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  • 1
    Electronic Resource
    Electronic Resource
    A New Route of Drug Administration: Intrauterine Delivery of Insulin and Calcitonin (1993)
    Springer
    Pharmaceutical research 10 (1993), S. 828-833 
    Details
    ISSN: 1573-904X
    Keywords: drug administration ; drug delivery ; absorption ; controlled release ; drug implants ; peptides ; intrauterine ; calcitonin ; insulin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract High molecular weight drugs in general, and peptides in particular, are usually delivered by parenteral route because they are poorly absorbed or degraded in the gastrointestinal tract. To optimize therapy, it is desirable to search for nonparenteral routes of administration and to deliver the drug in a controlled-release fashion. We report here on the absorption and the systemic biological effect of two peptides, insulin and calcitonin, after instillation into the uterus of the rat. Intrauterine delivery was compared to subcutaneous injections in intact and ovariectomized rats. In addition, we describe results of a preliminary study on calcitonin absorption from controlled-release matrices inserted in the rat uterus. The amount and duration of the hypoglycemic and the hypocalcemic effects induced by intrauterine delivery of insulin and calcitonin, respectively, were equivalent to those obtained after subcutaneous injections. The results were similar in intact and ovariectomized rats. It is concluded that the intrauterine administration of both insulin and calcitonin is bioequivalent to subcutaneous injection. The therapy of a number of clinically important diseases could benefit from this discovery.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018948924992
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  • 2
    Electronic Resource
    Electronic Resource
    Improved Lipid Lowering Activity of Bezafibrate Following Continuous Gastrointestinal Administration: Pharmacodynamic Rationale for Sustained Release Preparation of the Drug (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1093-1097 
    Details
    ISSN: 1573-904X
    Keywords: bezafibrate ; hyperlipidemia ; pharmacodynamics ; pharmacokinetics ; sustained release
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To evaluate the role of different routes and modes of administration of bezafibrate (BZF) on its hypolipidemic activity. We hypothesize that the major sites of BZF action are located presystemically as in other 'gastrointestinal (GI) drugs.' Thus, continuous administration of the drug to the GI tract is expected to augment its efficacy and provides a rationale for an oral sustained release preparation of the drug. Methods. The hypothesis was investigated in three experimentally induced-hyperlipidemia rat models. Models A and B were based on cholesterol-enriched diets and Model C on induced acute hyperlipidemia by triton 225 mg/kg. The pharmacokinetics and the pharmacodynamics of the drug following various modes of administration were examined. Results. In all cases, continuous administration of the drug into the duodenum (IGI) at a dose of 30 mg/kg/day for 3 days (Models A and B) or over 18 hr (Model C) reduced significantly both total cholesterol and triglycerides levels and elevated HDL cholesterol levels in comparison to bolus oral administration of the same dose, as well as in comparison to equivalent intravenous infusion (Model C). Infusion of the drug directly into the portal vein produced an equivalent activity to IGI administration. The pharmacokinetic study showed 100% oral bioavailability, good colonic absorption properties and an indication for an enterohepatic cycle. Conclusions. The results confirm that BZF has a first pass hepatic pharmacodynamic effect. Administration of BZF in a slow release matrix tablet to the rats produced the same magnitude of effect as IGI administration, thus proving the pharmacodynamic rationale for this mode of administration for GI drugs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018900219616
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  • 3
    Electronic Resource
    Electronic Resource
    Pharmacodynamics of Phenobarbital Anesthesia and Pentylenetetrazol-Induced Maximal Seizures in a Rat Model of Neoplastic Spinal Cord Compression (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 536-540 
    Details
    ISSN: 1573-904X
    Keywords: pharmacodynamics ; anesthesia ; seizures ; phenobarbital ; pentylenetetrazol ; spinal cord compression ; paraplegia ; tumor ; concentration–effect relationship
