ALBERT

Notizen: Summary The systemic availability of a new antidepressant, zimelidine, and of its pharmacologically active metabolite, norzimelidine, was studied in six healthy male volunteers. Three single doses of zimelidine (25 mg and 100 mg orally and 25 mg i.v.) and two single doses of norzimelidine (25 mg orally and i. v.) were given to each volunteer allowing at least seven days between administrations. Plasma concentrations of zimelidine and norzimelidine were determined in serial blood samples by HPLC. Following oral zimelidine peak plasma concentrations of the metabolite were attained about 3 h after dosing. Oral administration of norzimelidine itself resulted in a plasma concentration profile for this compound that was similar to that observed after oral zimelidine. Utilising the plasma concentration data following intravenous infusion of each compound, the elimination half-lives for zimelidine and norzimelidine were calculated to be 5.1 h (range 4.3–6.0) and 15.5 h (range 10.6–22.9) respectively. The total body clearances of the 2 compounds were similar at 0.52 l · min−1 (range 0.26–0.70) for zimelidine and 0.56 l · min−1 (range 0.28–0.83) for norzimelidine. The substantially longer elimination half-life of norzimelidine was apparently the result of a larger volume of distribution (9.4 l · kg−1; range 7.8–11.4) for this metabolite, as compared to zimelidine (3.21 · kg−1; range 1.6–4.9). The calculated bioavailability of zimelidine was 26% (range 9.1–39) after the 25 mg oral dose, and 29% (range 14–46) after the 100 mg dose. The bioavailability of norzimelidine was 66% (range 36–91). However, oral administration of zimelidine resulted in as much or more norzimelidine reaching the systemic circulation, as the oral administration of norzimelidine itself. This is important as a large part of the activity of the drug may be due to the metabolite.

Notizen: Summary We compared our ability to predict the dose of medigoxin and of digoxin required to achieve a fixed serum concentration (the dose requirement) in 33 outpatients. Preliminary work supported the assumptions that the steady state glycoside concentration achieved was proportional to the daily dose given to an individual, and that the bioavailability of the different tablet presentations was similar for either glycoside. We were not able to predict the dose requirement from patient characteristics with any more certainty for medigoxin than for digoxin. Not only the between-patient variability in dose requirement, but also the within-patient variability, was similar for the two glycosides. However the digoxin used had a dissolution rate of over 90% in 1 h. When comparing medigoxin with digoxin of lower, or more variable dissolution rate, medigoxin may be preferable.

Notizen: Summary Procainamide was given to 20 patients with normal renal function as an i.v. bolus of 500 mg followed by 1.0 or 1.5 g eight-hourly by mouth in the form of a slow release preparation (Durules). 97.6±27.1 (SD)% of the oral procainamide was absorbed, the absorption half life being 1.54 h. The elimination half life following the oral formulation was 6.0±0.8 h, compared to a mean of 3.4±0.4 h following i.v. administration. Elimination half life following i.v. administration was slightly related to acetylator status, being 2.75±0.9 h in fast acetylators, and 4.4±2.4 h in slow acetylators. This dependence on acetylator status was not seen in half life following oral administration. Total body clearance, steady state plasma procainamide and N-acetylprocainamide were not significantly dependent on acetylator status, although a few patients who are slow acetylators had unexpectedly low clearance and high steady state procainamide concentrations when given the higher dose.

Notizen: Summary The absolute oral bioavailability of a sustained release theophylline tablet (Nuelin-SR250), given 12 hourly was determined in 14 asthmatic children aged 5 to 13 years. In 4 of the patients, mean bioavailability of the fourth dose was 38.9±8.4% and that of the sixth dose was 67.9±25.9% (p〈0.05) in the other ten patients. This suggests steady-state had not been achieved after four doses. In the initial study with 9 patients, a significant diurnal variation in predose plasma theophylline concentrations was observed, as the mean morning predose concentrations were 2.9 fold greater than the mean evening predose concentrations (p〈0.005). Dual peak plasma concentrations occurred in 5 out of the 9 patients. The mechanism of this diurnal variation was investigated in a further 5 asthmatic children (10.8 years ±1.6). Morning and night steady-state plasma theophylline concentrations during a continuous intravenous infusion of aminophylline were not different (14.9±5.3 mg/l vs. 15.6±5.9 mg/l), demonstrating that there was no diurnal variation in the plasma clearance of theophylline. The diurnal variation in predose concentrations with Neulin-SR250 was confirmed with the morning concentrations again being 2.6 fold greater than those in the evening. However, bioavailability was not significantly different for day (09.00–21.00) and night (21.00–09.00) dosing intervals after doses 6 and 7 respectively of Nuelin-SR250. The plasma concentration versus time profiles suggested that the diurnal variation in predose concentrations was due to slower absorption of the evening dose.

