 (2013): 418–431, doi:10.1175/JPO-D-12-087.1.
    Description: The overflow of the dense water mass across the Greenland–Scotland Ridge (GSR) from the Nordic Seas drives the Atlantic meridional overturning circulation (AMOC). The Nordic Seas is a large basin with an enormous reservoir capacity. The volume of the dense water above the GSR sill depth in the Nordic Seas, according to previous estimates, is sufficient to supply decades of overflow transport. This large capacity buffers overflow’s responses to atmospheric variations and prevents an abrupt shutdown of the AMOC. In this study, the authors use a numerical and an analytical model to show that the effective reservoir capacity of the Nordic Seas is actually much smaller than what was estimated previously. Basin-scale oceanic circulation is nearly geostrophic and its streamlines are basically the same as the isobaths. The vast majority of the dense water is stored inside closed geostrophic contours in the deep basin and thus is not freely available to the overflow. The positive wind stress curl in the Nordic Seas forces a convergence of the dense water toward the deep basin and makes the interior water even more removed from the overflow-feeding boundary current. Eddies generated by the baroclinic instability help transport the interior water mass to the boundary current. But in absence of a robust renewal of deep water, the boundary current weakens rapidly and the eddy-generating mechanism becomes less effective. This study indicates that the Nordic Seas has a relatively small capacity as a dense water reservoir and thus the overflow transport is sensitive to climate changes.
    Description: This study has been supported by National Science Foundation (OCE0927017,ARC1107412).
    Description: 2013-08-01
    Keywords: Bottom currents ; Drainage flow ; Meridional overturning circulation ; Ocean dynamics ; Potential vorticity ; Topographic effects
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  • 4
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    Laboratory experiments on the interaction of a buoyant coastal current with a canyon : application to the East Greenland Current (2010)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 39 (2009): 1258-1271, doi:10.1175/2008JPO4028.1.
    Description: This paper presents a set of laboratory experiments focused on how a buoyant coastal current flowing over a sloping bottom interacts with a canyon and what controls the separation, if any, of the current from the upstream canyon bend. The results show that the separation of a buoyant coastal current depends on the current width W relative to the radius of curvature of the bathymetry ρc. The flow moved across the mouth of the canyon (i.e., separated) for W/ρc 〉 1, in agreement with previous results. The present study extends previous work by examining both slope-controlled and surface-trapped currents, and using a geometry specific to investigating buoyant current–canyon interaction. The authors find that, although bottom friction is important in setting the position of the buoyant front, the separation process driven by the inertia of the flow could overcome even the strongest bathymetric influence. Application of the laboratory results to the East Greenland Current (EGC), an Arctic-origin buoyant current that is observed to flow in two branches south of Denmark Strait, suggests that the path of the EGC is influenced by the large canyons cutting across the shelf, as the range of W/ρc in the ocean spans those observed in the laboratory. What causes the formation of a two-branched EGC structure downstream of the Kangerdlugssuaq Canyon (68°N, 32°W) is still unclear, but potential mechanisms are discussed.
    Description: This work was partially funded by NSF Grant OCE-0450658. DS also received support from the Academic Programs Office of the Woods Hole Oceanographic Institution, while CC had partial support from NSF OCE-0350891.
    Keywords: Coastal flows ; Buoyancy ; Currents ; Experimental design ; Topographic effects
    Repository Name: Woods Hole Open Access Server
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  • 5
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    Interannual variability in the pathways of the North Atlantic Current over the Mid-Atlantic Ridge and the impact of topography (2010)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2008. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 38 (2008): 104–120, doi:10.1175/2007JPO3686.1.
    Description: Recent studies have indicated that the North Atlantic Ocean subpolar gyre circulation undergoes significant interannual-to-decadal changes in response to variability in atmospheric forcing. There are also observations, however, suggesting that the southern limb of the subpolar gyre, namely, the eastward-flowing North Atlantic Current (NAC), may be quasi-locked to particular latitudes in the central North Atlantic by fracture zones (gaps) in the Mid-Atlantic Ridge. This could constrain the current’s ability to respond to variability in forcing. In the present study, subsurface float trajectories at 100–1000 m collected during 1997–99 and satellite-derived surface geostrophic velocities from 1992 to 2006 are used to provide an improved description of the detailed pathways of the NAC over the ridge and their relationship to bathymetry. Both the float and satellite observations indicate that in 1997–99, the northern branch of the NAC was split into two branches as it crossed the ridge, one quasi-locked to the Charlie–Gibbs Fracture Zone (CGFZ; 52°–53°N) and the other to the Faraday Fracture Zone (50°–51°N). The longer satellite time series shows, however, that this pattern did not persist outside the float sampling period and that other branching modes persisted for one or more years, including an approximately 12-month time period in 2002–03 when the strongest eastward flow over the ridge was at 49°N. Schott et al. showed how northward excursions of the NAC can temporarily block the westward flow of the Iceland–Scotland Overflow Water through the CGFZ. From the 13-yr time series of surface geostrophic velocity, it is estimated that such blocking may occur on average 6% of the time, although estimates for any given 12-month period range from 0% to 35%.
    Description: This research was supported by National Science Foundation Grants OCE-9531877 to the Woods Hole Oceanographic Institution (WHOI) and OCE-9906775 to the University of Rhode Island, by the WHOI Summer Student Fellowship Program, and by the Lawrence J. Pratt and Melinda M. Hall Endowed Fund for Interdisciplinary Research at the Woods Hole Oceanographic Institution.
    Keywords: Currents ; Topographic effects ; Interannual variability ; Forcing ; Gyres
    Repository Name: Woods Hole Open Access Server
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  • 6
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    Direct breaking of the internal tide near topography : Kaena Ridge, Hawaii (2010)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2008. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 38 (2008): 380-399, doi:10.1175/2007JPO3728.1.
    Description: Barotropic to baroclinic conversion and attendant phenomena were recently examined at the Kaena Ridge as an aspect of the Hawaii Ocean Mixing Experiment. Two distinct mixing processes appear to be at work in the waters above the 1100-m-deep ridge crest. At middepths, above 400 m, mixing events resemble their open-ocean counterparts. There is no apparent modulation of mixing rates with the fortnightly cycle, and they are well modeled by standard open-ocean parameterizations. Nearer to the topography, there is quasi-deterministic breaking associated with each baroclinic crest passage. Large-amplitude, small-scale internal waves are triggered by tidal forcing, consistent with lee-wave formation at the ridge break. These waves have vertical wavelengths on the order of 400 m. During spring tides, the waves are nonlinear and exhibit convective instabilities on their leading edge. Dissipation rates exceed those predicted by the open-ocean parameterizations by up to a factor of 100, with the disparity increasing as the seafloor is approached. These observations are based on a set of repeated CTD and microconductivity profiles obtained from the research platform (R/P) Floating Instrument Platform (FLIP), which was trimoored over the southern edge of the ridge crest. Ocean velocity and shear were resolved to a 4-m vertical scale by a suspended Doppler sonar. Dissipation was estimated both by measuring overturn displacements and from microconductivity wavenumber spectra. The methods agreed in water deeper than 200 m, where sensor resolution limitations do not limit the turbulence estimates. At intense mixing sites new phenomena await discovery, and existing parameterizations cannot be expected to apply.
    Description: This work was funded by the National Science Foundation as a component of the Hawaii Ocean Mixing Program. Added support for FLIP was provided by the Office of Naval Research.
    Keywords: Pacific Ocean ; Topographic effects ; Internal waves ; Barotropic flows ; Baroclinic flows
    Repository Name: Woods Hole Open Access Server
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  • 7
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    Cross-shelf and out-of-bay transport driven by an open-ocean current (2012)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2011. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 41 (2011): 2168–2186, doi:10.1175/JPO-D-11-08.1.
    Description: This paper studies the interaction of an Antarctic Circumpolar Current (ACC)–like wind-driven channel flow with a continental slope and a flat-bottomed bay-shaped shelf near the channel’s southern boundary. Interaction between the model ACC and the topography in the second layer induces local changes of the potential vorticity (PV) flux, which further causes the formation of a first-layer PV front near the base of the topography. Located between the ACC and the first-layer slope, the newly formed PV front is constantly perturbed by the ACC and in turn forces the first-layer slope with its own variability in an intermittent but persistent way. The volume transport of the slope water across the first-layer slope edge is mostly directly driven by eddies and meanders of the new front, and its magnitude is similar to the maximum Ekman transport in the channel. Near the bay’s opening, the effect of the topographic waves, excited by offshore variability, dominates the cross-isobath exchange and induces a mean clockwise shelf circulation. The waves’ propagation is only toward the west and tends to be blocked by the bay’s western boundary in the narrow-shelf region. The ensuing wave–coast interaction amplifies the wave amplitude and the cross-shelf transport. Because the interaction only occurs near the western boundary, the shelf water in the west of the bay is more readily carried offshore than that in the east and the mean shelf circulation is also intensified along the bay’s western boundary.
    Description: Y. Zhang acknowledges the support of the MIT-WHOI Joint Program in Physical Oceanography and NSF OCE-9901654 and OCE- 0451086. J. Pedlosky acknowledges the support of NSF OCE-9901654 and OCE-0451086.
    Keywords: Baroclinic flows ; Eddies ; Fronts ; Mass fluxes/transport ; Mesoscale processes ; Topographic effects
    Repository Name: Woods Hole Open Access Server
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  • 8
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    Mixing variability in the Southern Ocean (2015)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2015. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 45 (2015): 966–987, doi:10.1175/JPO-D-14-0110.1.
    Description: A key remaining challenge in oceanography is the understanding and parameterization of small-scale mixing. Evidence suggests that topographic features play a significant role in enhancing mixing in the Southern Ocean. This study uses 914 high-resolution hydrographic profiles from novel EM-APEX profiling floats to investigate turbulent mixing north of the Kerguelen Plateau, a major topographic feature in the Southern Ocean. A shear–strain finescale parameterization is applied to estimate diapycnal diffusivity in the upper 1600 m of the ocean. The indirect estimates of mixing match direct microstructure profiler observations made simultaneously. It is found that mixing intensities have strong spatial and temporal variability, ranging from O(10−6) to O(10−3) m2 s−1. This study identifies topographic roughness, current speed, and wind speed as the main factors controlling mixing intensity. Additionally, the authors find strong regional variability in mixing dynamics and enhanced mixing in the Antarctic Circumpolar Current frontal region. This enhanced mixing is attributed to dissipating internal waves generated by the interaction of the Antarctic Circumpolar Current and the topography of the Kerguelen Plateau. Extending the mixing observations from the Kerguelen region to the entire Southern Ocean, this study infers a large water mass transformation rate of 17 Sverdrups (Sv; 1 Sv ≡ 106 m3 s−1) across the boundary of Antarctic Intermediate Water and Upper Circumpolar Deep Water in the Antarctic Circumpolar Current. This work suggests that the contribution of mixing to the Southern Ocean overturning circulation budget is particularly significant in fronts.
    Description: AM was supported by the joint CSIRO–University of Tasmania Quantitative Marine Science (QMS) program and the 2009 CSIRO Wealth from Ocean Flagship Collaborative Fund. BMS was supported by the Australian Climate Change Science Program, jointly funded by the Department of the Environment and CSIRO. KLPs salary support was provided by Woods Hole Oceanographic Institution bridge support funds.
    Description: 2015-10-01
    Keywords: Geographic location/entity ; Southern Ocean ; Circulation/ Dynamics ; Diapycnal mixing ; Fronts ; Ocean circulation ; Topographic effects ; Atm/Ocean Structure/ Phenomena ; Mixing
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  • 9
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    Length scale of the finite-amplitude meanders of shelfbreak fronts (2015)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2015. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 45 (2015): 2598–2620, doi:10.1175/JPO-D-14-0249.1.
    Description: Through combining analytical arguments and numerical models, this study investigates the finite-amplitude meanders of shelfbreak fronts characterized by sloping isopycnals outcropping at both the surface and the shelfbreak bottom. The objective is to provide a formula for the meander length scale that can explain observed frontal length scale variability and also be verified with observations. Considering the frontal instability to be a mixture of barotropic and baroclinic instability, the derived along-shelf meander length scale formula is [b1/(1 + a1S1/2)]NH/f, where N is the buoyancy frequency; H is the depth of the front; f is the Coriolis parameter; S is the Burger number measuring the ratio of energy conversion associated with barotropic and baroclinic instability; and a1 and b1 are empirical constants. Initial growth rate of the frontal instability is formulated as [b2(1 + a1S1/2)/(1 + a2αS1/2)]NH/L, where α is the bottom slope at the foot of the front, and a2 and b2 are empirical constants. The formulas are verified using numerical sensitivity simulations, and fitting of the simulated and formulated results gives a1 = 2.69, b1 = 14.65, a2 = 5.1 × 103, and b2 = 6.2 × 10−2. The numerical simulations also show development of fast-growing frontal symmetric instability when the minimum initial potential vorticity is negative. Although frontal symmetric instability leads to faster development of barotropic and baroclinic instability at later times, it does not significantly influence the meander length scale. The derived meander length scale provides a framework for future studies of the influences of external forces on shelfbreak frontal circulation and cross-frontal exchange.
    Description: WGZ and GGG were supported by the National Science Foundation through Grant OCE-1129125.
    Description: 2016-04-01
    Keywords: Circulation/ Dynamics ; Instability ; Ocean circulation ; Topographic effects ; Atm/Ocean Structure/ Phenomena ; Fronts ; Models and modeling ; Numerical analysis/modeling
    Repository Name: Woods Hole Open Access Server
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  • 10
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    Spreading of Denmark Strait overflow water in the western subpolar North Atlantic : insights from eddy-resolving simulations with a passive tracer (2016)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2015. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 45 (2015): 2913–2932, doi:10.1175/JPO-D-14-0179.1.
    Description: The oceanic deep circulation is shared between concentrated deep western boundary currents (DWBCs) and broader interior pathways, a process that is sensitive to seafloor topography. This study investigates the spreading and deepening of Denmark Strait overflow water (DSOW) in the western subpolar North Atlantic using two ° eddy-resolving Atlantic simulations, including a passive tracer injected into the DSOW. The deepest layers of DSOW transit from a narrow DWBC in the southern Irminger Sea into widespread westward flow across the central Labrador Sea, which remerges along the Labrador coast. This abyssal circulation, in contrast to the upper levels of overflow water that remain as a boundary current, blankets the deep Labrador Sea with DSOW. Farther downstream after being steered around the abrupt topography of Orphan Knoll, DSOW again leaves the boundary, forming cyclonic recirculation cells in the deep Newfoundland basin. The deep recirculation, mostly driven by the meandering pathway of the upper North Atlantic Current, leads to accumulation of tracer offshore of Orphan Knoll, precisely where a local maximum of chlorofluorocarbon (CFC) inventory is observed. At Flemish Cap, eddy fluxes carry ~20% of the tracer transport from the boundary current into the interior. Potential vorticity is conserved as the flow of DSOW broadens at the transition from steep to less steep continental rise into the Labrador Sea, while around the abrupt topography of Orphan Knoll, potential vorticity is not conserved and the DSOW deepens significantly.
    Description: This work is supported by ONR Award N00014-09-1-0587, the NSF Physical Oceanography Program, and NASA Ocean Surface Topography Science Team Program.
    Description: 2016-06-01
    Keywords: Circulation/ Dynamics ; Abyssal circulation ; Boundary currents ; Ocean circulation ; Ocean dynamics ; Potential vorticity ; Topographic effects
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  • 11
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    ACC meanders, energy transfer, and barotropic–baroclinic instability (2017)
    American Meteorological Society
    Details
    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2017. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 47 (2017): 1291-1305, doi:10.1175/JPO-D-16-0160.1.
    Description: Along-stream variations in the dynamics of the Antarctic Circumpolar Current (ACC) impact heat and tracer transport, regulate interbasin exchange, and influence closure of the overturning circulation. Topography is primarily responsible for generating deviations from zonal-mean properties, mainly through standing meanders associated with regions of high eddy kinetic energy. Here, an idealized channel model is used to explore the spatial distribution of energy exchange and its relationship to eddy geometry, as characterized by both eddy momentum and eddy buoyancy fluxes. Variations in energy exchange properties occur not only between standing meander and quasi-zonal jet regions, but throughout the meander itself. Both barotropic and baroclinic stability properties, as well as the magnitude of energy exchange terms, undergo abrupt changes along the path of the ACC. These transitions are captured by diagnosing eddy fluxes of energy and by adopting the eddy geometry framework. The latter, typically applied to barotropic stability properties, is applied here in the depth–along-stream plane to include information about both barotropic and baroclinic stability properties of the flow. These simulations reveal that eddy momentum fluxes, and thus barotropic instability, play a leading role in the energy budget within a standing meander. This result suggests that baroclinic instability alone cannot capture the dynamics of ACC standing meanders, a challenge for models where eddy fluxes are parameterized.
    Description: The authors all acknowledge support from NSF OCE-1235488. MKY also acknowledges support from the AMS Graduate Student Fellowship.
    Description: 2017-10-12
    Keywords: Southern Ocean ; Channel flows ; Stability ; Topographic effects ; Eddies ; Mesoscale models
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  • 12
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    Wind-driven circulation in a shelf valley. Part II : Dynamics of the along-valley velocity and transport (2018)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2018. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 48 (2018): 883-904, doi:10.1175/JPO-D-17-0084.1.
