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Biomedical subjects

I Ramzan

Publications and source records attributed to I Ramzan.

At least 37 records · Page 2Linked to original sources
PubMed1996

Determinants of acute regional toxicity following isolated limb perfusion for melanoma.

Hyperthermic isolated limb perfusion (ILP) with melphalan is well established as an effective form of treatment for recurrent melanoma confined to an extremity. High drug concentrations in the limb are readily achieved, without systemic side-effects. However, regional toxicity can lead to considerable morbidity and functional disturbance. This study was undertaken to evaluate factors which might contribute to acute regional toxicity following ILP. Melphalan concentrations in limb blood samples taken at regular intervals during 135 ILPs were measured by HPLC, allowing peak melphalan concentration and area under the curve (AUC) for each procedure to be determined. Acute regional toxicity associated with ILP was found to be significantly correlated with limb tissue temperatures > 40 degrees C, peak melphalan concentration and melphalan AUC, in decreasing order, but was not correlated with tourniquet time. Further studies are required to directly assess melphalan uptake by tumour tissue, and to relate this to both limb toxicity and tumour response.

Antineoplastic Agents, Alkylating↗
PubMed1994

Pharmacokinetics of fluconazole in cats after intravenous and oral administration.

Fluconazole (100 mg) was administered to six adult cats as an intravenous infusion over 30 minutes, and the same cats received 100 mg of the drug orally 16 weeks later. The cats were bled repeatedly through an indwelling jugular catheter, the plasma fluconazole concentrations were assayed by high performance liquid chromatography, and the concentration-time data were subjected to a non-compartmental pharmacokinetic analysis. The mean (SD) intravenous half-life (13.8 [2.6] hours) was similar to that observed after oral dosing (12.4 [3.0] hours). The plasma clearances (intravenous 0.9 [0.1], oral 0.9 [0.2] ml min-1 kg-1) and the volumes of distribution at steady state (intravenous 1.1 [0.1], oral 1.0 [0.1] litre kg-1) were also similar after the two routes of dosing. The peak plasma concentration was reached 2.6 hours after oral dosing and the drug was completely bioavailable (1.09 [0.05]). On the basis of this single dose study, the administration of 50 mg fluconazole every eight hours to a 4 kg cat should produce average steady state plasma fluconazole concentrations of approximately 33 mg litre-1.

Administration, Oral↗
PubMed1994

In-vitro interaction between H2 antagonists and vecuronium.

The interaction between histamine H2 antagonists and the neuromuscular blocking drug vecuronium was investigated in the rat phrenic nerve-hemidiaphragm preparation. Cimetidine alone, in the concentration range 800-4000 microM produced between 14 and 74% neuromuscular paralysis with an EC50 (mean +/- s.e.) of 2900 +/- 100 microM. Ranitidine augmented the indirectly-evoked muscle response at concentrations between 30 and 160 microM but at higher concentrations, between 300 and 1800 microM, produced neuromuscular paralysis. Famotidine produced negligible and statistically insignificant (0-5%) neuromuscular paralysis at concentrations between 0.3 and 300 microM. Cimetidine (800 microM) shifted the neuromuscular concentration-effect curve of vecuronium to the left in a parallel manner, while ranitidine (160 microM) shifted it to the right. The potentiation ratio was 1.90 +/- 0.14 for cimetidine and 0.62 +/- 0.05 for ranitidine. Famotidine (30 microM) did not alter the response to vecuronium. These data indicate that higher than clinically relevant concentrations of cimetidine and ranitidine produce neuromuscular paralysis and may potentiate the action of vecuronium. Low concentrations of ranitidine may antagonize the action of vecuronium. Famotidine, in contrast, lacks significant neuromuscular effects.

Animals↗
PubMed1994

Omeprazole potentiates atracurium and succinylcholine paralysis in vivo in rats.

