Effect of nimodipine, a dihydropyridine calcium channel antagonist on the pharmacokinetics of carbamazepine in rhesus monkeys.

Calcium channel antagonists have been shown to have an anticonvulsant activity in a variety of seizure models and also to potentiate the anticonvulsant activity of other standard antiepileptic drugs like carbamazepine, phenytoin and valporoate. A pharmacokinetic interaction may be involved in such potentiation. This cross over single dose study was carried out to find out if there was a pharmacokinetic interaction between carbamazepine, a commonly used antiepileptic drug and nimodipine, a dihydropyridine calcium channel antagonist in rhesus moneys. Carbamazepine 46 mg/kg and nimodipine 9.6 mg/kg was administered through a nasogastric tube and blood samples were collected at 0.5, 1, 2, 3, 6, 9, 12, 24, 48, 72 and 96 hours after drug administration and were assayed for carbamazepine. Nimodipine caused a significant increase in peak plasma concentration (C(max)) of carbamazepine and a decrease in plasma absorption half life (t1/2 alpha). There was no significant change in other pharmacokinetic parameters between the two groups. The results of the study suggest that concurrent administration of carbamazepine and nimodipine may cause a significant rise in carbamazepine concentration as may contribute to a potentiation of anticonvulsant effect of carbamazepine and an increase in the incidence of adverse effects warranting that nimodipine should be prescribed cautiously in epileptic patients receiving carbamazepine and it might be very appropriate to do therapeutic drug monitoring of carbamazepine in such patients.

Effect of melatonin and beta-carotene on indomethacin induced gastric mucosal injury.

The study was conducted to examine the role of free radicals in Indomethacin induced gastric mucosal injury and to evaluate the gastroprotective effects of melatonin and beta-carotene. Gastric mucosal injury was produced in rats by administering indomethacin 30 mg/kg subcutaneously. Melatonin was administered in three different doses of 5, 10 and 20 mg/kg, 30 minutes prior to the administration of indomethacin. Beta-carotene was administered as a single dose of 100 mg/kg. Following parameters were calculated: ulcer index, lipid peroxidation and antioxidant defense enzymes i.e. superoxide dismutase, glutathione peroxidase and catalase. Indomethacin caused gastric mucosal injury in the form of haemorrhages, increased the lipid peroxidation and decreased the levels of the antioxidant defense enzymes. Melatonin (20 mg/kg) and beta-carotene decreased the ulcer index and lipid peroxidation, and reduced the decrease in antioxidant enzyme levels. These findings suggest the melatonin and beta-carotene show protective effect against indomethacin induced gastric injury and this effect is mediated by scavenging of oxygen derived free radicals.

Nifedipine potentiates gabapentin antinociception in rats.

To evaluate the involvement of Ca++ channels in Gabapentin antinociception. In healthy male albino rats formalin (50 microliters, 5%) was injected at the planter surface of the paw. Pain score was calculated. Antinociceptive effect of (10, 30 mg/kg) gabapentin and (3, 10 mg/kg) nifedipine alone and on co-administration of sub analgesic doses was studied 30 minutes after formalin injection and reduction in pain scores was calculated. Gabapentin (30 mg/kg) and nifedipine (10 mg/kg) reduced the pain score in formalin injected rats. Gabapentin (10 mg/kg) and nifedipine (3 mg/kg) given alone did not modify pain score, however, on co-administration they significantly reduced the pain score. Study provides evidence of involvement of Ca++ channels in gabapentin antinociception.

Pharmacokinetics of ciprofloxacin in patients with liver cirrhosis.