    Description: The dynamics controlling the along-valley (cross shelf) flow in idealized shallow shelf valleys with small to moderate Burger number are investigated, and analytical scales of the along-valley flows are derived. This paper follows Part I, which shows that along-shelf winds in the opposite direction to coastal-trapped wave propagation (upwelling regime) force a strong up-valley flow caused by the formation of a lee wave. In contrast, along-shelf winds in the other direction (downwelling regime) do not generate a lee wave and consequently force a relatively weak net down-valley flow. The valley flows in both regimes are cyclostrophic with 0(1) Rossby number. A major difference between the two regimes is the along-shelf length scales of the along-valley flows L. In the upwelling regime Ls, depends on the valley width W, and the wavelength lambda(1w) of the coastal-trapped lee wave arrested by the along-shelf flow U-s. In the downwelling regime L depends on the inertial length scale U-s|'f and W-c. The along-valley velocity scale in the upwelling regime, given by V-u approximate to root pi H-c/H-s integral W-c lambda(1w)/2 pi L-x (1+L-x(2)/L-c(2))(-1) e(-(pi Wc)/(lambda 1w),) is based on potential vorticity (PV) conservation and lee-wave dynamics (Hs and H, are the shelf and valley depth scales, respectively, and fis the Coriolis parameter). The velocity scale in the downwelling regime, given by |v(d)| approximate to (H-s/H-s)[1 + (L-x(2)/L-x(2))](-1) fL, is based on PV conservation. The velocity scales are validated by the numerical sensitivity simulations and can be useful for observational studies of along -valley transports. The work provides a framework for investigating cross -shelf transport induced by irregular shelf bathymetry and calls for future studies of this type under realistic environmental conditions and over a broader parameter space.
    Description: Both WGZ and SJL were supported by the National Science Foundation (NSF) through Grant OCE 1154575.WGZis also supported by the NSF Grant OCE 1634965 and SJL by NSF Grant OCE 1558874.
    Description: 2018-10-16
    Keywords: Ocean circulation ; Topographic effects ; Upwelling/downwelling ; Waves, oceanic ; Wind stress ; Ocean models
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  • 13
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    Marginal sea overflows and the upper ocean interaction (2010)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2009. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 39 (2009): 387-403, doi:10.1175/2008JPO3934.1.
    Description: Marginal sea overflows and the overlying upper ocean are coupled in the vertical by two distinct mechanisms—by an interfacial mass flux from the upper ocean to the overflow layer that accompanies entrainment and by a divergent eddy flux associated with baroclinic instability. Because both mechanisms tend to be localized in space, the resulting upper ocean circulation can be characterized as a β plume for which the relevant background potential vorticity is set by the slope of the topography, that is, a topographic β plume. The entrainment-driven topographic β plume consists of a single gyre that is aligned along isobaths. The circulation is cyclonic within the upper ocean (water columns are stretched). The transport within one branch of the topographic β plume may exceed the entrainment flux by a factor of 2 or more. Overflows are likely to be baroclinically unstable, especially near the strait. This creates eddy variability in both the upper ocean and overflow layers and a flux of momentum and energy in the vertical. In the time mean, the eddies accompanying baroclinic instability set up a double-gyre circulation in the upper ocean, an eddy-driven topographic β plume. In regions where baroclinic instability is growing, the momentum flux from the overflow into the upper ocean acts as a drag on the overflow and causes the overflow to descend the slope at a steeper angle than what would arise from bottom friction alone. Numerical model experiments suggest that the Faroe Bank Channel overflow should be the most prominent example of an eddy-driven topographic β plume and that the resulting upper-layer transport should be comparable to that of the overflow. The overflow-layer eddies that accompany baroclinic instability are analogous to those observed in moored array data. In contrast, the upper layer of the Mediterranean overflow is likely to be dominated more by an entrainment-driven topographic β plume. The difference arises because entrainment occurs at a much shallower location for the Mediterranean case and the background potential vorticity gradient of the upper ocean is much larger.
    Description: SK’s support during the time of his Ph.D. research in the MIT/WHOI Joint Program was provided by the National Science Foundation through Grant OCE04-24741. JP and JY have also received support from the Climate Process Team on Gravity Current Entrainment, NSF Grant OCE-0611530. JY has also been supported by NSF Grant OCE-0351055.
    Keywords: Baroclinic flows ; Mass fluxes/transport ; Entrainment ; Topographic effects ; Potential vorticity
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    Subharmonic energy transfer from the semidiurnal internal tide to near-diurnal motions over Kaena Ridge, Hawaii (2013)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2013. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 43 (2013): 766–789, doi:10.1175/JPO-D-12-0141.1.
    Description: Nonlinear energy transfers from the semidiurnal internal tide to high-mode, near-diurnal motions are documented near Kaena Ridge, Hawaii, an energetic generation site for the baroclinic tide. Data were collected aboard the Research Floating Instrument Platform (FLIP) over a 35-day period during the fall of 2002, as part of the Hawaii Ocean Mixing Experiment (HOME) Nearfield program. Energy transfer terms for a PSI resonant interaction at midlatitude are identified and compared to those for near-inertial PSI close to the M2 critical latitude. Bispectral techniques are used to demonstrate significant energy transfers in the Nearfield, between the low-mode M2 internal tide and subharmonic waves with frequencies near M2/2 and vertical wavelengths of O(120 m). A novel prefilter is used to test the PSI wavenumber resonance condition, which requires the subharmonic waves to propagate in opposite vertical directions. Depth–time maps of the interactions, formed by directly estimating the energy transfer terms, show that energy is transferred predominantly from the tide to subharmonic waves, but numerous reverse energy transfers are also found. A net forward energy transfer rate of 2 × 10−9 W kg−1 is found below 400 m. The suggestion is that the HOME observations of energy transfer from the tide to subharmonic waves represent a first step in the open-ocean energy cascade. Observed PSI transfer rates could account for a small but significant fraction of the turbulent dissipation of the tide within 60 km of Kaena Ridge. Further extrapolation suggests that integrated PSI energy transfers equatorward of the M2 critical latitude may be comparable to PSI energy transfers previously observed near 28.8°N.
    Description: This work was supported by the National Science Foundation and the Office of Naval Research.
    Description: 2013-10-01
    Keywords: Diapycnal mixing ; Energy transport ; Internal waves ; Nonlinear dynamics ; Topographic effects ; In situ oceanic observations
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    An inertial model of the interaction of Ekman layers and planetary islands (2014)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2013. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 43 (2013): 1398–1406, doi:10.1175/JPO-D-13-028.1.
    Description: An adiabatic, inertial, and quasigeostrophic model is used to discuss the interaction of surface Ekman transport with an island. The theory extends the recent work of Spall and Pedlosky to include an analytical and nonlinear model for the interaction. The presence of an island that interrupts a uniform Ekman layer transport raises interesting questions about the resulting circulation. The consequential upwelling around the island can lead to a local intake of fluid from the geostrophic region beneath the Ekman layer or to a more complex flow around the island in which the fluid entering the Ekman layer on one portion of the island's perimeter is replaced by a flow along the island's boundary from a downwelling region located elsewhere on the island. This becomes especially pertinent when the flow is quasigeostrophic and adiabatic. The oncoming geostrophic flow that balances the offshore Ekman flux is largely diverted around the island, and the Ekman flux is fed by a transfer of fluid from the western to the eastern side of the island. As opposed to the linear, dissipative model described earlier, this transfer takes place even in the absence of a topographic skirt around the island. The principal effect of topography in the inertial model is to introduce an asymmetry between the circulation on the northern and southern sides of the island. The quasigeostrophic model allows a simple solution to the model problem with topography and yet the resulting three-dimensional circulation is surprisingly complex with streamlines connecting each side of the island.
    Description: This research was supported in part by NSF Grant OCE Grant 0925061.
    Keywords: Baroclinic flows ; Large-scale motions ; Nonlinear dynamics ; Ocean circulation ; Ocean dynamics ; Topographic effects
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    Transport and dynamics of the Panay Sill overflow in the Philippine Seas (2011)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2010. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 40 (2010): 2679–2695, doi:10.1175/2010JPO4395.1.
    Description: Observations of stratification and currents between June 2007 and March 2009 reveal a strong overflow between 400- and 570-m depth from the Panay Strait into the Sulu Sea. The overflow water is derived from approximately 400 m deep in the South China Sea. Temporal mean velocity is greater than 0.75 m s−1 at 50 m above the 570-m Panay Sill. Empirical orthogonal function analysis of a mooring time series shows that the flow is dominated by the bottom overflow current with little seasonal variance. The overflow does not descend below 1250 m in the Sulu Sea but rather settles above high-salinity deep water derived from the Sulawesi Sea. The mean observed overflow transport at the sill is 0.32 × 106 m3 s−1. The observed transport was used to calculate a bulk diapycnal diffusivity of 4.4 × 10−4 m2 s−1 within the Sulu Sea slab (575–1250 m) ventilated from Panay Strait. Analysis of Froude number variation across the sill shows that the flow is hydraulically controlled. A suitable hydraulic control model shows overflow transport equivalent to the observed overflow. Thorpe-scale estimates show turbulent dissipation rates up to 5 × 10−7 W kg−1 just downstream of the supercritical to subcritical flow transition, suggesting a hydraulic jump downstream of the sill.
    Description: This work was supported by the Office of Naval Research Grant N00014-09-1-0582 to Lamont-Doherty Earth Observatory of Columbia University; Grants ONR-13759000 and N00014-09-1-0582 to the Woods Hole Oceanographic Institution; Grant ONR-N00014-06-1-0690 to Scripps Institute of Oceanography; and a National Defense Science and Engineering Graduate Fellowship.
    Keywords: Transport ; Dynamics ; Topographic effects ; Currents ; Empirical orthogonal functions
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    The impact of finite-amplitude bottom topography on internal wave generation in the Southern Ocean (2014)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2014. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 44 (2014): 2938–2950, doi:10.1175/JPO-D-13-0201.1.
    Description: Direct observations in the Southern Ocean report enhanced internal wave activity and turbulence in a kilometer-thick layer above rough bottom topography collocated with the deep-reaching fronts of the Antarctic Circumpolar Current. Linear theory, corrected for finite-amplitude topography based on idealized, two-dimensional numerical simulations, has been recently used to estimate the global distribution of internal wave generation by oceanic currents and eddies. The global estimate shows that the topographic wave generation is a significant sink of energy for geostrophic flows and a source of energy for turbulent mixing in the deep ocean. However, comparison with recent observations from the Diapycnal and Isopycnal Mixing Experiment in the Southern Ocean shows that the linear theory predictions and idealized two-dimensional simulations grossly overestimate the observed levels of turbulent energy dissipation. This study presents two- and three-dimensional, realistic topography simulations of internal lee-wave generation from a steady flow interacting with topography with parameters typical of Drake Passage. The results demonstrate that internal wave generation at three-dimensional, finite bottom topography is reduced compared to the two-dimensional case. The reduction is primarily associated with finite-amplitude bottom topography effects that suppress vertical motions and thus reduce the amplitude of the internal waves radiated from topography. The implication of these results for the global lee-wave generation is discussed.
    Description: This research was supported by the National Science Foundation under Award CMG-1024198.
    Description: 2015-05-01
    Keywords: Circulation/ Dynamics ; Diapycnal mixing ; Internal waves ; Mixing ; Mountain waves ; Topographic effects ; Waves, oceanic
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    Some dynamical constraints on upstream pathways of the Denmark Strait Overflow (2015)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2014. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 44 (2014): 3033–3053, doi:10.1175/JPO-D-13-0227.1.
    Description: The East Greenland Current (EGC) had long been considered the main pathway for the Denmark Strait overflow (DSO). Recent observations, however, indicate that the north Icelandic jet (NIJ), which flows westward along the north coast of Iceland, is a major separate pathway for the DSO. In this study a two-layer numerical model and complementary integral constraints are used to examine various pathways that lead to the DSO and to explore plausible mechanisms for the NIJ’s existence. In these simulations, a westward and NIJ-like current emerges as a robust feature and a main pathway for the Denmark Strait overflow. Its existence can be explained through circulation integrals around advantageous contours. One such constraint spells out the consequences of overflow water as a source of low potential vorticity. A stronger constraint can be added when the outflow occurs through two outlets: it takes the form of a circulation integral around the Iceland–Faroe Ridge. In either case, the direction of overall circulation about the contour can be deduced from the required frictional torques. Some effects of wind stress forcing are also examined. The overall positive curl of the wind forces cyclonic gyres in both layers, enhancing the East Greenland Current. The wind stress forcing weakens but does not eliminate the NIJ. It also modifies the sign of the deep circulation in various subbasins and alters the path by which overflow water is brought to the Faroe Bank Channel, all in ways that bring the idealized model more in line with observations. The sequence of numerical experiments separates the effects of wind and buoyancy forcing and shows how each is important.
    Description: This study has been supported by National Science Foundation (OCE0927017 and ARC1107412).
    Description: 2015-06-01
    Keywords: Circulation/ Dynamics ; Boundary currents ; Channel flows ; Meridional overturning circulation ; Ocean circulation ; Topographic effects
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    Importance of Orography for Greenland cloud and melt response to atmospheric blocking (2020)
    American Meteorological Society
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    Publication Date: 2022-05-25
    Description: Author Posting. © American Meteorological Society, 2020. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Hahn, L. C., Storelvmo, T., Hofer, S., Parfitt, R., & Ummenhofer, C. C. Importance of Orography for Greenland cloud and melt response to atmospheric blocking. Journal of Climate, 33(10), (2020): 4187-4206, doi:10.1175/JCLI-D-19-0527.1.
    Description: More frequent high pressure conditions associated with atmospheric blocking episodes over Greenland in recent decades have been suggested to enhance melt through large-scale subsidence and cloud dissipation, which allows more solar radiation to reach the ice sheet surface. Here we investigate mechanisms linking high pressure circulation anomalies to Greenland cloud changes and resulting cloud radiative effects, with a focus on the previously neglected role of topography. Using reanalysis and satellite data in addition to a regional climate model, we show that anticyclonic circulation anomalies over Greenland during recent extreme blocking summers produce cloud changes dependent on orographic lift and descent. The resulting increased cloud cover over northern Greenland promotes surface longwave warming, while reduced cloud cover in southern and marginal Greenland favors surface shortwave warming. Comparison with an idealized model simulation with flattened topography reveals that orographic effects were necessary to produce area-averaged decreasing cloud cover since the mid-1990s and the extreme melt observed in the summer of 2012. This demonstrates a key role for Greenland topography in mediating the cloud and melt response to large-scale circulation variability. These results suggest that future melt will depend on the pattern of circulation anomalies as well as the shape of the Greenland Ice Sheet.
    Description: This research was supported by the Woods Hole Oceanographic Institution Summer Student Fellow program, by the U.S. National Science Foundation under AGS-1355339 to C.C.U., and by the European Research Council through Grant 758005.
    Keywords: Ice sheets ; Blocking ; Cloud cover ; Topographic effects ; Climate change ; Climate variability
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    Modeling and analysis of internal-tide generation and beamlike onshore propagation in the vicinity of shelfbreak canyons (2014)
    American Meteorological Society
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    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2014. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 44 (2014): 834-849, doi:10.1175/JPO-D-13-0179.1.
    Description: A hydrostatic numerical model with alongshore-uniform barotropic M2 tidal boundary forcing and idealized shelfbreak canyon bathymetries is used to study internal-tide generation and onshore propagation. A control simulation with Mid-Atlantic Bight representative bathymetry is supported by other simulations that serve to identify specific processes. The canyons and adjacent slopes are transcritical in steepness with respect to M2 internal wave characteristics. Although the various canyons are symmetrical in structure, barotropic-to-baroclinic energy conversion rates Cυ are typically asymmetrical within them. The resulting onshore-propagating internal waves are the strongest along beams in the horizontal plane, with the stronger beam in the control simulation lying on the side with higher Cυ. Analysis of the simulation results suggests that the cross-canyon asymmetrical Cυ distributions are caused by multiple-scattering effects on one canyon side slope, because the phase variation in the spatially distributed internal-tide sources, governed by variations in the orientation of the bathymetry gradient vector, allows resonant internal-tide generation. A less complex, semianalytical, modal internal wave propagation model with sources placed along the critical-slope locus (where the M2 internal wave characteristic is tangent to the seabed) and variable source phasing is used to diagnose the physics of the horizontal beams of onshore internal wave radiation. Model analysis explains how the cross-canyon phase and amplitude variations in the locally generated internal tides affect parameters of the internal-tide beams. Under the assumption that strong internal tides on continental shelves evolve to include nonlinear wave trains, the asymmetrical internal-tide generation and beam radiation effects may lead to nonlinear internal waves and enhanced mixing occurring preferentially on one side of shelfbreak canyons, in the absence of other influencing factors.
    Description: All three authors were supported by Office of Naval Research (ONR) Grant N00014-11-1-0701. WGZ was additionally supported by the National Science Foundation (NSF) Grant OCE-1154575, and TFD was additionally supported by NSF Grant OCE-1060430.
    Description: 2014-09-01
    Keywords: Circulation/ Dynamics ; Baroclinic flows ; Internal waves ; Ocean circulation ; Topographic effects ; Waves, oceanic ; Models and modeling ; Numerical analysis/modeling
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    Frontogenesis and variability in Denmark Strait and its influence on overflow water (2019)
    American Meteorological Society
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    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 49(7), (2019): 1889-1904, doi:10.1175/JPO-D-19-0053.1.