Notizen: Abstract Seasonal and regional variations in the speciation, sediment-water partitioning, and dynamics of mercury (Hg) were studied at selected sites along the Hg-polluted Wabigoon River, and at unpolluted headwater and tributary sites, during April–September, 1979. ‘Dissolved’ and ‘particulate’ forms of Hg in the water were separated by continuous-flow centrifugation in the field. The Hg and other pollutants such as wood chips and salt had been discharged from a chlor-alkali plant and paper mill at Dryden, Ontario. Concentrations and loadings of particulate methyl mercury (CH3Hg+) and total particulate Hg (and loadings of total ‘dissolved’ Hg) were greatest during the spring flood (April-May) owing to accelerated resuspension and transport of sediments. Concentrations of ‘dissolved’ CH3Hg+, however, were highest in the summer (July–September), probably reflecting stimulation of microbial methylating activity by elevated temperatures, together with factors such as reduced levels of metal-scavenging particulates and minimal dilution by runoff. Total dissolved Hg concentrations were relatively high in September at polluted sites only, possibly because of desorption from sediments due to elevated concentrations of Cl− ions. Loadings of dissolved CH3Hg+ tended to be high in the summer but were generally depressed (suggesting sorption by suspended particles) during the major spring-flood episode in May. During July–August dissolved CH3Hg+ was a function of total dissolved Hg, suggesting rapid biomethylation of desorbed inorganic Hg; but in general dissolved and suspended CH3Hg+ levels depended on environmental variables and were unrelated to total Hg concentrations. In the summer only, total dissolved Hg was a function of dissolved Cl−. Hg species in particulates were associated with sulfides, hydrated Fe and Mn oxides, organic matter (notably high molecular weight humic and humic-Fe components), and selenium (Se); but CH3Hg+ and total Hg differed in their specific preferences for binding agents, implying that binding sites discriminate between CH3Hg+ and Hg2+ ions. CH3Hg+ was associated with sulfide and (in the spring only) with Fe oxides, whereas total Hg was associated with organic matter and Se and with DTPA- and NaOH-extractable Fe in the spring but with Mn oxide and NaOH-extractable organics in the summer. Sulfides were most abundant in May, indicating that they were eroded from bottom sediments, but Fe and Mn oxides were most abundant in the summer, probably owing to activities of filamentous iron bacteria and other micro-organisms. Particulate Hg was 98–100% nonextractable by mild solvents such as Ca acetate, CaCl2, dilute acetic acid, and (at polluted sites only) DTPA solutions, suggesting that the particulate Hg mobilized in the spring may not be readily available to organisms; association with Se and high molecular weight humic matter also supports this hypothesis. Hg probably becomes more bio-available in the summer, as suggested by the upsurge in dissolved CH3Hg+ and total dissolved Hg levels, and by increases in the solubility of particulate Hg in acetic acid, DTPA, H2O2, and NaOH solutions, as well as an increase in the relative importance of lower molecular weight fractions of NaOH-extractable Hg (in September). Regional variations in Hg speciation and partitioning reflected a gradient in sediment composition from wood chips near Dryden to silt-clay mud further downstream. Hg in silt-clay mud relatively far (〉 35 km) downstream from the source of pollution or in unpolluted areas appeared to be more readily solubilized by Cl− ions or chelators such as DTPA, more readily methylated (as indicated by downstream increases in dissolved CH3Hg+ levels and CH3Hg+/total Hg ratios), and was to a greater degree organically bound (H2O2-extractable), and thus was probably more bio-available, than Hg in wood-chip deposits. Possible explanations include weaker binding of Hg by the mud, the more finely divided state of the mud, and improved microbial growth at lower concentrations of toxic pollutants. Owing to enrichment in sulfides and Fe oxides, resuspended wood-chip sediments were especially efficient scavengers of CH3Hg+. The results indicate that in any pollution abatement plan aimed at lowering the Hg levels in the biota of lakes fed by the Wabigoon River, immobilization, removal, or detoxification of dissolved as well as particulate forms of Hg in the river would probably have to be considered. Possibly, Hg species could be ‘scrubbed’ from the river water by increasing the suspended load and by sedimentation and treatment with Hg-binding agents in special receiving basins.

