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  • 1
    ISSN: 1432-1041
    Keywords: Ipsapirone ; CRF ; ACTH ; cortisol ; time series analysis ; hypothalamic-pituitary-adrenal axis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The neuroendocrine effects (changes in plasma CRF, ACTH and cortisol) of single and multiple (t.d.s. for 2 days) doses of ipsapirone (BAY Q 7821) 5 and 10 mg have been investigated in 6 healthy male volunteers. The study followed a balanced complete block, placebo-controlled and double blind design with two baseline phases (pre and post-treatment). Volunteers were investigated on identical days during 5 successive weeks. The results do not show a specific effect of ipsapirone on the hypothalamic-pituitary-adrenal axis when doses in the range of 5–30 mg per day were given.
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  • 2
    ISSN: 1432-1041
    Keywords: Key words Nisoldipine ; Hypertension; Ca antagonist ; pharmacokinetics ; pharmacodynamics ; PK/PD modelling
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Nisoldipine, a calcium antagonist of the dihydropyridine class, has been used in the treatment of hypertension and angina pectoris. A new controlled-release dosage form (nisoldipine coat-core, NCC) has been developed to allow once daily dosing. In addition to a formal food interaction study as requested by regulatory authorities for controlled-release dosage forms, a subsequent study was conducted to determine the clinical relevance of the changes in nisoldipine plasma concentration vs time profiles seen in the food effect study. Methods: After a placebo run-in phase of 6 days, 12 hypertensive patients started treatment with 20 mg NCC once daily (days 0–3, 5–6, 8–9). On days 4, 7 and 10 the NCC was substituted for 5, 10 and 20 mg nisoldipine solution, respectively, in order to obtain nisoldipine plasma concentration vs time profiles comparable to the ones resulting from the concomitant intake of food and NCC. Simultaneous measurements of blood pressure (BP) and nisoldipine concentration were performed on days 3, 4, 7 and 10. Results: The relationship between nisoldipine plasma concentrations and percentage reduction in BP [diastolic (DBP) and systolic (SBP), supine and standing] could be described by an Emax model. The mean maximum reduction (Emax) relative to baseline was about 36.4% and 37.7% (DBP, supine and standing) and 27.9% and 29.2% (SBP, supine and standing), respectively. The interindividual variability (% CV) in Emax was low, ranging from 17.6% to 28.8%. The mean nisoldipine plasma concentration corresponding to 50% of the maximum effect (EC50) ranged between 0.99 and 2.62 μg · l–1 with a pronounced interindividual variability (% CV) of 89.5–108.8%. Mean Cmax values after administration of the 30 and 40 mg NCC together with food were 4.5 and 7.5 μg · l–1, respectively. Based on the concentration-effect relationship established in the present study, the effect achieved with a concentration of 7.5 μg · l–1 will be about 77% of Emax for DBP and about 88% of Emax for SBP, respectively. Conclusion: At the time of maximum plasma concentration the additional decrease in BP relative to baseline due to the food effect will be about 7–15% for DBP and 3–9% for SBP. After administration of the 10␣mg solution with a mean Cmax of 8.7 μg · l–1, only headache and flush with mild severity have been reported as adverse events. These maximum concentrations are comparable to Cmax values seen after intake of 40 mg NCC with food. With regard to heart rate (HR) there were distinct differences between the two formulations: Following administration of 5, 10 and 20 mg nisoldipine solution, there were dose-dependent increases in HR by a maximum of 4, 12 and 16 beats · min−1, respectively, whereas the HR profile for the NCC was similar to that seen under placebo treatment.
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  • 3
    ISSN: 1432-1041
    Keywords: Digoxigenin-mono-digitoxoside ; cardiac glycosides ; metabolism ; excretion ; polar conjugates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 3H-digoxigenin-mono-digitoxoside 1 mg was swallowed by 6 healthy subjects. Maximum plasma levels of radioactivity were reached within 1–2 h; in two subjects there was a second peak at 8–12 h. No definite half lives could be determined because the falls in plasma activity were not exponential. 3.9–39% and 34.5–76.6% of the dose were eliminated in urine and faeces, respectively. 75–90% of the total radioactivity in plasma was CHCl3-insoluble, there was less of this fraction in urine, and the major portion in faceces was CHCl3-soluble. The CHCl3-insoluble fraction in urine was separated into 3 components by chromatography on an Al2O3-column and consisted mainly of conjugates of the monoglycoside and 3-epidigoxigenin. TLC-separation of the lipophilic fraction in urine also revealed unchanged monoglycoside and 3-epidigoxigenin, as well as traces of digoxigenin, 3-ketodigoxigenin and 2 unidentified, more polar metabolites. In faeces, the main excretion product was the unchanged compound, and traces of digoxigenin, 3-epidigoxigenin, 3-ketodigoxigenin and one of the more polar metabolites detected in urine. Two patients with surgical T-tube bile-duct drainage showed significantly greater biliary excretion after oral administration of the digoxigenin-mono-digitoxoside than after digoxin. Almost all the radioactivity excreted in bile was CHCl3-insoluble and the monoglycoside was shown to be the only conjugation partner present by incubation with arylsulfatase and β-glucuronidase. The results show that digoxigenin-mono-digitoxoside has such a rapid metabolic inactivation and biliary clearance in man that it is unlikely to be of any therapeutic value.