    Description: A high-resolution numerical model, together with in situ and satellite observations, is used to explore the nature and dynamics of the dominant high-frequency (from one day to one week) variability in Denmark Strait. Mooring measurements in the center of the strait reveal that warm water “flooding events” occur, whereby the North Icelandic Irminger Current (NIIC) propagates offshore and advects subtropical-origin water northward through the deepest part of the sill. Two other types of mesoscale processes in Denmark Strait have been described previously in the literature, known as “boluses” and “pulses,” associated with a raising and lowering of the overflow water interface. Our measurements reveal that flooding events occur in conjunction with especially pronounced pulses. The model indicates that the NIIC hydrographic front is maintained by a balance between frontogenesis by the large-scale flow and frontolysis by baroclinic instability. Specifically, the temperature and salinity tendency equations demonstrate that the eddies act to relax the front, while the mean flow acts to sharpen it. Furthermore, the model reveals that the two dense water processes—boluses and pulses (and hence flooding events)—are dynamically related to each other and tied to the meandering of the hydrographic front in the strait. Our study thus provides a general framework for interpreting the short-time-scale variability of Denmark Strait Overflow Water entering the Irminger Sea.
    Description: MAS was supported by the National Science Foundation (NSF) under Grants OCE-1558742 and OCE-1534618. RSP, PL, and DM were supported by NSF under Grants OCE-1558742 and OCE-1259618. WJvA was supported by the Helmholtz Infrastructure Initiative FRAM. TWNH and MA were supported by NSF under Grants OCE-1633124 and OCE-118123.
    Description: 2020-07-01
    Keywords: Baroclinic flows ; Frontogenesis/frontolysis ; Meridional overturning circulation ; Ocean dynamics ; Topographic effects
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    Bifurcation and upwelling of the equatorial undercurrent west of the Galapagos Archipelago (2020)
    American Meteorological Society
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    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2020. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 50(4), (2020): 887-905, doi:10.1175/JPO-D-19-0110.1.
    Description: The Equatorial Undercurrent (EUC) encounters the Galápagos Archipelago on the equator as it flows eastward across the Pacific. The impact of the Galápagos Archipelago on the EUC in the eastern equatorial Pacific remains largely unknown. In this study, the path of the EUC as it reaches the Galápagos Archipelago is measured directly using high-resolution observations obtained by autonomous underwater gliders. Gliders were deployed along three lines that define a closed region with the Galápagos Archipelago as the eastern boundary and 93°W from 2°S to 2°N as the western boundary. Twelve transects were simultaneously occupied along the three lines during 52 days in April–May 2016. Analysis of individual glider transects and average sections along each line show that the EUC splits around the Galápagos Archipelago. Velocity normal to the transects is used to estimate net horizontal volume transport into the volume. Downward integration of the net horizontal transport profile provides an estimate of the time- and areal-averaged vertical velocity profile over the 52-day time period. Local maxima in vertical velocity occur at depths of 25 and 280 m with magnitudes of (1.7 ± 0.6) × 10−5 m s−1 and (8.0 ± 1.6) × 10−5 m s−1, respectively. Volume transport as a function of salinity indicates that water crossing 93°W south (north) of 0.4°S tends to flow around the south (north) side of the Galápagos Archipelago. Comparisons are made between previous observational and modeling studies with differences attributed to effects of the strong 2015/16 El Niño event, the annual cycle of local winds, and varying longitudes between studies of the equatorial Pacific.
    Description: This work was supported by National Science Foundation (Grants OCE-1232971 and OCE-1233282) and the NASA Earth and Space Science Fellowship Program (Grant 80NSSC17K0443).
    Keywords: Tropics ; Boundary currents ; Topographic effects ; Transport ; Upwelling/downwelling ; In situ oceanic observations
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    Impact of shelf valleys on the spread of surface-trapped river plumes (2021)
    American Meteorological Society
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    Publication Date: 2022-05-27
    Description: Author Posting. © American Meteorological Society, 2021. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 51(1), (2021): 247-266, https://doi.org/10.1175/JPO-D-20-0098.1.
    Description: This study focuses on mechanisms of shelf valley bathymetry affecting the spread of riverine freshwater in the nearshore region. In the context of Changjiang River, a numerical model is used with different no-tide idealized configurations to simulate development of unforced river plumes over a sloping bottom, with and without a shelf valley off the estuary mouth. All simulated freshwater plumes are surface-trapped with continuously growing bulges near the estuary mouth and narrow coastal currents downstream. The simulations indicate that a shelf valley tends to compress the bulge along the direction of the valley long axis and modify the incident angle of the bulge flow impinging toward the coast, which then affects the strength of the coastal current. The bulge compression results from geostrophic adjustment and isobath-following tendency of the depth-averaged flow in the bulge region. Generally, the resulting change in the direction of the bulge impinging flow enhances down-shelf momentum advection and freshwater delivery into the coastal current. Sensitivity simulations with altered river discharges Q, Coriolis parameter, shelf bottom slope, valley geometry, and ambient stratification show that enhancement of down-shelf freshwater transport in the coastal current, ΔQc, increases with increasing valley depth within the bulge region and decreasing slope Burger number of the ambient shelf. Assuming potential vorticity conservation, a scaling formula of ΔQc/Q is developed, and it agrees well with results of the sensitivity simulations. Mechanisms of valley influences on unforced river plumes revealed here will help future studies of topographic influence on river plumes under more realistic conditions.
    Description: This work is conducted by Canbo Xiao and Weifeng (Gordon) Zhang during CX’s one-year visit at Woods Hole Oceanographic Institution (WHOI) in 2018–19. CX was supported by China Scholarship Council.
    Keywords: Continental shelf/slope ; Buoyancy ; Coastal flows ; Topographic effects ; Runoff ; Numerical analysis/modeling
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    Topographic influences on the wind-driven exchange between marginal seas and the open ocean (2022)
    American Meteorological Society
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    Publication Date: 2022-06-03
    Description: Author Posting. © American Meteorological Society, 2021. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 51(12),(2021): 3663–3678, https://doi.org/10.1175/JPO-D-21-0058.1.
    Description: The wind-driven exchange through complex ridges and islands between marginal seas and the open ocean is studied using both numerical and analytical models. The models are forced by a steady, spatially uniform northward wind stress intended to represent the large-scale, low-frequency wind patterns typical of the seasonal monsoons in the western Pacific Ocean. There is an eastward surface Ekman transport out of the marginal sea and westward geostrophic inflows into the marginal sea. The interaction between the Ekman transport and an island chain produces strong baroclinic flows along the island boundaries with a vertical depth that scales with the ratio of the inertial boundary layer thickness to the baroclinic deformation radius. The throughflows in the gaps are characterized by maximum transport in the center gap and decreasing transports toward the southern and northern tips of the island chain. An extended island rule theory demonstrates that throughflows are determined by the collective balance between viscosity on the meridional boundaries and the eastern side boundary of the islands. The outflowing transport is balanced primarily by a shallow current that enters the marginal sea along its equatorward boundary. The islands can block some direct exchange and result in a wind-driven overturning cell within the marginal sea, but this is compensated for by eastward zonal jets around the southern and northern tips of the island chain. Topography in the form of a deep slope, a ridge, or shallow shelves around the islands alters the current pathways but ultimately is unable to limit the total wind-driven exchange between the marginal sea and the open ocean.
    Description: This research is supported in part by the China Scholarship Council (201906330102). H. G. is financially supported by the China Scholarship Council to study at WHOI for 2 years as a guest student. M. A. S. is supported by the National Science Foundation Grant OCE-1922538.
    Keywords: Ekman pumping/transport ; Ocean circulation ; Topographic effects
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    Hydraulics and mixing of the deep overflow in the Lifamatola Passage of the Indonesian Seas (2021)
    American Meteorological Society
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    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2020. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 50(9),(2020): 2797-2814, https://doi.org/10.1175/JPO-D-19-0326.1.
    Description: Hydrographic measurements recently acquired along the thalweg of the Lifamatola Passage combined with historical moored velocity measurements immediately downstream of the sill are used to study the hydraulics, transport, mixing, and entrainment in the dense overflow. The observations suggest that the mean overflow is nearly critical at the mooring site, suggesting that a weir formula may be appropriate for estimating the overflow transport. Our assessment suggests that the weir formulas corresponding to a rectangular, triangular, or parabolic cross section all result in transports very close to the observation, suggesting their potential usage in long-term monitoring of the overflow transport or parameterizing the transport in numerical models. Analyses also suggest that deep signals within the overflow layer are blocked by the shear flow from propagating upstream, whereas the shallow wave modes of the full-depth continuously stratified flow are able to propagate upstream from the Banda Sea into the Maluku Sea. Strong mixing is found immediately downstream of the sill crest, with Thorpe-scale-based estimates of the mean dissipation rate within the overflow up to 1.1 × 10−7 W kg−1 and the region-averaged diapycnal diffusivity within the downstream overflow in the range of 2.3 × 10−3 to 10.1 × 10−3 m2 s−1. Mixing in the Lifamatola Passage results in 0.6–1.2-Sv (1 Sv ≡ 106 m3 s−1) entrainment transport added to the overflow, enhancing the deep-water renewal in the Banda Sea. A bulk diffusivity coefficient estimated in the deep Banda Sea yields 1.6 × 10−3 ± 5 × 10−4 m2 s−1, with an associated downward turbulent heat flux of 9 W m−2.
    Description: This study is supported by NSFC (91858204), the CAS Strategic Priority Research Program (XDB42000000), NSFC(41720104008, 41421005, 41876025), QMSNL (2018SDKJ0104-02), and the Shandong Provincial projects (U1606402). L. Pratt was supported by the U.S. NSF Grant OCE-1657870.
    Keywords: Diapycnal mixing ; Entrainment ; Internal waves ; Topographic effects ; In situ oceanic observations
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    Energy fluxes in coastal trapped waves (2020)
    American Meteorological Society
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    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 49(12), (2019): 3061-3068, doi: 10.1175/JPO-D-18-0172.1.
    Description: The calculation of energy flux in coastal trapped wave modes is reviewed in the context of tidal energy pathways near the coast. The significant barotropic pressures and currents associated with coastal trapped wave modes mean that large errors in estimating the wave flux are incurred if only the baroclinic component is considered. A specific example is given showing that baroclinic flux constitutes only 10% of the flux in a mode-1 wave for a reasonable choice of stratification and bathymetry. The interpretation of baroclinic energy flux and barotropic-to-baroclinic conversion at the coast is discussed: in contrast to the open ocean, estimates of baroclinic energy flux do not represent a wave energy flux; neither does conversion represent the scattering of energy from the tidal Kelvin wave to higher modes.
    Description: This work was supported by the Postdoctoral Scholar Program at the Woods Hole Oceanographic Institution, with funding provided by the Weston Howland Jr. Postdoctoral Scholarship, and by NSF under Grant OCE-1756781. I am grateful to K. Brink for the many useful conversations that contributed to this work and to J. Toole for providing detailed comments on an early version of this paper. The comments of three anonymous reviewers were very helpful in improving this paper.
    Description: 2020-06-03
    Keywords: Diapycnal mixing ; Internal waves ; Kelvin waves ; Topographic effects ; Waves, oceanic ; Tides
    Repository Name: Woods Hole Open Access Server
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  • 27
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    Transformation and upwelling of bottom water in fracture zone valleys (2020)
    American Meteorological Society
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2020. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 50(3), (2020): 715-726, doi:10.1175/JPO-D-19-0021.1.
    Description: Closing the overturning circulation of bottom water requires abyssal transformation to lighter densities and upwelling. Where and how buoyancy is gained and water is transported upward remain topics of debate, not least because the available observations generally show downward-increasing turbulence levels in the abyss, apparently implying mean vertical turbulent buoyancy-flux divergence (densification). Here, we synthesize available observations indicating that bottom water is made less dense and upwelled in fracture zone valleys on the flanks of slow-spreading midocean ridges, which cover more than one-half of the seafloor area in some regions. The fracture zones are filled almost completely with water flowing up-valley and gaining buoyancy. Locally, valley water is transformed to lighter densities both in thin boundary layers that are in contact with the seafloor, where the buoyancy flux must vanish to match the no-flux boundary condition, and in thicker layers associated with downward-decreasing turbulence levels below interior maxima associated with hydraulic overflows and critical-layer interactions. Integrated across the valley, the turbulent buoyancy fluxes show maxima near the sidewall crests, consistent with net convergence below, with little sensitivity of this pattern to the vertical structure of the turbulence profiles, which implies that buoyancy flux convergence in the layers with downward-decreasing turbulence levels dominates over the divergence elsewhere, accounting for the net transformation to lighter densities in fracture zone valleys. We conclude that fracture zone topography likely exerts a controlling influence on the transformation and upwelling of bottom water in many areas of the global ocean.
    Description: The data used in this study were collected in the context of several projects funded by the U.S. National Science Foundation (NSF), in particular BBTRE (OCE-9415589 and OCE-9415598) and DoMORE (OCE-1235094). Funding for the analysis was provided as part of the NSF DoMORE and DECIMAL (OCE-1735618) projects. Author Ijichi is a Japan Society for the Promotion of Science (JSPS) Overseas Research Fellow. Comments on an early draft of this paper by Jim Ledwell and Bryan Kaiser, as well as topical discussions with Jörn Callies and Trevor McDougall, are gratefully acknowledged. The paper was greatly improved during the review process, in particular because of the critical comments from one of the two anonymous reviewers.
    Keywords: Diapycnal mixing ; Topographic effects ; Turbulence ; Upwelling/downwelling ; Bottom currents/bottom water
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    Offshore transport of shelf water by deep-ocean eddies (2017)
    American Meteorological Society
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2016. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 46 (2016): 3599-3621, doi:10.1175/JPO-D-16-0085.1.
    Description: At continental margins, energetic deep-ocean eddies can transport shelf water offshore in filaments that wrap around the eddy. One example is that of Gulf Stream warm-core rings interacting with the Mid-Atlantic Bight shelf. The rate at which shelf water is exported in these filaments is a major unknown in regional budgets of volume, heat, and salt. This unknown transport is constrained using a series of idealized primitive equation numerical experiments wherein a surface-intensified anticyclonic eddy interacts with idealized shelf–slope topography. There is no shelfbreak front in these experiments, and shelf water is tracked using a passive tracer. When anticyclones interact with shelf–slope topography, they suffer apparent intrusions of shelf–slope water, resulting in a subsurface maximum in offshore transport. The simulations help construct an approximate model for the filament of exported water that originates inshore of any given isobath. This model is then used to derive an expression for the total volume of shelf–slope water transported by the eddy across that isobath. The transport scales with water depth, radius, and azimuthal velocity scale of the eddy. The resulting expression can be used with satellite-derived eddy properties to estimate approximate real-world transports ignoring the presence of a shelfbreak front. The expression assumes that the eddy’s edge is at the shelf break, a condition not always satisfied by real eddies.
    Description: The research presented here was funded by NSF Grants OCE-1059632 and OCE-1433953. Funding support from the Academic Programs Office, and WHOI is also gratefully acknowledged.
    Description: 2017-06-08
    Keywords: Continental shelf/slope ; Advection ; Dynamics ; Eddies ; Topographic effects
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    Wind-driven circulation in a shelf valley. Part I : Mechanism of the asymmetrical response to along-shelf winds in opposite directions (2018)
    American Meteorological Society
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2017. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 47 (2017): 2927-2947, doi:10.1175/JPO-D-17-0083.1.
    Description: Motivated by observations in Hudson shelf valley showing stronger onshore than offshore flows, this study investigates wind-driven flows in idealized shallow shelf valleys. This first part of a two-part sequence focuses on the mechanism of the asymmetrical flow response in a valley to along-shelf winds of opposite directions. Model simulations show that (i) when the wind is in the opposite direction to coastal-trapped wave (CTW) phase propagation, the shelf flow turns onshore in the valley and generates strong up-valley transport and a standing meander on the upstream side (in the sense of CTW phase propagation) of the valley, and (ii) when the wind is in the same direction as CTW phase propagation, the flow forms a symmetric onshore detour pattern over the valley with negligible down-valley transport. Comparison of the modeled upstream meanders in the first scenario with CTW characteristics confirms that the up-valley flow results from CTWs being arrested by the wind-driven shelf flow establishing lee waves. The valley bathymetry generates an initial excessive onshore pressure gradient force that drives the up-valley flow and induces CTW lee waves that sustain the up-valley flow. When the wind-driven shelf flow aligns with CTW phase propagation, the initial disturbance generated in the valley propagates away, allowing the valley flow to adjust to roughly follow isobaths. Because of the similarity in the physical setup, this mechanism of arrested CTWs generating stronger onshore than offshore flow is expected to be applicable to the flow response in slope canyons to along-isobath background flows of opposite directions.
    Description: WGZ and SJL were supported by the National Science Foundation through GrantOCE1154575.WGZ is also supported by the NSF Grant OCE 1634965 and SJL by NSF Grant OCE 1558874.
    Description: 2018-06-08
    Keywords: Ocean circulation ; Topographic effects ; Transport ; Vertical motion ; Waves, oceanic ; Wind stress
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    The Loop Current: Observations of deep eddies and topographic waves. (2019)
    American Meteorological Society
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2019. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 49(6), (2019):1463-1483, doi: 10.1175/JPO-D-18-0213.1.
    Description: A set of float trajectories, deployed at 1500- and 2500-m depths throughout the deep Gulf of Mexico from 2011 to 2015, are analyzed for mesoscale processes under the Loop Current (LC). In the eastern basin, December 2012–June 2014 had 〉40 floats per month, which was of sufficient density to allow capturing detailed flow patterns of deep eddies and topographic Rossby waves (TRWs), while two LC eddies formed and separated. A northward advance of the LC front compresses the lower water column and generates an anticyclone. For an extended LC, baroclinic instability eddies (of both signs) develop under the southward-propagating large-scale meanders of the upper-layer jet, resulting in a transfer of eddy kinetic energy (EKE) to the lower layer. The increase in lower-layer EKE occurs only over a few months during meander activity and LC eddy detachment events, a relatively short interval compared with the LC intrusion cycle. Deep EKE of these eddies is dispersed to the west and northwest through radiating TRWs, of which examples were found to the west of the LC. Because of this radiation of EKE, the lower layer of the eastern basin becomes relatively quiescent, particularly in the northeastern basin, when the LC is retracted and a LC eddy has departed. A mean west-to-east, anticyclone–cyclone dipole flow under a mean LC was directly comparable to similar results from a previous moored LC array and also showed connections to an anticlockwise boundary current in the southeastern basin.
