Arzneimittel Forsch
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Arzneimittel Forsch · Feb 1999
Molecular and neurochemical evaluation of the effects of etizolam on GABAA receptors under normal and stress conditions.
The thienobenzodiazepine derivative etizolam (CAS 40054-69-1, 6-(o-chlorophenyl)-8-ethyl-1-methyl-4H-s-triazolo-(3,4-c)thienol(1 ,4) diazepine) is a potent anxiolytic with a pharmacological profile similar to that of classical benzodiazepines. In order to rationalize the therapeutic use of etizolam, its pharmacodynamics properties on GABAA receptors were investigated by a comparative study with other ligands on human recombinant GABAA as well as rat brain native receptors. Etizolam inhibited in a concentration-dependent manner [3H]flunitrazepam (CAS 1622-62-4) binding to rat cortical membranes, with an affinity of 4.5 nmol/l greater than that of alprazolam (CAS 28981-97-7) (7.9 nmol/l). ⋯ Altogether, these results suggest that etizolam may have a reduced intrinsic activity, at least at specific subpopulations of GABAA receptors. This property, together with the pharmacokinetic indication of a short-acting drug, may characterize etizolam as a ligand endowed with less side-effects typical of full agonits such as diazepam (CAS 439-14-5) and alprazolam. Finally, given its marked efficacy under conditions of GABAergic deficit, etizolam may represent a possible drug of choice with reduced liability to produce tolerance and dependence after long-term treatment of anxiety and stress syndromes.
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Arzneimittel Forsch · Oct 1998
Disposition and metabolism of the new hypocholesterolemic compound S-8921 in rats and dogs.
S-8921 (methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimeth oxy-2- naphthoate, CAS 151165-96-7) is a novel hypocholesterolemic agent which was found to inhibit ileal Na+/bile acid cotransporter. In this report, the pharmacokinetic profile of S-8921 was studied in rats and dogs. After dosing of 14C-S-8921 to rats at 1 to 25 mg/kg as 0.5% methylcellulose (MC) suspension, tmax was observed during 5-6 h, and AUCs increased with the dose, but not proportionally. ⋯ The major metabolite of S-8921 in rat bile was its glucuronide. Other minor metabolites identified were the demethylated forms of 7-methoxy and 4'-methoxy moieties of S-8921. They were also excreted into bile as their glucuronides.
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Arzneimittel Forsch · Sep 1998
Comparative Study Clinical Trial Controlled Clinical TrialPharmacokinetics of tramadol and bioavailability of enteral tramadol formulations. 3rd Communication: suppositories.
The pharmacokinetics and the absolute bioavailability of tramadol hydrochloride (CAS 36282-47-0) after rectal administration of tramadol suppositories (Tramal) were determined in a balanced crossover study in 10 female volunteers in comparison with the intravenous injection. Each fasting volunteer received two single doses of 100 mg tramadol-HCl, one rectally (1 suppository) and one intravenously (2 ml of a solution for injection). The formulations were administered in the morning, the washout period was one week. ⋯ In the terminal phase the biological half-life (t1/2, beta) was 5.7 +/- 1.0 h (rectal) and 5.7 +/- 0.9 h (i.v.), respectively. The values determined after i.v. injection for the total distribution volume and the total clearance were 216 +/- 231 (Vd, beta) and 447 +/- 56 ml/min (Cltot). The results show that after rectal administration of the tramadol suppositories the absorption of the active ingredient is rapid enough for therapeutic purposes and that the extent of the absolute bioavailability is higher than after oral administration of tramadol-HCl, probably due to a reduced first-pass metabolisation after rectal administration.
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Arzneimittel Forsch · Jun 1998
Randomized Controlled Trial Comparative Study Clinical TrialComparison of the efficacy and tolerability of a paracetamol/codeine fixed-dose combination with tramadol in patients with refractory chronic back pain.
Fifty-five patients suffering from refractory chronic back pain took part in a double-blind, multiple-dose, randomised, cross-over study to compare the efficacy and tolerability of a fixed-dose capsule preparation containing 500 mg paracetamol (CAS 103-90-2) and 30 mg codeine phosphate 1/2 H2O (CAS 41444-62-6) (talvosilen forte, test preparation) with a reference capsule preparation containing 50 mg tramadol hydrochloride (CAS 22204-88-2), in a regimen of two capsules 8-hourly. There were two treatment periods of up to 7 days each. ⋯ The test preparation was at least as efficacious as the reference in the treatment of back pain (81% of patients experienced good or satisfactory pain relief). 81% of patients tolerated the test well compared to only 69% receiving the reference, as per protocol analysis. The results of this study suggest that the test product is at least as efficacious as tramadol in the treatment of patients with refractory chronic back pain, whilst being better tolerated.
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Arzneimittel Forsch · Jun 1998
Randomized Controlled Trial Multicenter Study Clinical TrialEfficacy of tetracycline and metronidazole alone or with ranitidine on the healing of duodenal ulcer and eradication of Helicobacter pylori. A randomized controlled multicenter study. Tetra-Metro-Ran Study Group.
In almost all eradication regimens, which contain antibiotics and bismuth derivatives, the administration of acid suppressing drugs for 4-6 weeks is recommended for healing of duodenal ulcer. The aim of this multicenter double blind study is to elucidate the effect of two classic antibiotics tetracycline (CAS 60-54-8) and metronidazole (CAS 443-48-1) alone or combined with ranitidine (CAS 66357-35-5) on the healing of duodenal ulcer and eradication of Helicobacter Pylori. Patients with duodenal ulcer were randomized to two treatment groups: group A received either ranitidine 4 x 150 mg or tetracycline 4 x 500 mg or metronidazole 3 x 250 mg for 2 weeks. ⋯ The present study shows that treatment with the two antibiotics tetracycline and metronidazole alone results in a very low H. pylori eradication, but almost complete healing of duodenal ulcer after 8 weeks. Prolonged administration of antisecretory drugs in eradication regimens containing two antibiotics is not necessary for duodenal ulcer healing. However, the addition of H2-receptor antagonists or proton pump inhibitors to antibiotics increases the eradication rate.