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The purpose of this investigation was to determine whether paraplegia induced by neoplastic cord compression affects the pharmacodynamics of phenobarbital general anesthesia or of pentylenetet-razol (PTZ)-induced convulsions. Paraplegic rats harboring a thora-columbar epidural tumor, or an identical hindlimb tumor mass, received an i.v. infusion of phenobarbital until the onset of anesthesia. At that point, the phenobarbital concentrations in the CSF and serum were measured. Similarly, PTZ was infused until the onset of maximal seizures. It was found that changes related to systemic tumor growth and newly developed paraplegia due to neoplastic spinal cord compression did not attenuate the pharmacodynamics of phenobarbital. However, sustained paraplegia of 4 days’ duration reduced CNS sensitivity to the hypnotic action of the barbiturate as evidenced by the higher cerebrospinal fluid phenobarbital concentration required to induce anesthesia (170 ± 31 vs 125 ± 20 mg/L; P 〈 0.05). On the other hand, sustained paraplegia did not affect brain threshold concentration for PTZ-induced seizures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018914532125
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  • 4
    Electronic Resource
    Electronic Resource
    Synthesis and Preclinical Pharmacology of 2-(2-Aminopyrimidinio) Ethylidene-1,1-Bisphosphonic Acid Betaine (ISA-13-1)-A Novel Bisphosphonate (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1399-1406 
    Details
    ISSN: 1573-904X
    Keywords: bisphosphonates (diphosphonates) ; calcium-related disorders ; bone-related disorders ; drug administration ; drug absorption tight junctions ; mannitol
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To validate our hypothesis that a bisphosphonate (BP) having a nitrogen-containing heterocyclic ring on the side chain, and with no hydroxyl on the geminal carbon would possess increased activity, and better oral bioavailability due to enhanced solubility of its calcium complexes/salts and weaker Ca chelating properties. Methods. A novel BP, 2-(2-aminopyrimidinio)ethylidene-l,l-bisphosphonic acid betaine (ISA-13-1) was synthesized. The physicochemical properties and permeability were studied in vitro. The effects on macrophages, bone resorption (young growing rat model), and tumor-induced osteolysis (Walker carcinosarcoma) were studied in comparison to clinically used BPs. Results. The solubility of the Ca salt of ISA-13-1 was higher, and the log βCa: BP stability constant and the affinity to hydroxyapatite were lower than those of alendronate and pamidronate. ISA-13-1 exhibited effects similar to those of alendronate on bone volume, on bone osteolysis, and on macrophages, following delivery by liposomes. ISA-13-1 was shown to have 1.5−1.7 times better oral absorption than the other BPs with no deleterious effects on the tight junctions of intestinal tissue. Conclusions. The similar potency to clinically used BPs, the increased oral absorption as well as the lack of effect on tissue tight junction of ISA-13-1 warrant its further consideration as a potential drug for bone diseases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018951025493
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  • 5
    Electronic Resource
    Electronic Resource
    The Effect of Immunosuppression by Total-Body Irradiation on the Pharmacodynamics of Centrally Active Drugs in Rats (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 704-708 
    Details
    ISSN: 1573-904X
    Keywords: total-body irradiation ; immunosuppression ; anesthesia ; phenobarbital ; ethanol ; induced seizures ; theophylline ; pentylenetetrazol ; pharmacodynamics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The aim of this investigation was to assess whether immunosuppression induced by total-body irradiation (TBI) affects the pharmacodynamics of centrally acting drugs. Female Sabra rats were exposed to a single dose of gamma irradiation (5.3 Gy). Four days later, when both the cellular and the humoral immune responses were impaired, they received an i.v. infusion of either phenobarbital (0.8 mg/min), ethanol (16.3 mg/min), pentylenetetrazol (PTZ; 0.618 mg/min), or theophylline (as aminophylline; 2 mg/min). The infusion was stopped at the onset of the pharmacologic end point—loss of righting reflex for the depressant agents or maximal seizures for the stimulant drugs—and the concentrations of the neuroactive drugs at that point were determined. In the ethanol experiment, blood samples were also taken upon awakening. The radiation-induced immunosuppression significantly decreased the CNS sensitivity to the depressant action of both phenobarbital and ethanol as indicated by the higher CSF phenobarbital concentrations required to induce sleep in the irradiated rats versus controls (156±4 vs 133 ±5 mg/L, respectively; P 〈 0.05), and the higher serum ethanol concentrations at the onset and offset of sleep in the immunosuppressed group versus control values (4.6±0.2 and 1.68±0.01 vs 3.79±0.17 and 1.32±0.9 mg/mL, respectively; P 〈 0.04). Exposure to TBI did not alter the pharmacodynamics of the two convulsant drugs (theophylline andPTZ).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018928329824
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  • 6
    Electronic Resource
    Electronic Resource
    The relationship between receptor-effector unit heterogeneity and the shape of the concentration-effect profile: Pharmacodynamic implications (1994)
    Springer
    Journal of pharmacokinetics and pharmacodynamics 22 (1994), S. 449-468 
    Details
    ISSN: 1573-8744