    Description: The authors were supported by the Department of the Interior, Bureau of Ocean Energy Management (BOEM), Contract M08PC20043 to Leidos, Inc., Raleigh, NC. The authors also wish to acknowledge the enthusiastic support of Dr. Alexis Lugo-Fernández, the BOEM Contracting Officer’s Technical Representative, during the study into the Deep Circulation of the Gulf of Mexico, using Lagrangian Methods. Thanks go to the captains and crews of the R/V Pelican and B/O Justo Sierra, J. Malbrough (LUMCON), J. Singer (Leidos), J. Valdes (WHOI), B. Guest (WHOI), and the CANEK group (CICESE).
    Description: 2020-05-29
    Keywords: Bottom currents ; Eddies ; Instability ; Lagrangian circulation/transport ; Mesoscale processes ; Topographic effects
    Repository Name: Woods Hole Open Access Server
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    Long-distance radiation of Rossby Waves from the equatorial current system (2022)
    American Meteorological Society
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2021. This article is posted here by permission of [publisher] for personal use, not for redistribution. The definitive version was published in Farrar, J. T., Durland, T., Jayne, S. R., & Price, J. F. Long-distance radiation of Rossby Waves from the equatorial current system. Journal of Physical Oceanography, 51(6), (2021): 1947–1966, https://doi.org/10.1175/JPO-D-20-0048.1.
    Description: Measurements from satellite altimetry are used to show that sea surface height (SSH) variability throughout much of the North Pacific Ocean is coherent with the SSH signal of the tropical instability waves (TIWs) that result from instabilities of the equatorial currents. This variability has regular phase patterns consistent with freely propagating barotropic Rossby waves radiating energy away from the unstable equatorial currents, and the waves clearly propagate from the equatorial region to at least 30°N. The pattern of SSH variance at TIW frequencies exhibits remarkable patchiness on scales of hundreds of kilometers, which we interpret as being due to the combined effects of wave reflection, refraction, and interference. North of 40°N, more than 6000 km from the unstable equatorial currents, the SSH field remains coherent with the near-equatorial SSH variability, but it is not as clear whether the variability at the higher latitudes is a simple result of barotropic wave radiation from the tropical instability waves. Even more distant regions, as far north as the Aleutian Islands off of Alaska and the Kamchatka Peninsula of eastern Russia, have SSH variability that is significantly coherent with the near-equatorial instabilities. The variability is not well represented in the widely used gridded SSH data product commonly referred to as the AVISO or DUACS product, and this appears to be a result of spatial variations in the filtering properties of the objective mapping scheme.
    Description: This work was supported by NASA Grants NNX13AE46G, NNX14AM71G, and NNX17AH54G.
    Keywords: Pacific Ocean ; Barotropic flows ; Instability ; Planetary waves ; Rossby waves ; Topographic effects
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  • 32
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    Rapid generation of upwelling at a shelf break caused by buoyancy shutdown (2015)
    American Meteorological Society
    Details
    Publication Date: 2022-05-26
    Description: Author Posting. © American Meteorological Society, 2015. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 45 (2015): 294–312, doi:10.1175/JPO-D-14-0104.1.
    Description: Model analyses of an alongshelf flow over a continental shelf and slope reveal upwelling near the shelf break. A stratified, initially uniform, alongshelf flow undergoes a rapid adjustment with notable differences onshore and offshore of the shelf break. Over the shelf, a bottom boundary layer and an offshore bottom Ekman transport develop within an inertial period. Over the slope, the bottom offshore transport is reduced from the shelf’s bottom transport by two processes. First, advection of buoyancy downslope induces vertical mixing, destratifying, and thickening the bottom boundary layer. The downward-tilting isopycnals reduce the geostrophic speed near the bottom. The reduced bottom stress weakens the offshore Ekman transport, a process known as buoyancy shutdown of the Ekman transport. Second, the thickening bottom boundary layer and weakening near-bottom speeds are balanced by an upslope ageostrophic transport. The convergence in the bottom transport induces adiabatic upwelling offshore of the shelf break. For a time period after the initial adjustment, scalings are identified for the upwelling speed and the length scale over which it occurs. Numerical experiments are used to test the scalings for a range of initial speeds and stratifications. Upwelling occurs within an inertial period, reaching values of up to 10 m day−1 within 2 to 7 km offshore of the shelf break. Upwelling drives an interior secondary circulation that accelerates the alongshelf flow over the slope, forming a shelfbreak jet. The model results are compared with upwelling estimates from other models and observations near the Middle Atlantic Bight shelf break.
    Description: J. Benthuysen acknowledges support from the ARC Centre of Excellence for Climate System Science (CE110001028) and the MIT/WHOI Joint Program, where this work was initiated.
    Description: 2015-07-01
    Keywords: Circulation/ Dynamics ; Boundary currents ; Diapycnal mixing ; Ekman pumping/transport ; Mixing ; Topographic effects ; Upwelling/downwelling
    Repository Name: Woods Hole Open Access Server
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    Dynamics of eddying abyssal mixing layers over sloping rough topography (2023)
    American Meteorological Society
    Details
    Publication Date: 2023-02-28
    Description: Author Posting. © American Meteorological Society, 2022. This article is posted here by permission of American Meteorological Society for personal use, not for redistribution. The definitive version was published in Journal of Physical Oceanography 52(12),(2022): 3199-3219, https://doi.org/10.1175/jpo-d-22-0009.1.
    Description: The abyssal overturning circulation is thought to be primarily driven by small-scale turbulent mixing. Diagnosed water-mass transformations are dominated by rough topography “hotspots,” where the bottom enhancement of mixing causes the diffusive buoyancy flux to diverge, driving widespread downwelling in the interior—only to be overwhelmed by an even stronger upwelling in a thin bottom boundary layer (BBL). These water-mass transformations are significantly underestimated by one-dimensional (1D) sloping boundary layer solutions, suggesting the importance of three-dimensional physics. Here, we use a hierarchy of models to generalize this 1D boundary layer approach to three-dimensional eddying flows over realistically rough topography. When applied to the Mid-Atlantic Ridge in the Brazil Basin, the idealized simulation results are roughly consistent with available observations. Integral buoyancy budgets isolate the physical processes that contribute to realistically strong BBL upwelling. The downward diffusion of buoyancy is primarily balanced by upwelling along the sloping canyon sidewalls and the surrounding abyssal hills. These flows are strengthened by the restratifying effects of submesoscale baroclinic eddies and by the blocking of along-ridge thermal wind within the canyon. Major topographic sills block along-thalweg flows from restratifying the canyon trough, resulting in the continual erosion of the trough’s stratification. We propose simple modifications to the 1D boundary layer model that approximate each of these three-dimensional effects. These results provide local dynamical insights into mixing-driven abyssal overturning, but a complete theory will also require the nonlocal coupling to the basin-scale circulation.
    Description: We acknowledge funding support from National Science Foundation Awards 1536515, 1736109, and 2149080. This material is based upon work supported by the National Science Foundation Graduate Research Fellowship Program under Grant 174530.
    Description: 2023-05-18
    Keywords: Abyssal circulation ; Diapycnal mixing ; Meridional overturning circulation ; Topographic effects ; Upwelling/downwelling ; Bottom currents/bottom water
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  • 34
    Electronic Resource
    Electronic Resource
    Human Interindividual Variability in Parameters Related to Health Risks (1999)
    Springer
    Risk analysis 19 (1999), S. 711-726 
    Details
    ISSN: 1539-6924
    Keywords: variability ; exposure ; susceptibility ; risk assessment ; pharmacokinetics ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract This paper reviews existing data on the variability in parameters relevant for health risk analyses. We cover both exposure-related parameters and parameters related to individual susceptibility to toxicity. The toxicity/susceptibility data base under construction is part of a longer term research effort to lay the groundwork for quantitative distributional analyses of non-cancer toxic risks. These data are broken down into a variety of parameter types that encompass different portions of the pathway from external exposure to the production of biological responses. The discrete steps in this pathway, as we now conceive them, are: •Contact Rate (Breathing rates per body weight; fish consumption per body weight) •Uptake or Absorption as a Fraction of Intake or Contact Rate •General Systemic Availability Net of First Pass Elimination and Dilution via Distribution Volume (e.g., initial blood concentration per mg/kg of uptake) •Systemic Elimination (half life or clearance) •Active Site Concentration per Systemic Blood or Plasma Concentration •Physiological Parameter Change per Active Site Concentration (expressed as the dose required to make a given percentage change in different people, or the dose required to achieve some proportion of an individual's maximum response to the drug or toxicant) •Functional Reserve Capacity–Change in Baseline Physiological Parameter Needed to Produce a Biological Response or Pass a Criterion of Abnormal Function Comparison of the amounts of variability observed for the different parameter types suggests that appreciable variability is associated with the final step in the process–differences among people in “functional reserve capacity.” This has the implication that relevant information for estimating effective toxic susceptibility distributions may be gleaned by direct studies of the population distributions of key physiological parameters in people that are not exposed to the environmental and occupational toxicants that are thought to perturb those parameters. This is illustrated with some recent observations of the population distributions of Low Density Lipoprotein Cholesterol from the second and third National Health and Nutrition Examination Surveys.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007045922532
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  • 35
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    Electronic Resource
    Evaluation of the Uncertainty in an Oral Reference Dose for Methylmercury Due to Interindividual Variability in Pharmacokinetics (1999)
    Springer
    Risk analysis 19 (1999), S. 547-558 
    Details
    ISSN: 1539-6924
    Keywords: MeHg ; pharmacokinetics ; PBPK model ; variability ; risk assessment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering
    Notes: Abstract An analysis of the uncertainty in guidelines for the ingestion of methylmercury (MeHg) due to human pharmacokinetic variability was conducted using a physiologically based pharmacokinetic (PBPK) model that describes MeHg kinetics in the pregnant human and fetus. Two alternative derivations of an ingestion guideline for MeHg were considered: the U.S. Environmental Protection Agency reference dose (RfD) of 0.1 μg/kg/day derived from studies of an Iraqi grain poisoning episode, and the Agency for Toxic Substances and Disease Registry chronic oral minimal risk level (MRL) of 0.5 μg/kg/day based on studies of a fish-eating population in the Seychelles Islands. Calculation of an ingestion guideline for MeHg from either of these epidemiological studies requires calculation of a dose conversion factor (DCF) relating a hair mercury concentration to a chronic MeHg ingestion rate. To evaluate the uncertainty in this DCF across the population of U.S. women of child-bearing age, Monte Carlo analyses were performed in which distributions for each of the parameters in the PBPK model were randomly sampled 1000 times. The 1st and 5th percentiles of the resulting distribution of DCFs were a factor of 1.8 and 1.5 below the median, respectively. This estimate of variability is consistent with, but somewhat less than, previous analyses performed with empirical, one-compartment pharmacokinetic models. The use of a consistent factor in both guidelines of 1.5 for pharmacokinetic variability in the DCF, and keeping all other aspects of the derivations unchanged, would result in an RfD of 0.2 μg/kg/day and an MRL of 0.3 μg/kg/day.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007017116171
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  • 36
    Electronic Resource
    Electronic Resource
    Das Rückstandsverhalten von Chloramphenicol nach intramuskulärer Applikation beim Schwein (1985)
    Springer
    European journal of nutrition 24 (1985), S. 113-119 
    Details
    ISSN: 1436-6215
    Keywords: Chloramphenicol ; pharmacokinetics ; residue ; pig
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Summary Residues of Chloramphenicol (CAP) were examined in 24 pigs after intramuscular injection of 30 mg CAP/kg body weight. Two pigs were slaughtered after 3, 6, 12,18, 24, 36 hours, 2, 3, 6, 10, 21 and 30 days, respectively. CAP-concentrations were determined in muscle, blood, urine, liver, kidney, bile, and fat. Methods used were gas-liquid chromatography and radioimmunoassay. Detection limits reached were 1−5 ppb. The concentration-time curves obtained reflected a long elimination phase and allowed only calculation of this half-life. Elimination half-life was estimated to be for muscle, blood and urine 160–170 hours, for kidney 310 and for bile 250 hours. Significant correlations were found to exist between CAP-concentrations in plasma and muscle. It appears that blood would be a good body fluid for monitoring CAP-residues in tissue.
    Notes: Zusammenfassung Zur Untersuchung des Rückstandsverhaltens von Chloramphenicol (CAP) wurden 24 Mastschweine, 24–28 Wochen alt, intramuskulär mit 30 mg CAP/kg Körpergewicht behandelt und je 2 Tiere nach 3, 6, 12, 18, 24, 36 Stunden, 2, 3, 6, 10, 21 und 30 Tagen geschlachtet. Die CAP-Gehalte in Muskulatur, Blut, Urin, Leber, Niere, Galle und Fett wurden gaschromatographisch und radioimmunologisch bestimmt. Die Nachweisgrenze beider Methoden liegt in Abhängigkeit von der Matrix zwischen 1 und 5 ppb. Die erhaltenen Kinetiken weisen eine terminale Elimination auf, deren Halbwertszeiten für Muskulatur, Blut und Urin ca. 160–170 Stunden, für Niere 310 Stunden und für Galle 250 Stunden betragen. Die CAP-Konzentration in Muskulatur und Blut weisen eine signifikante, lineare Korrelation auf. Blutuntersuchungen könnten deshalb als Screening-Methode bei umfangreichen Rückstandskontrollen eingesetzt werden.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02020458
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  • 37
    Electronic Resource
    Electronic Resource
    Enzymatic and pharmacokinetic studies on the metabolism of branched chain α-keto acids in the rat (1983)
    Springer
    European journal of nutrition 22 (1983), S. 14-26 
    Details
    ISSN: 1436-6215
    Keywords: branched chain α-keto acids ; 4-methyl-2-oxopentanoate, 3-methyl-2-oxopentanoate ; 3-methyl-2-oxobutyrate ; dehydrogenation ; transamination ; pharmacokinetics ; absorption
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition , Medicine
    Description / Table of Contents: Zusammenfassung Michaelis-Konstanten und Aktivitäten von Dehydrogenasen und Transaminasen der drei verzweigten α-Ketosäuren Keto-Valin, Keto-Leucin und Keto-Isoleucin in Leber, Niere, Skeletmuskel und Gehirn von Ratten werden mitgeteilt. Nach oraler Zufuhr passieren nur 11–22% der Ketosäuren unverändert die Leber. Aus pharmakokinetischen und Resorptions-Untersuchungen erhaltene Blutspiegel an Ketosäuren werden zu den Michaelis-Konstanten in Beziehung gesetzt. Bei den geringen Konzentrationen an Ketosäuren nach oraler Zufuhr kann angenommen werden, daß die oxidativen Prozesse in den nichthepatischen Geweben über die Transaminierung überwiegen. Daten über die Wachstumseffizienz von verzweigtkettigen α-Ketosäuren im Vergleich zu den entsprechenden Aminosäuren stimmen mit dieser Vorstellung überein. Bei intravenöser Verabreichung müßten die Voraussetzungen für Transaminierung besser sein als nach oraler Zufuhr. Auf der Basis von Daten aus der Literatur werden die Übertragbarkeit unserer Befunde auf den Menschen und die verschiedenen Faktoren, welche die Effizienz der verzweigten α-Ketosäuren durch Einwirkung auf ihren Stoffwechsel beeinflussen können, diskutiert.
    Notes: Summary Miehaelis-constants and enzyme activities for dehydrogenation and transamination of the three branched chainα-keto acids in liver, kidney, skeletal muscle, and brain of rats are reported. After oral load only 11–22 % of the keto acids pass the liver unchanged. Blood levels in pharmacokinetic and absorption studies are related to the Michaelis-constants. At the low keto-acid concentrations after oral application, dehydrogenation in the non-hepatic tissues is supposed to prevail over transamination. Data on feed efficiency of branched chain α-keto acids reported in the literature support this view. The chance for transamination is better after intravenous administration. The transferability of our data to humans, and various factors influencing the efficiency of branched chain α-keto acids are discussed in connection with data reported in the literature.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02020781
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  • 38
    Electronic Resource
    Electronic Resource
    The lymphatic route. 1) Albumin and hyaluronidase modify the normal distribution of interferon in lymph and plasma (1986)
    Springer
    Cellular and molecular life sciences 42 (1986), S. 432-433 
    Details
    ISSN: 1420-9071
    Keywords: Interferon ; immunomodulator ; catabolism ; pharmacokinetics ; administration routes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary When human recombinant interferon-α2 diluted in saline was injected s.c. into rabbits, the total amount recovered in thoracic lymph was less than 0.4%. Recoveries increased from 2- to 8-fold if interferon was injected in 4% albumin or with hyaluronidase, respectively. Albumin added to interferon acts as an interstitial fluid expander, thus favoring interferon absorption through lymphatics rather than blood capillaries. This strategy may increase the therapeutic index of interferon.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02118644
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  • 39
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and absolute bioavailability of salbutamol in healthy adult volunteers (1987)
    Springer
    European journal of clinical pharmacology 32 (1987), S. 631-634 
    Details
    ISSN: 1432-1041
    Keywords: salbutamol ; albuterol ; pharmacokinetics ; bioavailability ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design. Pharmacokinetic parameters from intravenous data were similar to previously reported values obtained with oral administration, with a mean terminal half-life of 3.8 h and a mean clearance of 439 ml·min−1·1.73 m−2. Peak plasma concentrations of 10–20 ng·ml−1 were obtained 1–3 h following oral administration. The absolute bioavailability of each of the oral preparations was 44%. While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
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    Pharmacokinetics of rufloxacin in healthy volunteers (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 101-105 
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    ISSN: 1432-1041
    Keywords: Rufloxacin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The plasma and urine kinetics of rufloxacin were assessed in healthy volunteers after single (100, 200, 400 and 800 mg) and multiple (300 mg followed by 150 mg daily, Group 1, and 400 mg followed by 200 mg daily, Group 2) oral doses. The kinetics of a single oral dose of 800 mg was assessed in fasting and non-fasting subjects to assess the influence of food intake on drug absorption. The AUCs were 134, 266 and 375 μg · h · ml−1 after 100, 200 and 400 mg, respectively. The AUC after 800 mg p. o. was 715 μg · h · ml −1 in fasting subjects and 614 μg · h · ml−1 in non-fasting subjects. The parameters of the model and the mean renal clearance values indicated some departure from linearity in rufloxacin kinetics. After multiple doses the plasma drug levels during the 6th treatment day were similar to those after the first dose in Group 1 and were about 30–40% higher after the first dose in Group 2. The half-lives after the last dose were much shorter than those estimated in the single dose studies (33–36 h and 50–80 h, respectively).