BACKGROUND: Bacterial infections are common in patients with cirrhosis of liver and are frequently treated with ciprofloxacin. Literature on pharmacokinetics of ciprofloxacin in patients with cirrhosis of the liver is scanty. The present study compared the pharmacokinetics of ciprofloxacin in cirrhotic patients with that in healthy volunteers. METHODS: In 20 patients with cirrhosis of liver (all Child-Pugh class B) and 10 healthy volunteers, plasma levels of ciprofloxacin were measured using high-performance liquid chromatography at several time points after a 500-mg oral dose. Various pharmacokinetic parameters were calculated. RESULTS: No significant differences were observed in maximum plasma levels reached (mean [SD] 2.6 [0.6] vs 2.6 [1.3] microg/ml), time taken for maximum plasma levels to be reached (1.3 [0.6] vs 1.5 [0.9] h), t1/2a (0.7 [0.3] vs 0.4 [0.9] h), elimination half-life (3.6 [1.2] vs 3.2 [1.8] h), and area under the curve (19.3 [3.8] vs 21.9 [4.5] microg/mL x h) in healthy volunteers and cirrhotic patients, respectively. CONCLUSIONS: Pharmacokinetics of ciprofloxacin is unaltered in patients with liver cirrhosis. Ciprofloxacin can be safely administered in the usual doses in such patients.

A meta-analysis of controlled clinical trials comparing low-molecular weight heparins with unfractionated heparin in unstable angina.

BACKGROUND: Unfractionated heparin has been used extensively for the treatment of unstable angina/non-Q wave myocardial infarction but it has several disadvantages. Low-molecular weight heparins are now recommended although they are 3-5 times costlier than unfractionated heparin since they are convinient to administer and do not require activated thromboplastin time monitoring. Whereas enoxaparin, a low-molecular weight heparin, has been demonstrated to be superior to unfractionated heparin, the results of other low-molecular weight heparins have not been so convincing. METHOD AND RESULTS: Through manual, MEDLINE and EMBASE search, we identified five randomized trials (excluding enoxaparin trials) that compared low-molecular weight heparins with unfractionated heparin in unstable angina. The prespecified efficacy end point of interest included a composite of death, myocardial infarction, recurrent angina and urgent revascularization. The safety end point was taken as a composite of major hemorrhage, minor hemorrhage, thrombocytopenia, allergic reaction and any other adverse event. We calculated odds ratio (95% confidence interval) for each trial for the composite end point, and the pooled odds ratio (95%) confidence interval) was calculated using two established methods of meta-analysis, the Mantel-Haenszel-Peto method and the DerSirmonian-Laird method. Both the methods yielded similar odds ratio (95% confidence interval). Separate odds ratio were calculated for efficacy and safety end points. There was a nonsignificant reduction in the incidence of the composite efficacy end point: the odds ratio (95% confidence interval) was 0.83 (0.70-0.99: p=0.08). The odds ratio (95% confidence interval) for the safety data was 0.78 (0.69-1.26: p=0.33). CONCLUSIONS: No statistically significant difference was observed when the efficacy and safety of low-molecular weight heparins were compared with those of unfractionated heparin. A cost-effectiveness analysis of low-molecular weight heparins versus unfractionated heparin must be done urgently to establish more firmly the place of low-molecular weight heparins in the management of unstable angina.

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test.

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.

Effect of nimodipine on male reproductive functions in rats.

Nimodipine, a dihydropyridine calcium channel blocker, was administered orally using two different doses (40 mg and 60 mg/kg/day) to rats. Both short term (2 weeks) and long term (6 weeks) effects of the drug were observed. The drug administration resulted in a marked decrease in sperm density, sperm motility and acrozomal reaction. Zona-pellucida penetration by the sperm obtained from drug-treated animals was significantly lower when compared with sperm from normal animals. Nimodipine stimulated Ca2+ ATPase activity in isolated plasma membrane of rate spermatozoa. In conclusion, short term and long term administration of nimodipine has deleterious effect on male reproductive functions in rats.

Influence of kinnow juice on the pharmacokinetics of sustained release theophylline in healthy male volunteers.

The effect of kinnow juice on the pharmacokinetics of a single dose of sustained release theophylline was investigated in healthy male volunteers. In a two phased open cross-over randomized study, ten healthy male volunteers were given sustained release theophylline (300 mg) along with 300 ml of water or kinnow juice, a routinely used citrus juice in India. Blood samples were collected at different time points from 0-48 hours. Plasma was assayed for theophylline by a HPLC method and various pharmacokinetic parameters were calculated and compared. The theophylline levels were lower at all the time points with kinnow juice co-administration as compared to water but were significantly so only during the absorption phase from 1-4 hours. The values for all the pharmacokinetic parameters evaluated were on the lower side with kinnow juice except Tmax which was slightly delayed. None of these alterations was found to be significantly different. The results indicate that since there is an interference with the absorption of the drug, the patients may be advised not to consume kinnow juice when taking a slow release theophylline preparation and the monitoring of plasma concentrations of theophylline in patients who routinely consume kinnow juice in their diet might be helpful in better management of these patients.