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  • 4
    ISSN: 1432-1041
    Keywords: Nimodipine ; Cimetidine ; Ranitidine ; pharmacokinetic interaction ; cytochrome P-450 ; healthy volunteers ; haemodynamics ; drug interation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary A possible interaction between the calcium antagonist nimodipine and the H2-receptor antagonists cimetidine and ranitidine has been investigated in two separate studies in healthy subjects. In eight young volunteers the concomitant administration of nimodipine 30 mg t.i.d. and cimetidine 1000 mg/d for 7 days led to a significant increase of the relative bioavailability of nimodipine. The changes in the pharmacokinetic parameters were not accompanied by discernible haemodynamic effects or any change in the tolerability of nimodipine. There was no evidence of any significant change in the steady-state pharmacokinetics of nimodipine during five days of combined treatment with 30 mg t.i.d. nimodipine and ranitidine 300 mg/d given as single morning dose to twelve healthy, elderly subjects. Analysis of haemodynamics, clinical chemistry and tolerance also did not reveal any difference between the two treatment periods.
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  • 5
    ISSN: 1432-1041
    Keywords: Calciumantagonists ; Oesophageal motility ; oesophageal pharmaco-manometry ; lower oesophageal sphincter pressure ; healthy volunteers ; dihydropyridines ; nifedipine ; nifedipine ; nisoldipine ; nitrendipine ; nimodipine ; side ; effects
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Nifedipine has been proven to be effective and safe in the treatment of primary oesophageal motility disorders which can cause angina-like chest pain and/or dysphagia. The effects of the calcium channel blockers nifedipine, nitrendipine, nimodipine and nisoldipine on oesophageal smooth muscle function in healthy male volunteers were studied by oesophageal manometry using the rapid pull-through-technique, in two randomized, double-blind crossover studies. Lower oesophageal sphincter pressure, oesophageal contraction amplitude and duration after a wet swallow (measured 5 cm and 10 cm above the lower oesophageal sphincter) were determined 30 min before and at 10 minute intervals up to 90 min after the administration of nimodipine and up to 120 min after nifedipine, nitrendipine and nisoldipine. The plasma drug concentration was measured at baseline (−15 min) and in parallel with the manometric measurements. Compared to placebo, lower oesophageal sphincter pressure was significantly decreased by 24% by nifedipine and 17% by nimodipine, whereas the effects of nitrendipine (decrease of 15%) and nisoldipine (9%) were not significant. Nifedipine significantly decreased by 17% the oral contraction amplitude compared to placebo and nimodipine by 11%. The duration of the contraction amplitudes was not altered. The decrease in sphincter pressure was correlated with the corresponding plasma drug levels of nifedipine r=0.92, nitrendipine r=0.80 and nisoldipine r=0.79. Nimodipine showed no such correlation. It is concluded that among the calcium antagonists studied, nifedipine exerted the strongest effect on oesophageal smooth muscle function, so it appears to be the most suitable compound for the treatment of primary motor abnormalities of the oesophagus.
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  • 6
    ISSN: 1432-1041
    Keywords: Pharmacokinetics ; Caucasians ; Repirinast ; Antiallergic drug ; single dose ; oral administration ; metabolite ; BAY w 8199
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The pharmacokinetics of BAY w 8199, the active metabolite of the prodrug repirinast (BAY u 2372), has been investigated after oral administration of 150, 300 and 450 mg repirinast to twelve healthy male Caucasians. Plasma BAY w 8199 concentrations were very variable between subjects. The mean peak level (geom. mean; 1s-range) was 0.14 (0.08–0.25), 0.19 (0.13–0.29) and 0.24 (0.14–0.42) mg/l after the 150, 300 and 450 mg doses, respectively. Peak levels were reached 0.5–2.5 h after drug intake. Terminal half-lives were calculated as 5.9 h (150 mg), 8.0 h (300 mg) and 9.8 h (450 mg). The dose proportionality of the plasma profiles of BAY w 8199 and of its excretion in urine was demonstrated by testing several parameters. About 7.4% of each dose (calculated as BAY w 8199) was excreted in urine over 36 h. The renal clearance of about 27 l/h suggests that BAY w 8199 is excreted by tubular secretion in addition to glomerular filtration.