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    Pharmacokinetics of meropenem in subjects with renal insufficiency (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 535-538 
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    ISSN: 1432-1041
    Keywords: Meropenem ; Carbapenem ; pharmacokinetics ; uraemia ; haemodialysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of IV meropenem (500 mg over 30 min) has been studied in 6 healthy volunteers and 26 patients with various degrees of renal impairment. Blood samples were taken at different times over 24 h in healthy subjects and 36 to 48 h in uraemic patients, and four or five urine samples were collected over 24 or 48 h. Meropenem concentrations in plasma and urine were measured by a microbiological assay. The mean peak plasma concentration of meropenem ranged from 28 to 40 μg·ml−1 and was not affected by the degree of renal impairment. The terminal half-life of meropenem was approximately 1 h in subjects with normal kidney function and it was proportionately increased as renal function decreased. A significant linear relationship between total body clearance and creatinine clearance as well as between renal clearance and creatinine clearance was observed. The mean apparent volume of distribution at steady state was not significantly altered in uraemic patients. The mean cumulative urinary recovery of meropenem in healthy volunteers was 77% of the administered dose and it was significantly decreased in patients with renal impairment. Haemodialysis shortened the elimination half-life, from 9.7 h during the predialysis period to 1.4 h during the dialysis period. The dose of meropenem should be reduced in relation to the decrease in creatinine clearance.
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    Comparative pharmacokinetics of ceftazidime in young, healthy and elderly, acutely ill males (1988)
    Springer
    European journal of clinical pharmacology 34 (1988), S. 179-186 
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    ISSN: 1432-1041
    Keywords: ceftazidime ; pharmacokinetics ; elderly patients ; young volunteers ; acute infection
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of ceftazidime have been investigated after single and multiple i.v. doses in 9 young healthy male volunteers and 15 elderly male patients with acute bacterial infections. All subjects had normal, age-correlated glomerular function. Distribution and elimination in young volunteers were unaffected by posture and were similar to what has been reported earlier. In contrast, elderly patients had longer t1/2β (3.1 vs 1.9 h), larger AUC (414.0 vs 276.6 h·mg/l), lower total and renal clearances, reduced urinary recovery over 12 h and enlarged Vss. Total serum clearance of ceftazidime was closely correlated with the51Cr-EDTA clearance. There was no significant change in51Cr-EDTA clearance after seven days of treatment. A reduction in the dose of betalactam antibiotics eliminated by the kidney is advisable in elderly patients with an acute bacterial infection.
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    Pharmacokinetics of mefloquine in the presence of primaquine (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 559-560 
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    ISSN: 1432-1041
    Keywords: Mefloquine ; Thai subjects ; pharmacokinetics ; Primaquine ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00314870
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    The effect of exercise on atropine pharmacokinetics (1990)
    Springer
    European journal of clinical pharmacology 39 (1990), S. 395-397 
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    ISSN: 1432-1041
    Keywords: atropine ; exercise ; pharmacokinetics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Seven healthy males (19–32 y) underwent each of four separate conditions in a repeated measures design. Five of these subjects underwent an additional trial. In four of five trials subjects received 2.0 mg atropine sulfate intramuscularly in the anterolateral portion of the left thigh: at rest (T1); following completion of a single exercise (Ex) bout (T2), (Each bout consisted of 25 min of stationary cycling at 40% VO2 max with 5 min of seated rest), prior to three Ex bouts (T3) and following one and prior to three Ex bouts (T5). Trial 4 (T4) was the same as T3 with the substitution of a saline placebo. Serum samples were collected over a 12 h period and atropine concentration was determined by RIA. Ex trials were compared to T1. Ex prior to atropine (T2) significantly decreased the mean volume of distribution (Vz, 278 vs 2321). Ex in T3 significantly decreased the serum half life (t1/2, 4.2 vs 3.5 h), Vz (278 vs 1981), and clearance (CL, 763 vs 638 ml·min−1) and significantly increased the peak concentration (Cp, 6.7 vs 12.3 ng·ml−1) and area under the curve (AUC, 44.1 vs 53.1 ng·ml−1). In T5, Ex significantly decreased the t1/2 (3.4 h), Vz (182 l) and CL (575 ml·min−1) and significantly increased the absorption rate constant (ka, 0.482 vs 1.1 min−1), elimination rate constant (ke, 0.0012 vs 0.0015 min−1), Cp (14 ng·ml−1) and AUC (53.3 ng·h·ml−1). These results demonstrate that moderate Ex either prior to and/or immediately following drug administration has the capacity to significantly modify atropine pharmacokinetics.
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    Pharmacokinetics of diphemanil methylsulphate in healthy subjects (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 689-691 
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    ISSN: 1432-1041
    Keywords: Diphemanil methylsulphate ; pharmacokinetics ; healthy subjects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetic parameters of oral diphemanil methylsulphate have been evaluated in six healthy male volunteers. Absorption of the drug was slow (tmax=2 to 4 h), the mean half-life was 8.35 h, and the amount of the drug recovered in urine within 48 h ranged from 0.6 to 7.4% of the administered dose. The results suggest low bioavailability, assuming that the drug is poorly metabolized.
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    Dose proportionality study of loperamide following oral administration of loperamide oxide (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 693-694 
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    ISSN: 1432-1041
    Keywords: Loperamide ; loperamide oxide ; diarrhoea ; pharmacokinetics ; dose-proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of loperamide, after oral administration of increasing doses (1 to 16 mg) of loperamide oxide, has been investigated in 10 healthy male volunteers, using a randomised cross-over design. Comparison of the maximum plasma loperamide concentration and AUC demonstrated that the bioavailability of loperamide was proportional to the dose of loperamide oxide administered.
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    Clinical pharmacokinetics and tolerability of alpidem in healthy subjects given increasing single doses (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 369-374 
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    ISSN: 1432-1041
    Keywords: Alpidem ; Anxiolytics ; pharmacokinetics ; tolerance ; metabolites ; sedation ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary In a double-blind, placebo-controlled, crossover experiment in 21 healthy male volunteers, aged 19 to 27 y, the pharmacokinetics and tolerance of the new anxiolytic drug alpidem (SL80.0342) and its three major metabolites were studied after single doses of 25, 50, 100 and 200 mg. Plasma concentrations of alpidem (in 20 subjects) and metabolites (in 6 subjects) were measured by HPLC over a period of 54 h after dosing. Cmax, tmax and AUC(0–54) and, when possible, t1/2 were determined for alpidem and metabolites and the dose linearity of the parameters was investigated. The time to peak of alpidem was dose independent in most subjects and was short (1–4 h); the mean values at the four dosing levels were 1.9, 1.7, 1.6 and 1.8 h. The peak concentration increased with the dose, the mean values being 17, 34, 88 and 115 ng · ml−1, respectively. In 50% of the subjects cmax tended to stabilize between the 100 and 200 mg dose. Dose linearity was also present for the AUC, which plateaued between the 100 and 200 mg dose in only 3 out of 20 subjects; the mean AUC was 119, 281, 669 and 1117 ng · ml−1 · h, respectively. The apparent half-life of elimination appeared to be dose independent, mean values at the increasing dosing levels being 18.7, 19.9, 18,1 and 17.9 h. A similar relationship between the kinetics parameters and dose of the alpidem was observed for the metabolites SL83.0912, SL80.0522 and SL83.0725. The formation of metabolites was not saturated as their AUCs relative to corresponding alpidem AUCs were not dose related. Thus the kinetics of alpidem and its three major metabolites were linear after doses of 25 to 200 mg. The drug was well tolerated by most of the subjects. Sedation and dizziness occurred mainly after the 100 and 200 mg doses.
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    Evaluation of the accuracy of a pharmacokinetically-based patient-controlled analgesia system (1992)
    Springer
    European journal of clinical pharmacology 43 (1992), S. 67-75 
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    ISSN: 1432-1041
    Keywords: Morphine ; Patient-controlled analgesia ; opioids ; pharmacokinetics ; bolus-elimination-transfer ; computer-assisted continuous infusion
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Bone marrow transplant patients having severe, prolonged oral mucositis pain (expected to last for one to three weeks) used a computer-controlled infusion system to self-administer morphine for pain control. Individual patient pharmacokinetic information, derived from a pretreatment bolus morphine dose, was used in a new bolus-elimination transfer algorithm to produce rapid adjustments of steady plasma morphine concentrations when the patient requested more or less drug. We evaluated the performance characteristics (bias and precision) of this pharmacokinetically based patient-controlled analgesic infusion system (PKPCA) in a group of 15 cancer patients over six to 14 days. Although we found a three- to fivefold pharmaco-kinetic variability in the tailoring morphine dose data, the PKPCA system was free of systematic bias (insignificant overall prediction error) during the patient-controlled infusions in this study population. The absolute prediction error was 19.9% for the group on the first study day and 25.6% over the entire study period (aggregate results; 6–14 days of continuous use). Two-thirds of the patients exhibited no bias throughout the study period, and individual bias in the others was symmetrically distributed (three patients with underpredictions and two overpredicted). Magnitude of prediction error during the patient-controlled morphine infusions was not related to the magnitude of pharmacokinetic deviation of individual subjects from group parameters. Our results indicate that this PKPCA system provides accurate control of plasma morphine concentration when used by patients to self-administer opioid for prolonged pain relief continuously over 1 to 2 weeks. Use of individual pharmacokinetic information, instead of population parameters, may account for superior performance characteristic of this computer-assisted continuous drug infusion system.
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    Steady state pharmacokinetic profile of indomethacin in elderly patients and young volunteers (1992)
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    European journal of clinical pharmacology 43 (1992), S. 77-80 
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    ISSN: 1432-1041
    Keywords: Indomethacin ; steady-state ; pharmacokinetics ; elderly
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The steady-state pharmacokinetic profile of indomethacin was examined in twelve healthy volunteers (4 m, 8 f; 20–34 y) and in 12 elderly subjects (7 m, 5 f; 70–88 y). Two formulations of indomethacin were examined, providing duplicate data for each subject group. The subjects received each formulation of indomethacin (25 mg tid) for 6 days in a single blind crossover fashion. On day 7, after an overnight fast, a final 25 mg dose of indomethacin was given and plasma concentrations measured over the following 12 h. Kinetic parameters Cpmin, tmx and AUC (0–12 h) were determined. There were no differences in the pharmacokinetic parameters between young and elderly subjects or between data for the two formulations of indomethacin. AUC values (μg · ml−1 · h), for example, for the two formulations in the young subjects were 5.85 and 6.85 while the values for the elderly subjects were 6.55 and 6.50 respectively. When each treatment period was considered independently there was a significant difference between young and elderly subjects with regard to compliance. The rates of non compliance (over and under compliance) using a capsule count technique were, however, low with a mean maximum value of 5.8% being recorded for the elderly subjects.
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    Pharmacokinetics of caffeine in patients with decompensated type I and type II diabetes mellitus (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 449-452 
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    ISSN: 1432-1041
    Keywords: Diabetes mellitus ; Caffeine ; pharmacokinetics ; P-450 mono-oxygenase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Diabetes may alter the pharmacokinetics of aminopyrine and antipyrine, which are used to assess liver function. Caffeine has recently been used to test liver function, but the effect of diabetes on caffeine kinetics is not known. The kinetics of caffeine has been examined in patients with decompensated Type I and Type II diabetes and in two age- and sex-matched control groups. In both types of diabetes the apparent caffeine clearance, half-life, and apparent volume of distribution were similar to controls. It is concluded that decompensated diabetes does not influence the cytochrome P-448 mono-oxygenase system responsible for caffeine metabolism.
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    Pharmacokinetics and dialysability of isradipine in chronic haemodialysis patients (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 231-233 
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    ISSN: 1432-1041
    Keywords: Isradipine ; Haemodialysis ; pharmacokinetics ; dialysability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of isradipine, a calcium-channel blocker, have been studied in eight patients on chronic haemodialysis. A single oral dose of 5 mg was administered on both a non-haemodialysis and a haemodialysis day and the plasma concentrations of isradipine were analyzed. The mean cmax, tmax, AUC, and t1/2 in plasma on the non-haemodialysis day were 5.2 ng·ml−1, 1.4 h, 23.8 ng·h·ml−1, and 3.1 h, respectively. The dialysis clearance of isradipine was negligible (5.0 ml·min−1). The t1/2 values during haemodialysis were not significantly different from those observed during the same period post dose on the non-haemodialysis day. The study demonstrates that supplemental doses of isradipine are not necessary in these patients since isradipine is not significantly removed by haemodialysis.
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    Pharmacokinetics and haemodynamic effects of a single oral dose of the novel ACE inhibitor spirapril in patients with chronic liver disease (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 247-253 
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    ISSN: 1432-1041
    Keywords: Liver cirrhosis ; Spirapril ; ACE inhibitor ; pharmacokinetics ; haemodynamic effects ; liver function tests
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics and haemodynamic effects of orally administered spirapril, a novel angiotensinconverting enzyme (ACE) inhibitor, have been investigated in patients with liver cirrhosis (n=10), in patients with chronic, non-cirrhotic liver disease (n=8) and in a control group of healthy subjects (n=16). The absorption and elimination of spirapril did not differ between patients with liver disease and control subjects. In contrast, the bioavailability of spiraprilat, the metabolite responsible for the pharmacological action of spirapril, was significantly reduced in patients (AUC 820 μg·h·l−1, 923 μg·h·l−1 and 1300 μg·h·l−1 in patients with cirrhosis, patients with non-cirrhotic liver disease and in healthy subjects, respectively. Compared to healthy subjects, cirrhotic patients had a reduced rate constant of spiraprilat formation (1.10 h−1 in patients vs. 2.00 h−1 in control subjects) while the elimination half-life of spiraprilat was not different. The effect of spirapril on diastolic blood pressure was decreased in patients with chronic liver disease as compared to the controls. Thus, the pharmacokinetics of spirapril was unchanged in patients with different types of liver disease, including cirrhosis. However, the bioavailability of spiraprilat and hypotensive effect of spirapril were reduced in patients.
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    Dopamine pharmacokinetics in critically ill newborn infants (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 593-597 
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    ISSN: 1432-1041
    Keywords: Dopamine ; Newborns ; critically ill patients ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Dopamine is frequently used in critically ill newborn infants for treatment of shock and cardiac failure, but its pharmacokinetics has not been evaluated using a specific analytical method. Steady-state arterial plasma concentrations of dopamine were measured in 11 seriously ill infants receiving dopamine infusion, 5–20 μg · kg−1 · min−1, for presumed or proven sepsis and hypotensive shock. Steady-state concentrations of dopamine ranged from 0.013–0.3 μg/ml. Total body clearance averaged 115 ml · kg−1 · min−1. The apparent volume of distribution and elimination half life averaged 1.8 1 · kg−1 and 6.9 min, respectively. No relationship was observed between dopamine pharmacokinetics and gestational age, postnatal age or birthweight. Substantial interindividual variation was seen in dopamine pharmacokinetics in seriously ill infants, and plasma concentrations could not be predicted accurately from its infusion rate. Marked variation in clearance explains in part, the wide dose requirements of dopamine needed to elicit clinical response in critically ill newborn infants.
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    The concentration-dependent disposition and kinetics of inulin (1991)
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    European journal of clinical pharmacology 40 (1991), S. 619-624 
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    ISSN: 1432-1041
    Keywords: Inulin ; pharmacokinetics ; half life ; distribution ; concentration-dependent clearance ; healthy subjects ; chronic renal failure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The disposition of inulin was studied in 30 healthy male and 10 healthy female volunteers, and 10 patients with stable chronic renal failure (mean creatinine clearance 45 ml·min−1) following intravenous infusion of 70 mg·kg−1 over 5 min. Plasma concentrations fell rapidly initially but the rate of decline decreased continuously over 8 h and a linear terminal elimination phase could not be identified. Inulin was excreted rapidly by the subjects with normal renal function and 97.3% of the dose was recovered in the urine in 8 h. There was a progressive highly significant fall in the renal clearance of inulin after 2 h as plasma concentrations fell below about 150 mg·l−1. Six to 8 h after administration the clearance was less than 50% of the initial value in the healthy volunteers and the corresponding fall in the renal patients was 33%. The concentration-dependent renal clearance of inulin was confirmed in “step-up” and “step-down” constant infusion studies in which clearances were measured at mean plasma concentrations ranging from 35.2 to 186.7 mg·l−1. These studies virtually excluded time, changes in posture and urine flow rate as important factors. There was no statistically significant fall in clearance during the first 2 h and kinetic analysis was based on data obtained over this time. Under these conditions the mean plasma half life, volume of distribution (Vss) and total body clearance of inulin in the healthy males, healthy females and patients with chronic renal failure were 73.2, 65.5 and 172.4 min, 10.5, 9.6 and 8.81·70 kg−1 and 113.3, 111.5 and 43.3 ml·min−1·70 kg−1 respectively. There were no sex differences in any of the kinetic variables. The mechanism of the concentration-dependent clearance of inulin is unknown but the findings are consistent with saturable renal tubular reabsorption. Care is required with the use of inulin for measurement of the glomerular filtration rate by the single injection technique.
