Acute cyclosporine pretreatment does not alter onset of loss of righting reflex during intravenous infusion of phenobarbital in rats.
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Animals↗
Biomedical subjects
I Ramzan
Publications and source records attributed to I Ramzan.
Theophylline neurotoxicity in pregnant rats.
The purpose of this investigation was to determine whether the neurotoxicity of theophylline is altered in advanced pregnancy. Sprague-Dawley rats that were 20 days pregnant and nonpregnant rats of the same age and strain received infusions of aminophylline until onset of maximal seizures which occurred after 28 and 30 minutes respectively. Theophylline concentrations at this endpoint in serum (total) and CSF were similar but serum (free) and brain concentrations were slightly different in pregnant rats. Theophylline serum protein binding determined by equilibrium dialysis was lower in pregnant rats. Fetal serum concentrations at onset of seizures in the mother were similar to maternal brain and CSF concentrations and correlated significantly with the former. It is concluded that advanced pregnancy has a negligible effect on the neurotoxic response to theophylline in rats.
Animals↗
4-Methylpyrazole alters phenobarbitone hypnotic concentrations in rats.
The liver alcohol dehydrogenase inhibitor, 4-methylpyrazole, has been tested for its ability to change the hypnotic concentrations of phenobarbitone (phenobarbital) in rats. Following a single dose of 1 mmol kg-1 i.v., administered 60 min before phenobarbitone, 4-methylpyrazole shortened the onset time and reduced the dose of phenobarbitone required to produce loss of righting reflex. Consistent with this, phenobarbitone concentrations in serum (both total and free), brain and in cerebrospinal fluid at onset of hypnosis were about half in 4-methylpyrazole compared with saline-treated rats. These results suggest that acute 4-methylpyrazole pretreatment increases the central nervous system sensitivity to phenobarbitone and presumably other barbiturates; an effect apparently distinct from its inhibition of liver alcohol dehydrogenase.
Animals↗
Influence of fluconazole on antipyrine kinetics in rats.
The present study was undertaken to examine the effect of fluconazole on in vivo drug metabolism in rats, using the model substrate antipyrine. Oral doses of fluconazole, 20 mg/kg, were administered once (acutely) or twice daily for 4 days (chronically). Control animals received oral drug vehicle. Antipyrine kinetics were determined following an intravenous dose of 20 mg/kg given either 1 or 12 h after the single or last dose of fluconazole respectively. Acute fluconazole treatment significantly increased antipyrine half-life by 250% and reduced its clearance by 50%, without affecting its volume of distribution. Chronic treatment with fluconazole failed to affect antipyrine pharmacokinetics. This study demonstrates that acute fluconazole inhibits the metabolism of antipyrine in rats.
Administration, Oral↗
Pharmacodynamics of phenytoin-induced ataxia in rats.
The relationship between phenytoin-induced ataxia and its concentration was characterized in rats who received i.v. infusions of the drug at either 0.52, 0.85 or 1.70 mg/min/rat until the onset of ataxia. Phenytoin dose to ataxia did not change with infusion rate but the total and unbound serum concentrations at onset of ataxia increased with increasing infusion (input) rate. Concentrations in cerebrospinal fluid, CSF, and in brain, at this end-point, were not affected by the infusion rate. Direct i.v. infusion of phenytoin major metabolite, p-HPPH, failed to produce ataxia. Thus phenytoin in CSF and brain, unlike serum phenytoin, equilibrates rapidly with site(s) of phenytoin neurotoxicity and represents appropriate sampling sites for identifying factors affecting phenytoin neurotoxicity.
Animals↗
Assessment of in vitro and in vivo recovery of gallamine using microdialysis.