Effect of the 5-HT3 receptor antagonist ondansetron on amphetamine-induced hyperactivity and stereotypy in rats.

The effects of different doses of ondansetron (0.1, 0.5, 1, 2 mg/kg) administered intra-peritoneally were studied on amphetamine-induced hyperactivity and stereotypy in wistar rats. Ondansetron was administered 30 minutes prior to d-amphetamine (3 mg/kg, i.p.). Ondansetron in doses of 0.5 and 1 mg/kg significantly decreased the mean number of head dippings and crossings in the hole board test and in doses of 0.1 and 0.5 mg/kg significantly decreased the average stereotypic score. Since the hyperactivity and stereotypy are dopamine mediated, the effect of ondansetron to reduce these states suggests a potential role for ondansetron in conditions with dopamine excess.

Role of nitric oxide on insulin induced seizures in mice.

The role of nitric oxide (NO) on acute hypoglycemia-induced seizures in mice was investigated using insulin as the hypoglycemic agent. The NO precursor L-arginine in the doses of 150, 500 and 750 mg/kg exhibited a dose-dependent protective effect against seizures induced by 8 mu/kg insulin. The NO synthase inhibitor (L-NMMA) at the doses of 50 and 100 mg/kg potentiated the subconvulsive doses of insulin (2 mu/kg). The onset, duration, number of seizures and the mortality were noted in a 2 hr study period. The results of this study suggest than NO plays an important protective role in acute hypoglycemia induced seizures which are known to occur through the activation of NMDA receptors.

Effect of 'Mentat' on the pharmacokinetics of single and multiple doses o phenytoin in rabbits.

The effect of 'Mentat', a herbal preparation, was studied on pharmacokinetics of single and multiple doses of phenytoin in rabbits. No significant effect was found after single oral dose of 'Mentat' on single dose kinetics of phenytoin. However, 'Mentat' administration for 7 days increased the steady state kinetic parameters. Peak plasma phenytoin concentration, area under the implasma concentration and elimination half life were significantly increased and t-max was significantly reduced, indicating the suppression of phenytoin metabolism by 'Mentat'.

Pharmacokinetics of phenytoin: unaltered by enalapril and amlodipine in rhesus monkeys.

A cross over single and multiple dose study was carried out to find out pharmacokinetic interactions between diphynylhydantoin (DPH) (35 mg/kg, p.o.) and antihypertensives enalapril (1.6 mg/kg; p.o.) and amlodipine (0.4 mg/kg, p.o.) in rhesus monkeys. Neither the plasma concentrations nor the pharmacokinetic parameters of DPH were altered by coadministration of enalapril or amlodipine, suggesting that enalapril and amlodipine can be safely administered to epileptic patients receiving phenytoin.

Anticonvulsant profile of nimodipine and nitrendipine against pentylenetetrazole induced seizures in rats.

The activity of nimodipine and nitrendipine against pentylenetetrazole (PTZ) induced seizures in Albino rats was studied alone and in combination with valproate. The median effective dose [ED50] of valproate, nimodipine and nitrendipine were initially determined. All the 3 drugs were injected i.p. 30 min before the induction of seizures. Seizures were induced by PTZ 85 mg/kg i.p., and subsequently the effect of combining ED50 doses of nimodipine and nitrendipine with ED50 dose of valproate was evaluated. ED50 of valproate and nitrendipine were 129 and 2.5 mg/kg respectively. ED50 of nimodipine could not be established since a dose-response relationship was not obtained. Hence, for the purpose of combination studies, 4 mg/kg of nimodipine was used. Both nimodipine (4 mg/kg) and nitrendipine (2.5 mg/kg) decreased the ED50 of valproate from 129 to 40 mg/kg. Both nimodipine and nitrendipine potentiate the activity of valproate against PTZ induced seizures and can be considered as potential adjuvant anticonvulsants which merit further study.