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    Effect of ampicillin on mefloquine pharmacokinetics in thai males (1991)
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    European journal of clinical pharmacology 40 (1991), S. 631-633 
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    ISSN: 1432-1041
    Keywords: Mefloquine ; ampicillin ; Thai subjects ; pharmacokinetics ; enterohepatic recycling ; drug interaction ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The kinetics of a single oral dose of mefloquine given either alone or with ampicillin has been studied in 8 healthy Thai male volunteers. There was a significantly higher maximum whole blood mefloquine concentration after coadministration with ampicillin (1648 vs 1228 ng·ml−1), as well as a significantly reduced terminal half life (15.3 vs 17.7 days), mean residence time (20.1 vs 23.4 days) and volume of distribution at steady state (14.1 vs 19.4 l·kg−1). Although there was no significant change in the AUC from zero time to infinity, the AUC from zero time to 5 days was significantly increased by ampicillin (4.86 vs 3.27 μg·ml−1 day). These changes in mefloquine disposition after antibiotic treatment may be due both to an increase in fractional bioavailability and a reduction in the enterohepatic recycling of mefloquine.
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    Lack of effect of multiple dose sucralfate on the pharmacokinetics of roxatidine acetate (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. 637-638 
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    ISSN: 1432-1041
    Keywords: Roxatidine acetate ; sucraflate ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    Modelling circadian variation in the pharmacokinetics of non-steroidal anti-inflammatory drugs (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 357-361 
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    ISSN: 1432-1041
    Keywords: Circadian rhythms ; Indomethacin ; Ketoprofen ; pharmacokinetics ; time-varying models ; nonsteroidal anti-inflammatory drugs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A one-compartment model with first-order absorption has provided good fits to five sets of indomethacin data and four sets of ketoprofen data taken at different times of day. There was substantial variation in the model parameters with time of administration and most of the features of this variation applied equally to both drugs. From the data examined, the source of variation appears to be mainly in the absorption phase and this was confirmed using a chronokinetic analysis, in which simultaneous fits were obtained with time-variant rate parameters. However, there may also be circadian variation in protein binding. The danger of quoting parameter values for either of these two drugs based on administration at a single time of day has been illustrated, and this may well be true for other drugs.
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    Dose-dependent absorption and elimination of gamma-hydroxybutyric acid in healthy volunteers (1993)
    Springer
    European journal of clinical pharmacology 45 (1993), S. 353-356 
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    ISSN: 1432-1041
    Keywords: Gamma-hydroxybutyric acid ; pharmacokinetics ; dose-proportionality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Gamma-hydroxybutyric acid (GHB) is effective in treatment of the alcohol and opiate withdrawal syndromes. Its absorption and disposition kinetics have been studied in 8 healthy male volunteers following oral administration of single doses of 12.5, 25 and 50 mg kg−1. The AUC increased disproportionately with the dose and so the apparent oral clearance decreased significantly as the dose was increased, whereas the terminal half-life and mean residence time increased. The peak plasma concentrations normalised to the lowest dose fell significantly with increasing doses, whilst the corresponding peak times increased. These findings suggest that both the oral absorption and the elimination of GHB are capacity-limited processes. GHB did not bind to significant extent to plasma proteins over the therapeutic concentration range. The pharmacokinetic parameters in healthy volunteers were not significantly different from those previously observed in alcohol-dependent patients with compensated alcoholic liver disease.
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    Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 451-456 
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    ISSN: 1432-1041
    Keywords: Glyceryl trinitrate spray ; pharmacokinetics ; a/b-ratio ; pulmonary artery diastolic pressure ; finger pulse curve ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II–III) with elevated PADd at rest (≥15 mm Hg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min. The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.
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    Pharmacokinetics and pharmacodynamics of benazepril hydrochloride in patients with major proteinuria (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 463-466 
    Details
    ISSN: 1432-1041
    Keywords: Benazepril ; Proteinuria ; benazeprilat ; ACE inhibitor ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o. The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients. Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42 %. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients. In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.
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    Absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin from different regions of the gastrointestinal tract in man (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 473-476 
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    ISSN: 1432-1041
    Keywords: dDAVP ; bioavailability ; gastrointestinal tract ; healthy volunteers ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The absolute bioavailability of an aqueous solution of 1-deamino-8-D-arginine vasopressin (dDAVP) from different regions of the gastrointestinal (GI) tract (stomach, duodenum, jejunum, ileum, colon, rectum) has been studied in 6 healthy, male volunteers aged 24 to 35 years, followed for 12 h after each drug administration. For i. v. administration the subjects received 4 μg dDAVP. For intestinal administration 400 μg dDAVP was directly applied to six distinct sites in the GI tract via two or four channel tubes with or without a distal occlusive balloon. Biological effects were assessed and plasma and urinary levels of dDAVP were measured using a specific, sensitive RIA. Urine osmolality remained elevated and diuresis decreased for 12 h following dDAVP administration irrespective of the site of application. After i. v. administration, the half-life of elimination of dDAVP was 60.0 min, plasma clearance 1.7 ml·min−1·kg−1, amount excreted in urine 2.0 μg and renal clearance was 0.8 ml·min−1·kg−1. The mean bioavailability (f) after gastric application was 0.19% (range 0.02–0.35%). f was 0.24% after duodenal application (range 0.04–0.62%), 0.19% after jejunal (range 0.01–0.41%), 0.03% after distal ileal (range 0.01–0.08%), 0.04% after proximal colonic (range 0.01–0.12%) and 0.04% after rectal (0.01–0.10%) application. The bioavailability was significantly higher in the three upper GI regions in comparison to the three lower regions. The bioavailability of dDAVP after gastric, duodenal and jejunal application was similar to that after swallowing a tablet in a previous study. Absorption from the ileum was lower than expected and no preferential site of absorption was found.
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    Disposition of quinine in plasma, red blood cells and saliva after oral and intravenous administration to healthy adult Africans (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 171-174 
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    ISSN: 1432-1041
    Keywords: Quinine ; Malaria ; pharmacokinetics ; red blood cells ; plasma ; saliva ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of quinine has been studied in ten healthy adult Africans after intravenous infusion and oral ingestion of a 500 mg dose. Blood and saliva samples were collected over 48 h and quinine in plasma, red cells and saliva was determined by HPLC. Quinine was rapidly and almost completely absorbed after an oral dose, with absorption half-life of 0.53 h, a tmax of 1–3 h and a bioavailability of 88%. Analysis of the i. v. data gave an apparent volume of distribution of 3.6 1·kg−1 and a plasma clearance of 0.19 l·kg−1·h−1. The concentration-time curves for plasma, red cells and saliva had declining phases were approximately parallel, giving a similar half-life that in all three media. The half-lives after the i. v. infusion also did not different from those after oral administration. The dose was well tolerated by both methods of administration.
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    Binding of a metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid) to serum proteins in rat and man (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 175-179 
    Details
    ISSN: 1432-1041
    Keywords: 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) ; Triflusal ; triflusal metabolite (HTB) ; pharmacokinetics ; protein binding ; ultrafiltration ; binding constant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet anti-aggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied. Rats were given a single oral dose of 50 mg·kg−1 triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC. HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K=intrinsic affinity constant, n=number of binding sites) were K1=1.4×105 l·mol−1, n1=1.23, and K2=4.1×103 l·mol−1 and n2=3.77. The mean plasma concentration in rats after oral administration was 185 (37) μg·ml−1 (protein-free HTB: 2.44 (0.77)%). The binding constants in human plasma were K1=4.7×105 l·mol−1, n1=1.93, K2=4.3 l·mol−1 and n2=4.28. The plasma HTB concentration in man (n=8) was 35 μg·ml−1 (Cmax) after a single oral dose of triflusal 300 mg, 172.96 μg·ml−1 (Cmax·ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 μg·ml−1 (Cmax·ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose. HTB had high affinity for plasma albumin, which was not saturable after therapeutic doses. It showed linear elimination.
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    Temporary reversal of serum to cerebrospinal fluid glycerol concentration gradient after intravenous infusion of glycerol (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 181-185 
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    ISSN: 1432-1041
    Keywords: Glycerol ; brain oedema ; serum ; cerebrospinal fluid ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Glycerol 50 g infused i. v. over 2 to 6 h is widely used to treat cerebral oedema in patients with acute stroke. Its transit through the blood-cerebrospinal fluid barrier in subjects with uninflamed meninges has now been examined. In 7 patients with an external ventriculostomy for occlusive hydrocephalus, each of whom was given 500 ml of a 10% solution IV over 4 h, serum and CSF were repeatedly sampled during and after the infusion and glycerol was measured enzymatically. The highest serum glycerol level of 191–923 mg/l was observed at the end of the infusion. The maximum CSF glycerol of 18.7–110.8 mg/l was attained 0–1 h after the end of the infusion. Elimination both from serum and CSF approximated a single-exponential decay; the elimination half-life from serum was 0.29–0.56 h compared to 1.03–3.68 h from CSF. In six of the seven cases there was a temporary reversal of the serum/CSF concentration gradient during glycerol elimination. The ratios of the AUCs of CSF and serum, which describe the overall penetration of glycerol into CSF, ranged from 0.09–0.31. In conclusion, the serum level of glycerol produced by giving 50 g IV glycerol over 4 h may not be sufficiently high reliably dehydrate to brain tissue in many patients, and the slow elimination of glycerol from the CSF may be related to the so-called rebound phenomenon.
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    Formation and excretion of dipyrone metabolites in man (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 187-191 
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    ISSN: 1432-1041
    Keywords: Dipyrone ; Acetylation phenotype ; metabolism ; pharmacokinetics ; urinary excretion ; metabolite clearance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The formation and urinary excretion of the dipyrone metabolites, methylaminoantipyrine (MAA), aminoantipyrine (AA), formylaminoantipyrine (FAA) and acetylaminoantipyrine (AAA) were determined following administration of a single oral 1.0 g dose of dipyrone to 12 healthy volunteers. The AAA/AA plasma ratio showed that 3 subjects were slow and 9 were rapid acetylators. Pharmacokinetic parameters were determined separately for each group. A good correlation was found between the plasma and urine AAA/AA ratios. The renal clearance of the four metabolites was similar for both phenotypes. A significant difference in the rate of formation of dipyrone metabolites was found for AA, 0.25 (slow) vs 0.1 ml·min−1·kg−1 (rapid), and for AAA 0.75 (slow) vs 7.53 ml·min−1·kg−1 (rapid). There were comparable differences between slow and rapid acetylators in the AUC and the urinary excretion extrapolated to infinity for AA and AAA. The present results show that the kinetics of dipyrone metabolites in plasma and urine can provide a useful measure of the activity of the enzymes involved in their production.
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    Effect of salbutamol on digoxin pharmacokinetics (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 197-201 
    Details
    ISSN: 1432-1041
    Keywords: Digoxin ; Salbutamol ; serum ; skeletal muscle digoxin ; pharmacokinetics ; drug interaction ; serum potassium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A single dose of the β2-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a β2-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man. Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 μg·kg−1·h−1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 μg·kg−1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a β2-adrenoceptor-mediated increase in Na-K-ATPase activity.
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    Pharmacokinetics of nicorandil in patients with normal and impaired renal function (1992)
    Springer
    European journal of clinical pharmacology 42 (1992), S. 203-207 
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    ISSN: 1432-1041
    Keywords: Nicorandil ; pharmacokinetics ; angina pectoris ; uraemia ; adverse effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of oral nicorandil 20 mg 12 hourly for 9 doses was evaluated in 21 hospitalized patients with angina pectoris due to coronary heart disease and with normal and impaired renal function. Patients were divided into 3 groups based on creatinine clearance (CLCr): GROUP I (n=6) 〉 80 ml/min, GROUP II (n=8) 20–80 ml/min, and GROUP III (n=7) 〈 20 ml/min. After the first dose, the total clearance of nicorandil (CL) value did not change with increasing renal failure and so was not dependent on creatinine clearance. After the last dose CL was 51 l·h−1 in Group I, 44 l·h−1 in Group II and 56 l·h−1 in Group III, and it was not related to creatinine clearance. The percentage of the dose excreted in the urine was 0.4%. No significant difference was noted in any of the other pharmacokinetic parameters examined in the three groups, not even on comparing values obtained on the first and last days of treatment. The findings suggest that there is no need to change the dose of nicorandil in subjects with different degrees of renal failure.
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    Plasma levels of oxybutynine chloride in children (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 83-85 
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    ISSN: 1432-1041
    Keywords: Enuresis ; Oxybutynine chloride ; children ; pharmacokinetics ; adverse effects ; anticholinergic actions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Anticholinergic adverse-effects in children treated with conventional doses of oxybutynine led us to measure plasma oxybutynine levels in children. 18 children, aged 5 to 13 y, who required treatment with oxybutynine chloride for daytime incontinence were studied. Plasma concentrations were measured on the fifth day of a course of treatment in which the dose was adapted to the child's body weight; the dose was given twice daily at 12-hour intervals. In 10 children aged between 5 and 8 y, the mean dose was 0.1 mg · kg−1. In 8 children aged between 10 and 13 years, the mean dose was 0.15 mg · kg−1. The highest concentration was usually found between 1 and 2 h after administration. The subsequent fall in concentration was rapid and after 6 h oxybutynine was no longer measurable in 14 of the children. The concentrations found were not different from those seen in adults given equivalent doses. The results show that plasma concentrations in children were not very different from those observed in adults if the dose were adapted to the body weight of the children. No special differences in paediatric use were revealed that might explain the particular adverse-effects. The results of the study argue against the dosage regimen proposed before these adverse events were detected. They strongly favour a dose adapted to the body weight of the child, with a 12-hour interval between doses.
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    Plasma concentrations and effect on testosterone metabolism after single doses of MK-0434, a steroid 5 alpha-reductase inhibitor, in healthy subjects (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 123-126 
    Details
    ISSN: 1432-1041
    Keywords: Steroid 5α-reductase inhibitor ; Testosterone metabolism ; MK-0434 ; pharmacodynamics ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A four-period, two-panel, single-rising-dose study (0.1–100 mg) was conducted in healthy males to investigate the pharmacodynamics, tolerability and pharmacokinetics of MK-0434, a steroid 5α-reductase inhibitor. MK-0434 was associated with a significant reduction in dihydrotestosterone, which was maximal at 24 h and maintained through 48 h post treatment. The maximum reduction was approximately 50 % and occurred at all doses above 5 mg (10, 25, 50 and 100 mg). MK-0434 appeared to have no effect on serum testosterone at these single doses. Rising single doses of MK-0434 were associated with an increase in Cmax and AUC but the changes were less than proportional to dose, most likely due to nonlinear absorption. MK-0434 given in single doses up to 100 mg was without significant adverse effects in healthy male volunteers. In summary, MK-0434 is a well-tolerated, potent, orally active 5α-reductase inhibitor in man.
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    Cyclosporin pharmacokinetics in heart-lung transplant recipients with cystic fibrosis (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 261-265 
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    ISSN: 1432-1041
    Keywords: Cystic fibrosis ; Cyclosporin ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Cyclosporin (CsA) is currently the main immunosuppressive agent used in organ transplantation with considerable improvement in graft survival. Oral CsA solution is highly lipophilic, and its bioavailability may be reduced in cystic fibrosis (CF) heart-lung transplant recipients with pancreatic, gastrointestinal, and hepatic insufficiency. The bioavailability of oral CsA solution in 7 CF transplant recipients (5 male and 2 female with a mean age of 27 years and a mean weight of 49 kg) and 3 non-CF heart-lung recipients (1 male and 2 female with a mean age of 41 years and a mean weight of 60 kg) was studied. Following intravenous CsA administration, the kinetic curves were similar with no significant difference in the volume of distribution and clearance of CsA demonstrated between the CF and non-CF groups. The mean daily dose of oral CsA in 7 CF subjects (23.3 mg·kg−1) was significantly higher than the 3 non-CF heart-lung recipients (4.8 mg·kg−1). The mean maximum blood concentration of CsA for the oral dose was 776 ng·ml−1 for the 7 CF subjects, which was comparable with the mean peak values of 789 ng·ml−1 for the 3 non-CF control subjects. Poor enteral absorption of CsA probably accounts for the significantly lower mean bioavailability in the 7 CF subjects (14.9%) compared with the 3 non-CF control subjects (39.4%). The effects on the bioavailability of oral CsA solution by pancreatic enzymes (Creon) and histamine-2 antagonist (ranitidine) were also evaluated in the 7 CF subjects. No significant difference was demonstrated.