    Keywords: concentration-effect ; heterogeneity ; pharmacodynamics ; receptor ; E max model ; dose response ; shape factor ; effector unit ; Hill coefficient ; sigmoidalE max model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The apparent concentration-effect relationship is the ensemble of many effector units (such as individual cells or channels) that do not always exhibit a uniform stimulus-effect relationship. This concept is substantiated by many observations of heterogeneity in receptor-effector populations including hormone secreting cells, response to hormonal stimuli, activity pattern of second messengers, stimulus-evoked synaptic currents, and single ion channels. The relationship between drug concentration and magnitude of pharmacologic response is commonly described by the sigmoidalE max model which was derived from the Hill equation. The sigmoidicity factor (N) in this model is assumed to be a pure mathematical parameter without physiological connotations. This work demonstrates that the numerical value ofN (measured empirically) is the product of two factors: (i) the degree of heterogeneity of the effector subunits, i.e., the elemental component that upon drug stimulus contributes its pharmacological effect independently and does not interact with other subunits (it could range from a single receptor up to a whole tissue), and (ii) value ofN *—the shape factor of the subunits' concentration-effect relationship. A special case of this approach occurs whenN *〉5, which is an on-off case. HereN is determined by the distribution (density equation) of the subunit values. In case of heterogeneity of the microparameters of the effector subunits the apparentN will always have a lower value thanN *. According to this theory it can be concluded that without knowledge of the distribution of the microparameters no mechanistic interpretation can be deduced from the apparentN value. If in the futureN * can be determined by theoretical or experimental methods, the distribution function relatingN * toN can be calculated. The relevance of this theory is increased in view of the progress being made in advanced research techniques which may enable us to determine the concentration-effect relationship at the level of the individual effector unit.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02353789
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  • 7
    Electronic Resource
    Electronic Resource
    Relation Between Individual and Ensemble Release Kinetics of Indomethacin from Microspheres (1988)
    Springer
    Pharmaceutical research 5 (1988), S. 178-182 
    Details
    ISSN: 1573-904X
    Keywords: microspheres ; indomethacin ; cumulative release profile ; release, single microsphere ; controlled release, first-order kinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Indomethacin microspheres based on a combination of ethylcellulose and polyethyleneglycol were prepared using the solvent evaporation process. Release profiles of ensemble and individual microspheres were measured. Both were found to follow first-order kinetics, in contrast to what was expected. This was attributed to the fact that all the particles showed the same kinetic pattern and had a greater degree of homogeneity in the payload, mean particle size and shape, and k l values than in ensembles of microcapsules.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015917023949
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  • 8
    Electronic Resource
    Electronic Resource
    Measurement of Serum [3H]Tetracycline Kinetics and Indices of Kidney Function Facilitate Study of the Activity and Toxic Effects of Bisphosphonates in Bone Resorption (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1018-1023 
    Details
    ISSN: 1573-904X
    Keywords: bisphosphonates (diphosphonates) ; bisacylphosphonates ; bone resorption ; tetracycline ; mineralization ; nephrotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The [3H]tetracycline ([3H]TC) model is based on the observation that TC is released from the bones of rats prelabeled with [3H]TC via first-order kinetics, a factor directly reflecting the kinetics of bone resorption. In the present paper we applied the [3H]TC elimination model to rats treated with antiresorptive drugs. The validity of this model was evaluated by examining the effect of the bisphosphonate, 3-amino-1-hydroxypropylidene-1,1-bisphosphonate (ABP), and a novel bisphosphonate, dihydrogen disodium adipoylbisphosphonate (AdBP), on serum TC levels and the elimination rate constant. ABP and AdBP significantly inhibited the TC elimination rate. However, ABP treatment caused impairment of bone mineralization, renal dysfunction, and inhibition of somatic growth. It is concluded that antiresorptive effects of bisphosphonates could be evaluated by the [3H]TC model, but this model is limited to animals with normal kidney function. The experimental conditions provide a technically simple method which is sensitive enough to examine antiresorptive properties in a healthy animal and to detect adverse effects on the kidney. The activity of the novel bisacylphosphonate, AdBP, and lack of its adverse effects indicate the potential of this drug for clinical applications.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015898226519