Notizen: Abstract Seasonal and regional variations in the speciation, sediment-water partitioning, and dynamics of mercury (Hg) were studied at selected sites along the Hg-polluted Wabigoon River, and at unpolluted headwater and tributary sites, during April–September, 1979. ‘Dissolved’ and ‘particulate’ forms of Hg in the water were separated by continuous-flow centrifugation in the field. The Hg and other pollutants such as wood chips and salt had been discharged from a chlor-alkali plant and paper mill at Dryden, Ontario. Concentrations and loadings of particulate methyl mercury (CH3Hg+) and total particulate Hg (and loadings of total ‘dissolved’ Hg) were greatest during the spring flood (April-May) owing to accelerated resuspension and transport of sediments. Concentrations of ‘dissolved’ CH3Hg+, however, were highest in the summer (July–September), probably reflecting stimulation of microbial methylating activity by elevated temperatures, together with factors such as reduced levels of metal-scavenging particulates and minimal dilution by runoff. Total dissolved Hg concentrations were relatively high in September at polluted sites only, possibly because of desorption from sediments due to elevated concentrations of Cl− ions. Loadings of dissolved CH3Hg+ tended to be high in the summer but were generally depressed (suggesting sorption by suspended particles) during the major spring-flood episode in May. During July–August dissolved CH3Hg+ was a function of total dissolved Hg, suggesting rapid biomethylation of desorbed inorganic Hg; but in general dissolved and suspended CH3Hg+ levels depended on environmental variables and were unrelated to total Hg concentrations. In the summer only, total dissolved Hg was a function of dissolved Cl−. Hg species in particulates were associated with sulfides, hydrated Fe and Mn oxides, organic matter (notably high molecular weight humic and humic-Fe components), and selenium (Se); but CH3Hg+ and total Hg differed in their specific preferences for binding agents, implying that binding sites discriminate between CH3Hg+ and Hg2+ ions. CH3Hg+ was associated with sulfide and (in the spring only) with Fe oxides, whereas total Hg was associated with organic matter and Se and with DTPA- and NaOH-extractable Fe in the spring but with Mn oxide and NaOH-extractable organics in the summer. Sulfides were most abundant in May, indicating that they were eroded from bottom sediments, but Fe and Mn oxides were most abundant in the summer, probably owing to activities of filamentous iron bacteria and other micro-organisms. Particulate Hg was 98–100% nonextractable by mild solvents such as Ca acetate, CaCl2, dilute acetic acid, and (at polluted sites only) DTPA solutions, suggesting that the particulate Hg mobilized in the spring may not be readily available to organisms; association with Se and high molecular weight humic matter also supports this hypothesis. Hg probably becomes more bio-available in the summer, as suggested by the upsurge in dissolved CH3Hg+ and total dissolved Hg levels, and by increases in the solubility of particulate Hg in acetic acid, DTPA, H2O2, and NaOH solutions, as well as an increase in the relative importance of lower molecular weight fractions of NaOH-extractable Hg (in September). Regional variations in Hg speciation and partitioning reflected a gradient in sediment composition from wood chips near Dryden to silt-clay mud further downstream. Hg in silt-clay mud relatively far (〉 35 km) downstream from the source of pollution or in unpolluted areas appeared to be more readily solubilized by Cl− ions or chelators such as DTPA, more readily methylated (as indicated by downstream increases in dissolved CH3Hg+ levels and CH3Hg+/total Hg ratios), and was to a greater degree organically bound (H2O2-extractable), and thus was probably more bio-available, than Hg in wood-chip deposits. Possible explanations include weaker binding of Hg by the mud, the more finely divided state of the mud, and improved microbial growth at lower concentrations of toxic pollutants. Owing to enrichment in sulfides and Fe oxides, resuspended wood-chip sediments were especially efficient scavengers of CH3Hg+. The results indicate that in any pollution abatement plan aimed at lowering the Hg levels in the biota of lakes fed by the Wabigoon River, immobilization, removal, or detoxification of dissolved as well as particulate forms of Hg in the river would probably have to be considered. Possibly, Hg species could be ‘scrubbed’ from the river water by increasing the suspended load and by sedimentation and treatment with Hg-binding agents in special receiving basins.