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    Single dose pharmacokinetics of proguanil and its metabolites in pregnancy (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 247-251 
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    ISSN: 1432-1041
    Keywords: Proguanil ; Pregnancy ; Malaria ; cycloguanil ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Plasma and whole blood concentrations of proguanil, its active metabolite cycloguanil, and the inactive metabolite 4-chlorophenyl-biguanide, were measured by HPLC in 10 healthy Karen women in the last trimester of pregnancy, following a 200 mg single oral dose of proguanil. Four of these women were restudied 2 months after delivery. The pharmacokinetic properties of proguanil were similar during and after pregnancy. Median peak plasma concentrations of proguanil during pregnancy and following delivery were 212 and 215 ng·ml−1, and occurred at 4.5 and 5 h, respectively. Mean plasma AUC values for proguanil during and following pregnancy were 94 and 98 ng·h·ml−1·kg−1, respectively. Corresponding whole blood AUC values were 361 and 396 ng·h·ml−1·kg−1. The mean elimination half lives and mean residence times of proguanil in plasma and whole blood were 12.3 and 19.6 h and 13.8 and 20.7 h respectively during pregnancy. Following pregnancy these values were 17.1 and 19.7 h for plasma and 19.7 h and 20.2 h for whole blood respectively. Mean peak plasma and whole blood concentrations of cycloguanil following pregnancy were 25 and 22 ng·ml−1 respectively. During pregnancy peak cycloguanil concentrations in both plasma and whole blood were markedly lower, 13 and 12 ng ml−1, respectively. Two pregnant women (neither of whom were restudied) were probably poor metabolisers of proguanil. The mean ratio of proguanil to cycloguanil plasma AUC was 16.7 in the third trimester of pregnancy and 7.8 following pregnancy, compared with less than 5 in previously reported studies. The concentrations of 4-chlorophenylbiguanide in both plasma and whole blood in pregnant subjects were also lower than those after pregnancy. These data show that blood concentrations of the active antimalarial metabolite cycloguanil are reduced in late pregnancy and that the currently recommended dose of proguanil could be inadequate for antimalarial prophylaxis in pregnant women.
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    On the intraindividual variability and chronobiology of cyclosporine pharmacokinetics in renal transplantation (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 265-269 
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    ISSN: 1432-1041
    Keywords: Cyclosporine ; Renal transplantation ; pharmacokinetics ; intraindividual variation ; circadian variation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The intraindividual variability and circadian variation of oral cyclosporine (CsA) pharmacokinetics were studied over 24 h in 18 renal transplant recipients at steady state, and in 10 of the patients during a second 24 h period. The absolute percentage intraindividual difference in daytime AUC (0–12 h) ranged from 2% to 54% (mean 30%), and the corresponding variability in nighttime AUC (0–12 h) ranged from 5% to 80% (mean 34%). The pharmacokinetic variables t1/2, tmax and Cmax were more variable than the AUC (0–12 h) both during the day and at night. The evening trough level was significantly lower than the morning trough level; 185 ng · ml−1 versus 223 ng · ml−1. This, together with a significantly longer t1/2 in the night than the day, suggested circadian variability in the pharmacokinetics of CsA. In a separate retrospective study in 162 renal transplant recipients given CsA by constant intravenous infusion, repeated CsA blood concentration measurements at steady state showed lower concentrations during the day than the night, suggesting higher CsA clearance during daytime. It is concluded that CsA pharmacokinetics in renal transplant recipients, besides the well-known interindividual variability, also displays large intraindividual variability as well as circadian variation. Our findings further emphasize the necessity and difficulty of pharmacological monitoring in the clinical use of CsA in organ transplantation.
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    Delayed disposition of adriamycin and its active metabolite in haemodialysis patients (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 301-302 
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    ISSN: 1432-1041
    Keywords: Adriamycin ; Haemodialysis ; adriamycinol ; pharmacokinetics ; moment analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    Dose proportional absorption of 25–150 mg atenolol (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 305-306 
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    ISSN: 1432-1041
    Keywords: Atenolol ; bioavailability ; intestinal absorption ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary We investigated the dose proportionality after the intake of oral atenolol 25, 50, 100 and 150 mg. Standard tablets were taken by 8 healthy volunteers in randomised order of doses. The area under the curve divided by dose did not differ between the doses, indicating that the absorption of this hydrophilic compound, with known incomplete bioavailability, was constant over the range tested.
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    Esmolol, an ultrashort-acting, selective β1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 399-404 
    Details
    ISSN: 1432-1041
    Keywords: Esmolol ; β1-Adrenoceptor antagonist ; tricresylphosphate ; pharmacokinetics ; effect kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of esmolol at different rates of infusion (100, 250 and 500 μg·kg−1 BW·min−1) were compared with β-adrenoceptor occupancy (β1 and β2, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 μg·kg−1 BW·min−1 there was a maximal β1-receptor occupancy of 84.7% while β2-receptor occupancy was below the detection limit; confirming the β1 selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC50 values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 μg·kg−1 BW · min−1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 μg·ml−1) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 μg·kg−1 BW·min−1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r=0.97). Since the cardiovascular effects, determined before and 45 min after termination of infusion of esmolol were similar, it can be concluded that the observed effects on heart rate and systolic blood pressure are exclusively mediated by esmolol.
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    Influence of age, frailty and liver function on the pharmacokinetics of brofaromine (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 387-391 
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    ISSN: 1432-1041
    Keywords: Key words Liver function tests; elderly ; pharmacokinetics ; geriatrics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66–92 y) and 12 healthy volunteers (20–35 y). Methods: Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffeine clearance) or liver plasma flow (sorbitol clearance). Results: In the elderly the AUC of brofaromine was significantly increased (e.g. for the 75 mg dose 43.2 vs 19.9 μmol*h⋅l−1, clearance was reduced (5.0 vs. 11.8 l⋅h−1), the volume of distribution was smaller (130 vs. 230 l), and the half-life was slightly increased (19.0 vs. 14.2 h). No significant correlation was observed between hepatic plasma flow and brofaromine clearance (r = 0.41, P = 0.05), whereas CYP1A2 activity and brofaromine clearance were tightly correlated (r = 0.94, P 〈 0.0001). Conclusion: Caffeine clearance, a simple, noninvasive test of CYP1A2 activity, is predictive of brofaromine clearance.
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    Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 545-550 
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    ISSN: 1432-1041
    Keywords: Ramipril ; Piretanide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0–4 h) and ramiprilat (0–24 h) (from 15.8 to 19.8 ng·ml−1·h, and from 63.4 to 74.6 ng·ml−1·h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73 % of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.
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    On the relation between standard deviation and arithmetic mean in pharmacokinetic studies (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 573-574 
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    ISSN: 1432-1041
    Keywords: Standard deviation ; Arithmetic mean ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00196120
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    Effect of saliva flow rate on saliva phenytoin concentrations: implications for therapeutic monitoring (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 565-567 
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    ISSN: 1432-1041
    Keywords: Phenytoin ; Saliva ; therapeutic drug monitoring ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of atropine-induced reductions in saliva flow rate on saliva phenytoin concentrations were evaluated in a randomised placebo-controlled crossover study in a group of epileptic patients stabilised on the drug. Pretreatment with atropine caused significant reductions in saliva flow rates during the first 4 h, compared to saline. The AUC0–4 h for saliva flow rate was significantly reduced by atropine (245 g vs 327 g) and the saliva phenytoin AUC0–4 h was significantly increased (5.6 μg · ml−1 · h vs 4.5 μg · ml−1 · h) without affecting plasma phenytoin concentrations. The saliva/plasma phenytoin AUC0–4 h ratio was therefore significantly increased by atropine (0.15 vs 0.12). However, there was a poor correlation between saliva/plasma phenytoin concentration ratios and saliva flow rates for the two treatments in the individual patients (correlation coefficient ranged from 0.25 to 0.65). These findings demonstrate that saliva phenytoin concentrations are increased by reductions in saliva flow rate. Caution is therefore required when saliva phenytoin concentrations are used for therapeutic monitoring in the presence of factors which may affect saliva flow rate.
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    Cyclosporine pharmacokinetics in nephrotic and kidney-transplanted children (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 61-65 
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    ISSN: 1432-1041
    Keywords: Cyclosporine A ; kidney transplant ; nephrotic syndrome ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetic parameters of cyclosporine (CsA) were determined in 23 kidney transplant recipients and 19 children with nephrotic syndrome, after intravenous and oral administration. The mean bioavailability was 39 %, blood clearance was 0.55 l · h-1 · kg-1 and volume of distribution at steady-stade was 2.77 l · kg-1. The absorption profile was monophasic (67 %), biphasic (29 %) or poor (4 %). The maximum blood concentration of CsA was significantly higher in children with a monophasic profile than in children with a biphasic profile (550 vs 380 ng · ml-1). Blood clearance was significantly higher in the transplant recipients than in the patients with nephrotic syndrome (0.65 vs 0.43 l · h-1 · kg-1. Although age, haematocrit, creatinine clearance, serum albumin and cholesterol differed between the two groups, only haematocrit and creatinine clearance were significantly (negatively) correlated with CsA clearance.
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    Differences in the bioavailability of dihydrotachysterol preparations (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 81-84 
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    ISSN: 1432-1041
    Keywords: Dihydrotachysterol ; bioavailability ; pharmacokinetics ; human ; HPLC
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The bioavailability of four preparations containing dihydrotachysterol (DHT2) was tested in two separate trials with administration of single, oral doses of 1 mg per individual. The relative bioavailability of corresponding preparations (capsules vs capsules and oral solution vs oral solution) was tested in a randomised, crossover pattern within the same group of volunteers. Two different groups of 24 healthy volunteers took part in each trial. Solution and capsule bioavailability was also compared inter-individually. A new sensitive HPLC-method (quantification limit 0.5 ng · ml-1) was used for the measurement of DHT2 concentration in serum. Three of the preparations tested had a similar bioavailability (mean AUC values of 195.5–223 ng · h · ml-1); the bioavailability of the fourth preparation (A.T.10 oral solution) was considerably lower (mean AUC value 111.5 ng · h · ml-1). The present dosage recommendations of all four preparations are identical. A new dosage recommendation is thus required for the oral solution with low bioavailability (A.T.10).
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    Doxycycline carrageenate — an improved formulation providing more reliable absorption and plasma concentrations at high gastric pH than doxycycline monohydrate (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 143-146 
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    ISSN: 1432-1041
    Keywords: Doxycycline ; bioavailability ; pH dependent absorption ; pharmacokinetics ; carrageenate ; adverse events
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of increased gastric pH (obtained by pre-treatment with omeprazole) on the bioavailability of doxycycline monohydrate and doxycycline carrageenate has been investigated in 24 healthy volunteers, using an open, randomised, four-treatment, four-period, crossover, 2×2 factorial design. Each subject received a single dose of 100 mg of each of the doxycycline formulations with and without pre-treatment with omeprazole (40 mg daily for 7 days). The two formulations were bioequivalent (rate and extent) during fasting without omeprazole pre-treatment, whereas after omeprazole, the monohydrate showed a highly significant decrease in bioavailability (38% for AUC and 45% for Cmax) compared to the carrageenate formulation, which was not affected by prior administration of omeprazole. Many of the subjects did not reach a therapeutic plasma level of doxycycline during the combination of omeprazole and doxycycline monohydrate, and most adverse events (mainly gastrointestinal) were reported after this combination. As large populations of patients have a high gastric pH due to frequent use of H2-blockers, proton pump inhibitors and antacids, as well as to physiological achlorhydria, the decreased absorption of doxycycline monohydrate may well have a clinical impact, for example when the patients are treated with tetracyclines for an infection.
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    The pharmacokinetics and pharmacodynamics of medifoxamine after oral administration in healthy elderly volunteers (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 163-166 
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    ISSN: 1432-1041
    Keywords: Medifoxamine ; pharmacokinetics ; pharmacodynamics ; elderly volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics and psychomotor effects of medifoxamine, a 5 HT reuptake inhibitory antidepressant, were studied in healthy elderly volunteers after single and multiple dosing. The elimination half life (t1/2z) after single doses of 300 mg was 2.8 h — almost identical to that found in young volunteers. After seven days of dosing at 100 mg three times daily the mean corrected AUC after 300 mg significantly increased from 1.04 to 1.34 mg.h.l−1 and t1/2z increased to 4.0 h (NS). There were no significant changes in critical flicker fusion frequency, symbol digit substitution, continuous attention or choice reaction times.
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    Pharmacokinetics and dosage recommendations of teicoplanin in patients treated by continuous veno-venous haemodialysis (CVVHD) (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 179-180 
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    ISSN: 1432-1041
    Keywords: Teicoplanin ; haemodialysis ; renal failure ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00199886
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    Receptor binding assays in analysing the bioavailability and pharmacodynamic bioequivalence of active drug moieties (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 237-242 
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    ISSN: 1432-1041
    Keywords: Metoprolol ; bioavailability ; bioequivalence ; receptor binding assay ; pharmacokinetics ; sustained release formulation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The bioavailability and pharmacodynamic bioequivalence of a conventional and an experimental sustained-release formulation of 100 mg metoprolol tartrate were studied in a randomised cross-over study in seven healthy volunteers by assessing over 24 h the plasma kinetics of R,S-metoprolol, its β1-adrenoceptor binding component, and by determining the extent to which the active drug moiety in plasma occupied rabbit lung β1-and rat reticulocyte β2-adrenoceptors. The formulations differed markedly in their kinetic characteristics: the peak plasma concentration (Cmax) of R,S-metoprolol after administration of the conventional formulation was 140 ng·ml−1, (n=7) and it was approximately one-third of that after the sustained-release formulation, 49 ng·ml−1, (n=6); the AUC0–24 h-values for the formulations were 700 and 310 ng·h·ml−1, respectively. The Cmax for the β1-adrenoceptor binding component of metoprolol was 180 ng·ml−1 (n=7) after administration of the conventional, and 74 ng·ml−1 after administration of the sustained-release formulation. The corresponding AUC0–24 h-values for the receptor binding component were 920 and 470 ng·h·ml−1 (n=7). Thus, the kinetic differences between R,S-metoprolol and the β1-receptor binding component were considerable and they were affected by the type of formulation. In general, after administration of the sustained-release formulation, the percentage β1- and β2-adrenoceptor occupancy of metoprolol in plasma was 5–15% less than after administration of the conventional formulation. At 0.5–1.5 h after drug intake the average β1-adrenoceptor occupancy of the conventional formulation varied between 80–90% and that of the sustained release formulation between 20–76%. At these times the differences in receptor occupancy were significant; at 0.5–2 h after drug intake the average β2-adrenoceptor occupancy of the conventional formulation varied from 20–30%, and that of the sustained-release formulation was 2–17%. At other times the difference in receptor occupancy between the formulations was not significant. The results demonstrate that plasma concentration-kinetics were more discriminating than β-adrenoceptor-binding in analysing bioequivalence. It was possible to determine the bioavailability of the active ingredient of metoprolol and to study pharmacodynamic bioequivalence by using receptor binding assays.
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    Methotrexate in juvenile rheumatoid arthritis (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 507-511 
    Details
    ISSN: 1432-1041
    Keywords: Methotrexate ; Juvenile rheumatoid arthritis ; pharmacokinetics ; age dependence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Children with juvenile rheumatoid arthritis (JRA) have been reported to require higher doses (per kg body weight) of methotrexate (MTX) than adults with rheumatoid arthritis to control their disease. The purpose of the present study was to characterise the plasma pharmacokinetics of MTX and its major metabolite, 7-hydroxymethotrexate (7-OHMTX) in children, and to compare the results with those previously obtained in adults. Thirteen patients (age 5–16 y) with JRA (median disease duration 5.5 y) were studied after once weekly oral administration of MTX (median 0.21 mg·kg−1). The analytical method was sufficiently sensitive to permit determination of plasma and urinary concentrations of MTX and 7-OHMTX during the entire dose interval in most of the patients. The dose normalized area under the plasma concentration versus time-curve (AUC) of MTX increased with the age of the children and was lower than previously found in adults. The dose normalized AUC of 7-OHMTX was not dependent on age. No correlation was found between the AUCs of MTX and 7-OHMTX. The results suggest that the age-dependence of the pharmacokinetics of MTX might explain the observation that at least some children require higher doses of MTX than adults to obtain a sufficient therapeutic effect.
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    Antipyrine disposition in obesity: evidence for negligible effect of obesity on hepatic oxidative metabolism (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 525-530 
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    ISSN: 1432-1041
    Keywords: Antipyrine disposition ; Obesity ; pharmacokinetics ; oxidative metabolism ; weight reduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Following an overnight fast and 2 days of abstention from caffeine, a single 1.0-g oral dose of antipyrine was administered to 20 obese but otherwise healthy subjects (group A) and 11 healthy volunteers (group B). Weight, Body Mass Index (BMI) and % of Ideal Body Weight (IBW) were significantly greater in the obese than in the lean group. (Mean 110.4 vs 62.7 kg; 38.5 vs 22.3 kg · m−2 and 181vs 106 % respectively). In a subgroup of 6 obese subjects (group C) antipyrine was given again 11.3 months later after a 29.8 kg mean weight loss. Antipyrine apparent volume of distribution (V) and elimination half-life (t 1/2) were significantly greater in the obese than in the lean group (V 49.9 vs 34.3 l respectively; t 1/2 15.5 vs 12.0 h respectively), but its clearance rate (CLo) values were similar. V corrected for total body weight was significantly reduced in group A than in group B (0.45 vs 0.55 l · kg−1 respectively). Stratified comparison of antipyrine pharmacokinetics between obese and lean subjects according to age, gender and smoking habits did not alter the overall results. In group C, weight reduction was associated with a significant decrease in antipyrine V (from 51.8 to 47.5 l) and t 1/2 (from 15.1 to 12.7 h), and a non-significant increase in antipyrine CLo. We conclude that in severely obese subjects, antipyrine total V is mildly increased but V corrected for total body weight is significantly decreased. In addition, obesity is associated with a slight prolongation of antipyrine t 1/2 whereas its CLo is unaltered. These findings may indicate that obesity, even in its extreme form, has a negligible effect on the oxidative metabolic capacity of the liver.
