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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.

Notes: Summary The influence of probenecid on the pharmacokinetics of paracetamol was investigated in a group of healthy volunteers. Pretreatment with probenecid caused a significant decrease in paracetamol clearance (6.23 to 3.42 ml·min−1·kg−1). The urinary excretion of paracetamol sulphate (243 to 193 mg); and paracetamol glucuronide (348 to 74.5 mg) were significantly reduced, whereas that of paracetamol was unchanged. Probenecid was shown to be an uncompetitive inhibitor of paracetamol glucuronidation in vitro, using rat liver microsomes.

Notes: Abstract The influence of pretreatment with a three day course of ciprofloxacin (500 mg twice daily) on a single oral dose of ethanol (30 g) was investigated in 12 healthy male volunteers in a double blind placebo controlled study. Pretreatment with ciprofloxacin was shown to have no significant effect on ethanol AUC (736 mg·l-1 h placebo; 734 mg·l-1 h ciprofloxacin), Cmax (466 mg·l-1 placebo; 483 mg·l-1 ciprofloxacin) tmax (0.6 h placebo; 0.5 h ciprofloxacin) or the elimination rate (134 mg·l-1 h-1 placebo; 133 mg·l-1 h-1 ciprofloxacin). The effect of ciprofloxacin on ethanol pharmacodynamics was measured by the use of psychomotor tests, such as the critical flicker fusion threshold, choice reaction time, pursuit rotor, tapping rate, digit symbol substitution and digit span. Subjective feelings of concentration, vigilance and relaxation were also measured using visual analogue scales. Pretreatment with ciprofloxacin was found to have no significant effect on any of these tests, compared to placebo.

Notes: Summary The effects of pretreatment with a seven day course of ciprofloxacin on pharmacokinetics and pharmacodynamics of an intravenous (5 mg) dose of diazepam were investigated in a group of 12 healthy volunteers in a double-blind placebo-controlled crossover study. Ciprofloxacin pretreatment significantly reduced diazepam CL (without ciprofloxacin: 19.5 ml·h−1kg−1; with ciprofloxacin: 12.3 ml·h−1kg−1). Diazepam t1/2 was also prolonged (without ciprofloxacin: 36.7 h; with ciprofloxacin: 71.1 h), but volume of distribution was unaltered (without ciprofloxacin: 1.1 l·kg−1; with ciprofloxacin: 1.1 l·kg−1). However, no significant changes were detected in psychometric tests of digit symbol substitution, tapping rate and short memory, as well as levels of concentration, vigilance and tension measured by visual analogue scales.

Notes: Summary The antihistaminic effects of 7 days treatment with each of three doses of noberastine (10, 20 and 30 mg) were compared to placebo in 12 healthy male volunteers. The antihistaminic activity was assessed from the inhibition of weal and flare formation after intradermal histamine injections. For both weal and flare there was a highly significant effect of treatment with each of the three doses of noberastine, compared to placebo. The 30 mg daily dose produced the maximum inhibition of weal and flare. The daily mean values for the assessment of sedation by visual analogue scales at 09.00 h, 15.00 h and 21.00 h showed no significant treatment, or order, effect for any of the three doses of noberastine compared to placebo. The mean steady-state plasma concentrations of noberastine were significantly higher with increasing daily doses of noberastine (trough concentrations: 1.0, 1.6 and 2.2 ng·ml−1; peak concentrations: 3.5, 13.4 and 20.9 ng·ml−1 for 10, 20 and 30 mg daily dose, respectively). The percentage weal inhibition correlated (r=0.77) with steady-state noberastine plasma trough levels. The percentage flare inhibition showed a weaker correlation (r=0.35) with steady-state noberastine plasma trough levels.

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.

Notes: Abstract. The potential effect of co-medication with phenobarbitone, primidone and carbamazepine on plasma and saliva concentrations of 5-(4-hydroxyphenyl)-5-phenylhydantoin (4-HPPH), the major metabolite of phenytoin in man and on the incidence of phenytoin-induced gingival overgrowth was investigated in a group of 36 adult epileptic patients. There were no signifiant differences in plasma or saliva concentrations of 4-HPPH or phenytoin in patients prescribed phenytoin alone, compared to those who received phenytoin with either phenobarbitone, primidone, or carbamazepine. In addition, the extent and the incidence of gingival overgrowth were similar in the 2 groups. The results suggest that chronic co-medication with other anti-convulsant drugs which induce phenytoin metabolism, does not affect the plasma or saliva 4-HPPB steady-state levels, nor the degree of gingival overgrowth in adult epileptic patients on therapy with phenytoin.〈section xml:id="abs1-1"〉〈title type="main"〉ZusammenfassungDie Wirkimg einer multiplen antikonvulsiven Therapie auf die Ausprägung der durch Phenytoin ausgelösten GingivahyperplasieIn einer Gruppe von 36 erwachsenen Epileptikern wurde der potentielle Effekt der Ko-Medikation von Phenobarbiton, Primidon und Carbamizepin auf die Plasma- und Speichelkonzentration von 5-(4-Hydroxyphenyl)-5-Phenylhydantoin (4-HPPH), dem Hauptmetaboliten von Phenytoin beim Menschen, und die Inzidenz der durch Phenytoin ausgelösten Gingivahyperplasie untersucht. Verglichen mit den Patienten denen allein Phenytoin verschrieben wurde, gab es bei den Patienten, die Phenytoin mit entweder Phenobarbiton, Primidon oder Carbamizepin verschrieben bekamen, keine signifikanten Unterschiede in der Plasma- und Speichelkonzentration von 4-HPPH oder Phenytoin. Des weiteren waren das Ausmaß und die Inzidenz der Gingivahyperplasie in beiden Gruppen ähnlich. Die Ergebnisse lassen annehmen, daß die chronische Ko-Medikation mit anderen antikonvulsiven Medikamenten, die den Phenytoin-Metabolismus induzieren, weder die plasma- und Speicheltiter von 4-HPPH noch den Grad der Gingivahyperplasie bei erwachsenen Epileptikern mit Phenytoinbehandlung beeinflußt.〈section xml:id="abs1-2"〉〈title type="main"〉RésuméEffect du traitement anticonvulsivant multiple sur l'expression de l'hypertrophie gingivale induite par la phénytoïneNous avons étudié dans un groupe de 36 épileptiques adultes l'effet potentiel d'une médication combinant phénobarbital, primidone et carbamazépine sur les concentrations plasmatiques et salivaires de 5-(4-hydroxyphényl)-5-phénylhydantoïne (4-HPPH), métabolite principal de la phénytoïne chez l'humain, et sur l'incidence des hypertrophies gingivales induites par la phénytoïne. Il n'existait pas de différences statistiquement significatives dans les concentrations plasmatiques et salivaires de 4-HPPH ou de phénytoïne chez les patients à qui on avait prescrit la phénytoïne seule par rapport à ceux qui receivaient la phénytoïne avec phénobarbital, primidone ou carbamazépine. De plus, l'étendue et l'incidence de l'hypertrophie gingivale étaient de même ordre dans les deux groupes. Ces résultats semblent indiquer qu'une co-médication chronique avec d'autres anticonvulsivants induisant le métabolisme de la phénytoïne n'a pas d'influence sur les niveaux plasmatiques ou salivaires de 4-HPPH à l'état d'équilibre, ni sur le degré d'hypertrophie gingivale chez les épileptiques adultes traités par la phénytoïne.