Notizen: Abstract Seasonal and regional variations in the speciation, sediment-water partitioning, and dynamics of mercury (Hg) were studied at selected sites along the Hg-polluted Wabigoon River, and at unpolluted headwater and tributary sites, during April–September, 1979. ‘Dissolved’ and ‘particulate’ forms of Hg in the water were separated by continuous-flow centrifugation in the field. The Hg and other pollutants such as wood chips and salt had been discharged from a chlor-alkali plant and paper mill at Dryden, Ontario. Concentrations and loadings of particulate methyl mercury (CH3Hg+) and total particulate Hg (and loadings of total ‘dissolved’ Hg) were greatest during the spring flood (April-May) owing to accelerated resuspension and transport of sediments. Concentrations of ‘dissolved’ CH3Hg+, however, were highest in the summer (July–September), probably reflecting stimulation of microbial methylating activity by elevated temperatures, together with factors such as reduced levels of metal-scavenging particulates and minimal dilution by runoff. Total dissolved Hg concentrations were relatively high in September at polluted sites only, possibly because of desorption from sediments due to elevated concentrations of Cl− ions. Loadings of dissolved CH3Hg+ tended to be high in the summer but were generally depressed (suggesting sorption by suspended particles) during the major spring-flood episode in May. During July–August dissolved CH3Hg+ was a function of total dissolved Hg, suggesting rapid biomethylation of desorbed inorganic Hg; but in general dissolved and suspended CH3Hg+ levels depended on environmental variables and were unrelated to total Hg concentrations. In the summer only, total dissolved Hg was a function of dissolved Cl−. Hg species in particulates were associated with sulfides, hydrated Fe and Mn oxides, organic matter (notably high molecular weight humic and humic-Fe components), and selenium (Se); but CH3Hg+ and total Hg differed in their specific preferences for binding agents, implying that binding sites discriminate between CH3Hg+ and Hg2+ ions. CH3Hg+ was associated with sulfide and (in the spring only) with Fe oxides, whereas total Hg was associated with organic matter and Se and with DTPA- and NaOH-extractable Fe in the spring but with Mn oxide and NaOH-extractable organics in the summer. Sulfides were most abundant in May, indicating that they were eroded from bottom sediments, but Fe and Mn oxides were most abundant in the summer, probably owing to activities of filamentous iron bacteria and other micro-organisms. Particulate Hg was 98–100% nonextractable by mild solvents such as Ca acetate, CaCl2, dilute acetic acid, and (at polluted sites only) DTPA solutions, suggesting that the particulate Hg mobilized in the spring may not be readily available to organisms; association with Se and high molecular weight humic matter also supports this hypothesis. Hg probably becomes more bio-available in the summer, as suggested by the upsurge in dissolved CH3Hg+ and total dissolved Hg levels, and by increases in the solubility of particulate Hg in acetic acid, DTPA, H2O2, and NaOH solutions, as well as an increase in the relative importance of lower molecular weight fractions of NaOH-extractable Hg (in September). Regional variations in Hg speciation and partitioning reflected a gradient in sediment composition from wood chips near Dryden to silt-clay mud further downstream. Hg in silt-clay mud relatively far (〉 35 km) downstream from the source of pollution or in unpolluted areas appeared to be more readily solubilized by Cl− ions or chelators such as DTPA, more readily methylated (as indicated by downstream increases in dissolved CH3Hg+ levels and CH3Hg+/total Hg ratios), and was to a greater degree organically bound (H2O2-extractable), and thus was probably more bio-available, than Hg in wood-chip deposits. Possible explanations include weaker binding of Hg by the mud, the more finely divided state of the mud, and improved microbial growth at lower concentrations of toxic pollutants. Owing to enrichment in sulfides and Fe oxides, resuspended wood-chip sediments were especially efficient scavengers of CH3Hg+. The results indicate that in any pollution abatement plan aimed at lowering the Hg levels in the biota of lakes fed by the Wabigoon River, immobilization, removal, or detoxification of dissolved as well as particulate forms of Hg in the river would probably have to be considered. Possibly, Hg species could be ‘scrubbed’ from the river water by increasing the suspended load and by sedimentation and treatment with Hg-binding agents in special receiving basins.