The application of microdialysis technique for the investigation of pharmacokinetics and pharmacodynamics of drugs requires careful assessment of probe performance to ensure validity of the data obtained using this technique. The aim of this study was to establish and validate the microdialysis technique for investigation of the pharmacokinetics and pharmacodynamics of the neuromuscular blocker, gallamine. In vitro recovery of gallamine from the microdialysis probe when different perfusion flow rates were employed was evaluated leading to selection of a flow rate of 2 microl/min with 15-min sampling intervals for the subsequent studies. In vitro recovery of gallamine from the microdialysis probe was independent of concentration, stable over an 8-h period and reproducible. Comparable in vitro recoveries were obtained by different established approaches including recovery estimation by gain, loss and the zero-net flux (ZNF) method. Recovery by loss was used to study the in vivo recovery of gallamine from rat muscle tissue. The in vivo recovery was stable over a 5.5-h sampling period. In vitro performance of the probe subsequent to the in vivo study remained stable supporting reusage of the probe. These data highlight the importance of a systematic examination of microdialysis probe validation.
Animals↗
Enhancement by cimetidine of neuromuscular paralysis induced with atracurium in rats.
The neuromuscular action of cimetidine, the prototype of H2 antagonists, was examined in urethane-anaesthetized and mechanically ventilated rats that were paralyzed with the non-depolarizing agent atracurium. Cimetidine, administered i.v. at doses of 3.2 to 56.2 mg/kg (13 to 223 microM/kg), produced an immediate potentiation of a steady 50% atracurium paralysis which was observed within 28 +/- 5 sec and which plateaued after 24 +/- 3 min. The dose of cimetidine that produced a 50% potentiation during peak effect was 14.5 mg/kg (58 microM/kg) and was associated with a serum cimetidine concentration of 47.5 micrograms/ml (or 188 microM). In a separate experiment, cimetidine, administered i.v. in a dose of 56.2 mg/kg (223 microM/kg), shifted the atracurium dose-effect curve to the left by 1.32-fold. Cimetidine alone, at either 10 or 100 mg/kg, did not affect the neuromuscular function by itself. These results suggest that high doses of cimetidine potentiate the neuromuscular paralysis induced with atracurium. This effect is opposite to that noted previously with ranitidine, a newer H2 antagonist which reverses atracurium neuromuscular paralysis in rats.
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Neuromuscular blocking drug pharmacodynamics after chronic exposure to H2- antagonists.
This study tested the hypothesis that chronic exposure to H2-antagonists may affect neuromuscular function. Cimetidine or ranitidine was administered to rats for twenty one days as subcutaneously implanted biodegradable pellets. Control rats received placebo pellets. Serum cimetidine and ranitidine concentrations ranged from 0.1 to 0.5 micrograms/mL over this period. On the study day, surgically prepared anaesthetized rats received either succinylcholine (SCh) or atracurium (ATr) to achieve complete paralysis of the tibialis anterior muscle. After recovery an infusion dose of each neuromuscular blocker was titrated to produce 50% muscle paralysis with each blocker. Exposure to cimetidine or ranitidine did not alter SCh or ATr dose to maximum paralysis or the time course of recovery from the initial paralysis. SCh or ATr infusion rates required to elicit 50% paralysis were also unaffected by cimetidine or ranitidine pretreatment. These results indicate that chronic exposure to cimetidine or ranitidine at human therapeutic concentrations does not affect the neuromuscular pharmacodynamics of SCh or ATr in rats.
Animals↗
Effect of fluconazole on neuromuscular transmission.
The effect of the anti-fungal agent fluconazole on neuromuscular transmission was evaluated in vivo using the rat sciatic nerve-anterior tibialis muscle preparation. Fluconazole, 20 mg/kg, administered orally one hour before the experiment failed to alter the infusion rate of succinylcholine required to maintain 50% neuromuscular paralysis. In addition, the rate of recovery from succinylcholine induced paralysis or the final recovery of the muscle twitch response did not differ between control and fluconazole treated rats. Fluconazole alone at 20 or 40 mg/kg I.V. also failed to produce any observable effect in neuromuscular function. Acute fluconazole, therefore, at human therapeutic concentrations, fails to alter neuromuscular transmission in vivo in rats.
Animals↗