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  • 9
    Electronic Resource
    Electronic Resource
    Kinetics of Drug Action in Disease States. XXXIX. Effect of Orally Administered Activated Charcoal on the Hypnotic Activity of Phenobarbital and the Neurotoxicity of Theophylline Administered Intravenously to Rats with Renal Failure (1990)
    Springer
    Pharmaceutical research 7 (1990), S. 242-246 
    Details
    ISSN: 1573-904X
    Keywords: phenobarbital ; theophylline ; renal failure ; activated charcoal ; pain sensitivity ; convulsions ; loss of righting reflex
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The central nervous system (CNS) sensitivity to the hypnotic (general anesthetic) action of pheno-barbital and to the neurotoxic (convulsive) action of theophylline is greater in rats with acute renal failure than in normal animals, consistent with clinical observations. In the case of phenobarbital, this increased sensitivity can be produced in normal rats by infusion of a solution of the lyophilized dialysate of serum from rats with renal failure. It was hypothesized that the relevant constituent(s) of this dialysate may circulate between the blood and the intestinal lumen and that it (they) can be adsorbed by orally administered activated charcoal and thereby removed from the body. If so, treatment of renal failure rats with activated charcoal should partly reverse the increased CNS sensitivity to phenobarbital and to other drugs similarly affected. Accordingly, rats with renal failure produced by bilateral ligation of ureters were given an aqueous suspension of activated charcoal, about 1 g per kg body weight, orally every 8 hr for six doses. Uremic controls received equal volumes of water. About 2 hr after the last dose, the animals were infused i.v. with phenobarbital to onset of loss of righting reflex or with theophylline to onset of maximal seizures. In the phenobarbital study, charcoal treatment partly reversed the hypothermia associated with renal failure and caused a reduction of creatinine and total bilirubin concentrations in serum. The cerebrospinal fluid (CSF) concentration of phenobarbital at onset of loss of the righting reflex was significantly higher in charcoal treated rats than in their controls. In the theophylline experiment, charcoal treatment had no significant effect on the measured biochemical variables but caused a large increase in the dose and concentrations of theophylline required to produce maximal seizures. In both experiments, administration of activated charcoal caused a reversal of the hyperalgesia associated with renal failure, as determined before drug administration by tail flick latency. These results are consistent with the hypothesis that oral administration of activated charcoal can cause a reduction in the concentration of the circulating endogenous substance(s) that alters the pharmacodynamics of certain drugs in renal failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015865810667
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  • 10
    Electronic Resource
    Electronic Resource
    High-Dose Methotrexate Does Not Affect the Pharmacodynamics of Phenobarbital Hypnotic Action but Decreases the Central Nervous System (CNS) Sensitivity to Pentylenetetrazol-Induced Maximal Seizures in Rats (1992)
    Springer
    Pharmaceutical research 9 (1992), S. 1295-1298 
    Details
    ISSN: 1573-904X
    Keywords: pharmacodynamics ; high-dose methotrexate ; neurotoxicity ; pentylenetetrazol ; phenobarbital ; induced seizures ; brain ; brain glucose metabolism ; drug interaction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Chemotherapy with high-dose methotrexate (HD-MTX) is often associated with acute neurotoxicity. We determined whether the altered neuronal function after HD-MTX [such as the reduced regional cerebral metabolic glucose rate (rCMRGlc) and slow electroencephalographic pattern] affects the sensitivity of the CNS to centrally acting drugs: the depressant phenobarbital, which reduces rCMRGlc, and the analeptic agent pentylenetetrazol (PTZ), which elevates rCMRGlc. Adult male Sabra rats received an i.v. infusion of MTX, 0.51 mg/min, to induce neurotoxicity or saline solution for 24 hr. Subsequently, MTX-treated and control groups were infused in one experiment with phenobarbital until loss of the righting reflex and in the second experiment with PTZ until the onset of maximal seizures. HD-MTX did not affect the infused hypnotic dose or serum, brain, and cerebrospinal fluid concentrations of phenobarbital at the onset of anesthesia. The convulsive dose and PTZ concentrations in the serum and brain at the onset of maximal seizures were significantly higher in the HD-MTX-treated animals. These outcomes indicate that HD-MTX and the reduced rCMRGlc that follows this treatment do not contribute to the hypnotic action of phenobarbital. On the other hand, treatment with HD-MTX exhibited anticonvulsant properties as evidenced by the reduced CNS sensitivity to PTZ-induced seizures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015857301445
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