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  • 7
    ISSN: 1432-1041
    Keywords: Key words Cerivastatin; cytochrome P450 3A4 inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: Cerivastatin is a novel, synthetic, highly potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that effectively reduces serum cholesterol levels at very low doses. It is exclusively cleared from humans via cytochrome P450-mediated biotransformation (demethylation M1; hydro‐xylation M23) and subsequent biliary/renal excretion of the metabolites. The influence of concomitant administration of erythromycin, a potent CYP3A4 inhibitor, on cerivastatin bioavailability and pharmacokinetics was investigated. Methods: Twelve healthy young male subjects received single oral doses of 300 μg cerivastatin alone or on the 4th day of a 4-day pre- and co-treatment with erythromycin 500 mg t.i.d. in a randomised, non-blind crossover study. Plasma and urine samples were analysed for cerivastatin and its major metabolites by validated specific high-performance liquid chromatography assays. Results: Cerivastatin was safe and well tolerated. No clinically relevant treatment-emergent changes in laboratory parameters were observed. The pre- and co-treatment with erythromycin 500 mg t.i.d. had a modest influence on cerivastatin clearance, leading to a mean increase in the maximum plasma concentration (Cmax) of 13% and a slightly increased terminal half-life (approximately 10%), resulting in a mean elevation of the area under the curve (AUC) of 21%; time to peak (tmax) remained unchanged. While the mean AUC of the metabolite M1 following the combined dosing was decreased by 60% compared with mono-dosing, the mean AUC of M23 exhibited an increase of approximately 60%. The respective Cmax results paralleled these pronounced effects, whereas the influence on mean terminal half-lives was small (i.e. for M23, an approximate 20% increase) or not observable (i.e. for M1). Conclusions: Concomitant administration of erythromycin 500 mg t.i.d. affects, to a certain extent, the metabolism of cerivastatin, administered as a single oral dose of 300 μg, resulting in a slightly increased exposure of the parent drug and active metabolites which, however, does not need dose adjustment. In addition, the small increase in cerivastatin half-life does not predict an accumulation beyond steady state. The pharmacokinetic data for the major metabolites suggest that the M1 metabolic pathway is more sensitive to CYP3A4 inhibition than the parallel M23 pathway, supporting recent in vitro findings that further cytochrome P450 isozymes are differently involved in the metabolic pathways of cerivastatin.
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  • 8
    ISSN: 1432-1041
    Keywords: Key words Drug development ; Nephrotoxicity ; Pro- teinuria ; Albuminuria ; α1-Microglobulin ; N-Acetyl-β-d-glucosaminidase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract Objective: The quantitative measurement of urinary marker proteins may improve the sensitivity of monitoring renal function in healthy male subjects in phase I studies. Little is known about the variability of physiological proteinuria in young, healthy male subjects. Thus, the biological and analytical variability of three marker proteins, i.e. albumin, α1-microglobulin and N-acetyl-β-d-glucosaminidase (NAG), were investigated in this population. Methods: Seven young, healthy male subjects participated in a prospective two-way cross-over study, and 139 in a retrospective study. Albumin and α1-microglobulin were determined by immunological methods (radial immunodiffusion and/or kinetic nephelometry), and NAG by enzyme activity in a colorimetric assay. Results: The inter-assay precision of NAG, albumin and α1-microglobulin is good (〈15%) if automated kinetic nephelometry is applied for albumin and α1-microglobulin determination, but less impressive (〈25%) with radial immunodiffusion. The highest frequency of detectable proteinuria and highest creatinine-adjusted protein levels are found in the second morning urine voided after a night's rest. The intra-individual biological variability of NAG excretion from day to day is low (CV: 15–25%), irrespective of outpatient or inpatient settings. By contrast, albumin and α1-microglobulin excretion can differ by a factor of 2–3 from day to day, and higher levels are predominantly found in outpatient settings. The reference ranges for young, healthy male subjects are generally lower than published in cross-sectional studies in the total healthy population. Conclusion: These findings and established reference ranges for young, healthy male subjects may assist in the evaluation of proteinuria in clinical pharmacological phase I trials.
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  • 9
    ISSN: 1432-1041
    Keywords: Methyldigoxin ; repetitive doses ; bioavailability ; deep compartments ; oral and i.v. dose ; volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary To obtain true half lives, glycoside elimination from six healthy subjects was studied for 14 days after multiple intravenous doses or oral administration of a daily maintenance dose of β-methyldigoxin 0.3 mg. After oral or intravenous administration of β-methyldigoxin ceased, the plasma concentrations declined from the 14th to the 16th days with a half life of 1.7 days. From the 16th to the 20th day a change from a shorter to a longer half life of 2.8 and 2.9 days was observed. Similar half lives were found in urine: after the last dose the initial slope from the 14th to the 16th day had a half life of 1.8 days, and the terminal slope had one of 3.2 days. The results indicate release of the glycoside from slowly equilibrating tissues.
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  • 10
    ISSN: 0014-5793
    Keywords: Acetylcholine-gated cation channel ; Anticholinesterase ; Carbamate ; Desensitization ; Eserine ; Ion flux ; Nicotinic acetylcholine receptor ; Physostigmine
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Physics
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