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    Oral bioavailability of CHF1194, an inclusion complex of piroxicam and β-cyclodextrin, in healthy subjects under single dose and steady-state conditions (1995)
    Springer
    European journal of clinical pharmacology 47 (1995), S. 531-536 
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    ISSN: 1432-1041
    Keywords: Piroxicam ; β-Cyclodextrin ; pharmacokinetics ; healthy volunteers ; multiple dose ; adverse event
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract CHF1194 is an inclusion complex of β-cyclodextrin with the nonsteroidal anti-inflammatory drug piroxicam. In man, β-cyclodextrin acts as a carrier of piroxicam. As the inclusion complex of piroxicam-β-cyclodextrin is wettable and more water soluble, the absorption rate of the drug is increased whilst its other pharmacokinetic characteristics remain unchanged. The aim of the present study in 12 healthy subjects was to compare the oral bioavailability of 20 mg piroxicam in a CHF1194 tablet and a plain piroxicam capsule after a single dose and after two weeks of once daily administration, and also to assess the plasma levels and urinary excretion of β-cyclodextrin after CHF1194 administration. The two treatments were administered in cross-over fashion, separated by a wash-out period of three weeks. Piroxicam, 5′-hydroxypiroxicam and β-cyclodextrin were monitored in plasma and urine for 120 h after the first and last doses. Clinical tolerance was excellent and no adverse event occurred during either phase of the study. The extent of absorption of piroxicam from the CHF1194 tablet after the single dose was equivalent to that after the plain piroxicam capsule, within confidence limits of less than 80–125%. After repeated dosing, CHF1194 yielded the same steady-state systemic concentrations of piroxicam and 5′-hydroxypiroxicam as the reference capsule, and similar excretion pattern of the metabolite. After both single and multiple dosing, piroxicam was absorbed more rapidly after CHF1194, an expected consequence of the complexation of piroxicam with β-cyclodextrin. This may be of therapeutic interest as it might accelerate the onset of pain relief. The pharmacokinetics of piroxicam was linear after the doses used here, suggesting that long term treatment with CHF1194 should not require any change in dosing regimen. Even after 14 days of repeated administration of CHF1194, β-cyclodextrin could not be detected in plasma or urine, suggesting that in man the unchanged oligosaccharide was absorbed to a very small extent.
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    Changes in clearance create pharmacokinetic pitfalls as illustrated by studies on tiopronin (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 575-575 
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    ISSN: 1432-1041
    Keywords: Renal clearance ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
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    URL: http://dx.doi.org/10.1007/BF00196121
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    Conventional and controlled release diltiazem (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 75-79 
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    ISSN: 1432-1041
    Keywords: Diltiazem ; Angina pectoris ; controlled release formulation ; metoprolol ; bioavailability ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Diltiazem CR tablets 120 mg b.i.d. for 1 week were compared with plain tablets 60 mg q.i.d. in 13 healthy male volunteers in a study of pharmcokinetic variables. Their antianginal efficacy was also compared in 23 patients with stable angina pectoris who were already on metoprolol. Both studies were of randomised, cross over design, and the clinical study was double blind. The pharmacokinetic variables of the two formulations were very similar except for the longer tmax of 4.4 h for diltiazem CR in comparison to 2.9 h for the plain tablets. The mean relative bioavailability of diltiazem CR in comparison with plain tablets was 1.14. The clinical study showed that after four weeks on diltiazem CR 120 mg b.i.d. or diltiazem plain tablets 60 mg q.i.d. in addition to metoprolol, there were significant decreases in weekly anginal attacks from 11 to 5 attacks/week, the number of nitroglycerin tablets consumed from 6 to 3 tablets/week, and an increase in the maximum workload from 116 to 126 and 123 W for diltiazem CR and plain diltiazem tablets, respectively, as compared to placebo. Five of the patients were angina free during diltiazem treatment. No difference in antianginal efficacy between the two preparations was seen. It was concluded that CR 120 mg b.i.d. appears bioequivalent to plain diltiazem tablets 60 mg q.i.d.
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    The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites (1994)
    Springer
    European journal of clinical pharmacology 47 (1994), S. 161-167 
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    ISSN: 1432-1041
    Keywords: Oxcarbazepine ; 10,11-dihydro-10-hydroxy-carbamazepine ; renal impairment ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated. The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CLCR〈10 ml·min−1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects. The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance. The maximum target dose in patients with slight renal impairment (CLCR〉30 ml·min−1) should not be changed. In patients with moderate renal impairment (CLCR10–30 ml·min−1) it should be reduced by 50%. In patients with severe renal impairment (CLCR〈10 ml·min−1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.
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    Furosemide disposition in patients on CAPD (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 385-390 
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    ISSN: 1432-1041
    Keywords: Furosemide ; Dialysis ; continuous ambulatory peritoneal ; drug disposition ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Single doses of oral and intravenous furosemide were given to 8 healthy male volunteers (40 mg) and 11 patients with renal failure maintained on continuous ambulatory peritoneal dialysis (CAPD) (80 mg). In the volunteers, absorption was variable. Only one half of the intravenous dose and one third of the oral dose was available for renal pharmacological action as judged by the urinary recovery. In the patients, absorption was also variable and was markedly delayed (t max 128 vs 90 min) but more complete (bioavailability 70.1 vs 53.6%). The differences between the two groups were not significant, however (95% C.I.: -90 to 30 and -40.4 to 7.5 respectively). The mean elimination half-life was significantly longer in the patients following both the oral (228 vs 65.1 min) and intravenous dose (195 vs 60.3 min). The total body clearance of furosemide in the volunteers was 138 ml·min−1 and this was much lower in the CAPD patients (61.9 ml·min−1) in whom the renal clearance was minimal. The peritoneal clearance of furosemide was negligible. Although there were trends indicating differences in absorption between the two groups, the significant differences in furosemide disposition observed in CAPD patients were due to renal failure.
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    Effects of altitude (4300 M) on the pharmacokinetics of caffeine and cardio-green in humans (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 167-170 
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    ISSN: 1432-1041
    Keywords: Caffeine ; Cardio-green ; Indocyanine Green ; altitude ; metabolism ; pharmacokinetics ; hypoxia
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardiogreen (ICG) were examined in eight healthy males (23–35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg · kg−1) was administered as an intravenous bolus and caffeine (4 mg · kg−1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in the caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g · 1−1 · min−1), and increased clearance (117 vs 86 ml · min−1 · 70 kg−1). In ALT the area under the curve of ICG significantly decreased (85 vs 207 mg · 1−1 · min−1) and the volume of distribution and clearance increased (5.2 vs 2.41 and 532 vs 234 ml · min−1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192744
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  • 94
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    Pharmacokinetics and bioavailability of a sustained-release diltiazem formulation (Mono-Tildiem LP 300 mg) after repeated administration in healthy volunteers (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 259-264 
    Details
    ISSN: 1432-1041
    Keywords: Diltiazem ; sustained-release formulation ; pharmacokinetics ; bioavailability ; bioequivalence
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The usual dosage regimen of diltiazem (Tildiem) is 60 mg 3–4 times a day. A sustained-release formulation has been developed (Mono-Tildiem LP 300 mg) in order to allow a single daily administration. Two repeated dosing studies were performed in healthy volunteers. The absolute bioavailability of sustained-release diltiazem LP 300 mg was investigated using concomitant i.v. administration of 13C-labelled drug: absolute bioavailability of the “once a day” formulation was 35%. The second study compared sustained-release diltiazem LP 300 mg with the standard formulation of diltiazem. The results showed that the diltiazem plasma concentrations obtained after the LP formulation remained stable between 2 and 14 h after administration and were compatible with a once a day administration. Relative bioavailability of sustained-release diltiazem LP 300 mg was 79.3% compared with diltiazem. Therefore, a unitary dose of sustained-release diltiazem LP 300 mg was chosen as the dose equivalent to the daily dose administered with the standard diltiazem formulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198308
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  • 95
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    Disposition of lorazepam in diabetes: differences between patients treated with beef/pork and human insulins (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 253-258 
    Details
    ISSN: 1432-1041
    Keywords: Diabetes ; Human insulin ; Lorazepam ; pharmacokinetics ; glucuronidation ; enterohepatic circulation ; animal insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetics of lorazepam was examined in 10 male patients with insulin-dependent diabetes mellitus before and following treatment with neomycin and cholestyramine. Neomycin and cholestyramine were given in an attempt to block the enterohepatic circulation of lorazepam and so to permit an in vivo estimate of hepatic glucuronidation. The volume of distribution and clearance of free lorazepam in diabetic patients were not significantly different from the corresponding estimates in 14 normal controls. Neomycin and cholestyramine increased the clearance of lorazepam by 63% consistent with their effect in non-diabetic controls. However, patients on beef/pork insulin exhibited a greater than normal increase on this interupting regimen (125%), and had a significantly greater neomycin/cholestyramine cycling-interrupted clearance of lorazepam than either normal controls or patients on human insulin (15.4 vs. 6.96 and 7.87 ml·min−1·kg−1). The clearance was correlated positively and significantly with HbA1c and glycated proteins (fructosamine), but only in patients on human insulin. Thus, the pharmacokinetics of lorazepam was not altered in patients with insulin-dependent diabetes mellitus. However, it is possible that there are differences in the rate and extent of hepatic glucuronidation and enterohepatic circulation of lorazepam between patients treated with beef/pork and human insulins and between diabetics treated with beef/pork insulin and non-diabetic controls.
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    URL: http://dx.doi.org/10.1007/BF00198307
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  • 96
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    Pharmacokinetics of 5-aminosalicylic acid from controlled-release capsules in man (1995)
    Springer
    European journal of clinical pharmacology 48 (1995), S. 273-277 
    Details
    ISSN: 1432-1041
    Keywords: Mesalamine ; 5-aminosalicylic acid ; controlled release capsules ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract One gram single dose of Pentasa controlled-release capsules was administered to 24 healthy volunteers under fasting condition. Mean plasma 5-aminosalicylic acid (5-ASA) and acetyl 5-ASA concentrations peaked at 0.53 μg · ml−1 and 1.33 μg · ml−1 from 3 to 4 hours following dosing, respectively. The half-lives of both compounds could not be determined as absorption of 5-ASA was continuous throughout the gastrointestinal tract. An average of 29.4% (CV: 27%) of the dose was excreted in the urine primarily as acetyl 5-ASA. Up to 91.1% of the dose was released from the capsules. Forty percent of the dose (CV: 40%) was eliminated in the feces, with 8.9% of the dose remained as formulation bounded 5-ASA, indicating that controlled-release capsules continue to release drug throughout the GI tract. 5-ASA contributed 46.7% of the salicylates eliminated in the feces and acetyl 5-ASA accounted for the balance. Controlled-release capsules produced three times more total salicylates and 10 times more total and free 5-ASA in the feces than did 5-ASA suspension. Thus, while lower systemic levels of salicylates were absorbed, greater therapeutic quantities of 5-ASA were available in the bowel.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00198311
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  • 97
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    Pharmacokinetics of thiopental after single and multiple intravenous doses in critical care patients (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 127-137 
    Details
    ISSN: 1432-1041
    Keywords: Thiopental ; Pharmacokinetic modelling ; pharmacokinetics ; single dose ; multiple dosing ; neurosurgical patients ; variability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Thiopental was administered to neurosurgical patients for cerebral protection and its pharmacokinetic parameters were determined after a single bolus of 540, 1000 or 1500 mg (3 subjects) or after multiple doses of 250 mg (5 subjects) and 500 mg (2 subjects) every two hours for up to 7 days. The data were analysed by a two- or three- compartment model and linear kinetics. After a single IV bolus, the mean initial volume of distribution (V1) was 0.4811·kg−1, and the steady-state volume of distribution (Vss) was 2.16 1·kg−1. The distribution (t1/2α) and elimination (t1/2β) half-lives were 0.590 and 5.89 h, respectively, and the mean residence time (MRT) was 7.44 h. The clearance was 5.41 ml·min−1·kg−1. With repeated injections, the pharmacokinetic parameters for each patient were estimated taking into account all administered doses and blood samples, which were taken whenever possible daily at steady state and after the last dose. The variability observed in the pharmacokinetic parameters of thiopental reflected by the coefficient of variation (CV%) was wide but was of similar magnitude within patients (CVintra) as it was between patients (CVinter). The steady-state trough plasma concentration (Cmin obs) ranged from 4.8 to 30 mg·1−1 (mean 16.0 mg·1−1 and median 14.3 mg·1−1). Peak concentrations (Cmax obs) ranged from 8.35 to 45 mg·1−1 (25.4 mg·1−1, and median 23.3 mg·1−1). The values of V1 and Vss were similar to those obtained after a single dose. For V1, the mean was 0.333 1·kg−1. The mean Vss was 2.68 1·kg−1, with a CVintra of 12.6 to 56% and a CVinter of 13.2%. A shorter distribution half-life t1/2α was noted on multiple dosing; the mean value was 0.122 h. The elimination half-life t1/2β and the mean residence time became longer due to a decrease in clearance. For t1/2β the mean value was 16.3 h. The mean MRT was 21.9 h, CVintra 9.19 to 48.5%, and the CVinter 35.3%. The mean clearance was 2.16 ml·min−1·kg−1, CVintra 7.28 to 25.5%, and the CVinter 20.4%. This value is 50% lower than after a single dose. Identification of the kinetic parameters of thiopental allows simulation of the effects of doses on subsequent plasma levels and will permit a priori prediction of day to day adjustment of drug dosage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00192371
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  • 98
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    Limitations of the maximum entropy principle in devising drug input rate (1995)
    Springer
    European journal of clinical pharmacology 49 (1995), S. 139-143 
    Details
    ISSN: 1432-1041
    Keywords: Intestinal absorption ; Amoxicillin ; pharmacokinetics ; maximum entropy ; input rate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract A computer program applying the principle of maximum entropy to the analysis of drug absorption rate has been developed. Plasma concentrations of amoxicillin obtained after oral and intravenous dosing have been analysed, together with simulated data corresponding to a complex input. Amoxicillin absorption rates devised by the program were similar to those obtained by a standard deconvolution method, although they were displayed as an almost continuous profile. However, improbable fluctuations were obtained with some data sets and the fraction absorbed was underestimated by 13%. With the simulated data, the maximum entropy program did not provide a better solution than the standard deconvolution procedure, and it was sensitive to the addition of random error and to the number of samples. The maximum entropy principle, as implemented in our computer program, may not have a better performance than standard deconvolution procedures, especially in human experiments where the number of blood samples is usually limited.
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    URL: http://dx.doi.org/10.1007/BF00192372
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  • 99
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    Design of a suitable formulation of FK613, a novel antiallergic agent, based on its pharmacokinetic and pharmacodynamic properties in healthy subjects (1996)
    Springer
    European journal of clinical pharmacology 49 (1996), S. 279-284 
    Details
    ISSN: 1432-1041
    Keywords: Antiallergic drug ; FK613 ; pharmacokinetics ; histamine skin-test ; drug formulation ; urinary excretion ; safety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract The pharmacokinetic and pharmacodynamic properties of FK613, a novel indolyl piperidine derivative, were investigated after oral administrations of 5, 10 and 20 mg in hard gelatin capsules to healthy male volunteers. FK613 was rapidly and almost completely absorbed, and 〉89% was recovered in the urine as the unchanged form. The urinary excretion of FK613 was linearly correlated with plasma concentration and its low water solubility was the main concern regarding the safety. In another experiment using a double-blind crossover design, in which 0 (placebo), 5 and 20 mg FK613 were administered to determine the plasma concentration-effect relationship, suppression of the intradermal histamine-induced skin reaction by FK613 was observed. Thus, the maintenance of a plasma concentration of FK613 in the range of 80–250 ng · ml-1 was recommended to ensure the suppression of histamine-induced wheal by 〉50% and not to exceed the solubility in urine. To achieve this, a new hydrogel-type formulation of FK613 was developed, with the aim both of delaying its absorption, so as to suppress the sharp rise in plasma concentration, and of maintaining the effective concentration for a longer period of time. This formulation was administered after meals at the doses of 20, 30, 40, 50 and 60 mg, and at repeated doses of 40 mg twice daily for 6.5 days to evaluate the pharmacokinetics and safety in healthy subjects. The area under the plasma concentration curve increased linearly with dose, whereas maximum plasma concentration (Cmax) tended to peak as dose increased, indicating the desirable properties of this formulation. Although Cmax exceeded 250 ng/ml at doses of 30 mg or more, no urinary crystal formation was observed on careful inspection of urine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00226328
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  • 100
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    Pharmacological effects and serum levels of orally administered alprenolol in man (1972)
    Springer
    European journal of clinical pharmacology 5 (1972), S. 44-52 
    Details
    ISSN: 1432-1041
    Keywords: alprenolol ; serum drug level ; exercise ; man ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The effects of alprenolol on heart rate and systolic blood pressure were studied in healthy subjects during standardized exercise on a bicycle ergometer. In one series of experiments, in which serum concentrations of alprenolol were also measured, the effects of single oral doses of 50, 100 and 200 mg of alprenolol and a placebo were compared by a double blind cross-over technique. In a second series of experiments 100 mg alprenolol was given four times in one day and the effect was followed for up to eighteen hours after the last dose. — Alprenolol diminished the expected increase in heart rate and systolic blood pressure during exercise. The reduction of exercise tachycardia in a given individual was linearly related to the logarithm of the dose or the serum concentration of alprenolol. The serum concentrations required for a given reduction of exercise tachycardia varied almost one hundred-fold amongst the subjects studied. The biological availability of alprenolol was dose-dependent, probably due to a limited capacity biotransformation of the drug before it entered the general circulation. After a single dose the serum level of alprenolol and its chronotropic effect diminished at a rate corresponding to an elimination half life of about two hours. This rate of elimination was consistent with that calculated from the results of the four dose study.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00560895
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