Notizen: Abstract The pharmacokinetics and bioavailability of nitrazepam following intravenous, oral (tablet), and rectal (solution) administration were studied in seven healthy, young male volunteers. Nitrazepam plasma concentrations were determined by electron-capture GLC; pharmacokinetic evaluations were made by compartmental analysis (NONLIN) and compared with the results obtained by a less stringent modelling of the data. The plasma concentration-time profile was similar for all three routes of administration. Mean kinetic parameters as obtained by compartmental analysis of i.v. nitrazepam were: distribution half-life 17 min; volume of distribution after equilibrium 2.14 liters/kg; total plasma clearance 61.6 ml/min; elimination half-life 29.0 h. The mean protein unbound fraction of nitrazepam in plasma was 12.3% and the clearance of the unbound fraction was 506 ml/min. Absorption of oral nitrazepam started after the elapse of a lag time (mean value 12 min) and occurred as an apparent first-order process in all but one subject, with a mean absorption half-life of 16 min. Distribution and elimination half-lives were comparable with those following i.v. administration. Following rectal administration of the nitrazepam solution, rapid first-order absorption occurred with a mean lag time of 4 min and a mean absorption half-life of 9 min. Peak times (median 18 min) were significantly shorter than following oral administration (median 38 min), but there was little difference in peak concentrations. The distribution half-life was similar to i.v. and oral administration, but the elimination half-lives were longer with a mean value of 33.1 h. Following i.v. administration a good agreement was found between the results obtained by compartmental analysis using NONLIN and those obtained by a less stringent modelling of the data. Following oral and rectal administration, a good agreement between the two procedures was found for the elimination half-life; estimation of bioavailability, however, was higher by compartmental analysis. The mean bioavailability data showed that absorption is complete when nitrazepam is given orally and almost 20% lower when it is given rectally, but considerable interindividual differences were observed.

Notizen: Summary The bioavailability of chlorpropamide from two new formulations (Melitase® tablets) has been compared to that from a reference formulation which is currently in clinical use as a hypoglycaemic agent. In both rate and extent of bioavailability, all three formulations may be considered equivalent, providing allowances are made for differences in drug content. With 95% confidence, the mean bioavailability of chlorpropamide from the new formulations was within about 16% of the mean from the reference formulation, and formulation-related differences were not statistically significant. Although all three formulations were shown to have similar dissolution profiles, dissolution of chlorpropamide was pH-dependent in vitro. Dissolution was almost complete during 30 min at pH 7.2, but only 40%–60% had dissolved during 90 min at pH 2.0. A peak mean concentration of 22.7 µg/ml was reached 3 h after administration of 2×100 mg tablets of the new formulation and peak mean concentrations of 26.8 µg/ml and 27.4 µg/ml were reached 3 h and 4 hours after administration of one 250 mg tablet of the new formulation and one 250 mg tablet of the reference formulation respectively. Formulation-related differences of mean plasma concentrations (after scaling for equal doses of 250 mg) were not significant and each formulation provided similar plasma concentrations at corresponding times after administration. Statistically significant subject-related differences in all the parameters of bioavailability were shown by analyses of variance.

Notizen: Summary Two, separate 6×6 Latin square cross-over bioequivalence studies were performed in adult male volunteers using 10 different indomethacin capsule preparations marketed in India together with the pure drug powder as the standard. The products were evaluated with respect to plasma level at various times up to 8 h following administration of a 50 mg (2 × 25 mg) dose. Plasma samples were analysed by a fluorimetric method. Various pharmacokinetic parameters were calculated according to a two compartment model. Statistical evaluation of the data employed analysis of variance for a cross-over design (ANOVA) and Duncan's multiple range test to ascertain the significance of differences between the products. Of the 10 products studied, two were found to be bioinequivalent.