We examined the effect of proton pump inhibitor omeprazole on neuromuscular paralysis induced with either nondepolarizing or depolarizing neuromuscular blocking drugs in anesthetized and mechanically ventilated rats. Neuromuscular paralysis, as judged by tibialis anterior muscle twitch tension in response to sciatic nerve stimulation, was maintained at about 50% with intravenous (i.v.) bolus and infusion regimens of either atracurium or succinylcholine. Omeprazole, 0.5, 1, and 10 mg/kg i.v., was then administered at 10-min intervals while the infusion of the neuromuscular blocker was continued. Omeprazole at all three doses increased the steady-state neuromuscular paralysis produced with either atracurium (pre-omeprazole versus final post-omeprazole paralysis; mean +/- SE, n = 6, 53.0% +/- 2.3% vs 80.0% +/- 5.3%) or succinylcholine (50.8% +/- 1.5% vs 86.4% +/- 5.1%). Omeprazole, 0.5, 1.0, and 10 mg/kg i.v., given directly and without any neuromuscular blocker, produced approximately 5% depression of the muscle twitch response. Omeprazole, i.v. at human therapeutic doses, alters neuromuscular function and enhances the action of both atracurium and succinylcholine in vivo in rats.

Animals↗
PubMed1993

Interaction between succinylcholine and ranitidine in rats.

The hypothesis that the histamine H2 receptor blocker ranitidine potentiates neuromuscular paralysis during anaesthesia was tested in vivo in urethane anaesthetised and mechanically ventilated rats. Succinylcholine was administered as a bolus and constant-rate infusion to maintain 48.5% (+/- 2.5 SEM) tibialis anterior muscle paralysis in 14 rats. Ranitidine 2.5, 5, 10, or 20 mg.kg-1 iv, was then administered into groups of three or five rats. Ranitidine produced an immediate potentiation of neuromuscular paralysis followed by a transient reversal and then a continued steady-state potentiation. Peak potentiation occurred within 20 (+/- 3.3) sec and was maintained in all the rats to steady-state. Peak reversal was evident 70 (+/- 8.1) sec after ranitidine administration. There was an excellent relationship (r2 = 0.98, P < 0.001) between peak potentiation and serum ranitidine concentration with 50% potentiation occurring at 25.8 (+/- 1.1) micrograms.ml-1. There was a weak relationship (r2 = 0.39, P < 0.05) between peak reversal and serum ranitidine but potentiation at steady-state was not correlated to serum ranitidine concentration (r2 = 0.19, P > 0.05). These results show that ranitidine alters the neuromuscular action of succinylcholine in rats in a similar manner to cimetidine.

Anesthesia, Intravenous↗
PubMed1993

Pain sensitivity in dietary-induced obese rats.

Previous literature indicates possible interrelationships between the endogenous opioids or endorphins, pain response, and obesity or eating behaviour. The pain response was, therefore, examined in a rat model of obesity induced by palatable food high in unsaturated fats. Pellet-fed control and energy-dense obese and nonobese rats were tested for latency of response to a thermal stimulus using the tail flick test. Obese rats exhibited a statistically significant increase in tail flick latency compared to controls. In addition, the observed latencies were significantly correlated to the body weight of the rats (r = 0.52, p < 0.01). These data suggest that dietary-induced obese rats are similar to obese humans in being less sensitive to painful stimuli, consistent with an increase in endogenous opioids in obesity.

Animals↗
PubMed1993

Ranitidine reverses gallamine paralysis in rats.

The effect of ranitidine on gallamine-induced depression of twitch tension was evaluated in urethane-anaesthetized and mechanically ventilated male Sprague-Dawley rats. Gallamine was administered as an intravenous (IV) bolus and constant rate infusion in 15 rats to maintain 89 +/- 7% (SE) depression of twitch tension induced by electrical stimulation of a sciatic nerve. Ranitidine, IV at either 0.5, 1, 2.5, 5, or 10 mg/kg, was then administered into groups of three rats. Ranitidine produced an immediate dose- and serum concentration-dependent reversal (antagonism) of the twitch tension depression induced with gallamine. The reversal was observed within approximately 30 s and was maintained for 3-26 (12 +/- 2) min. The dose of ranitidine that produced 50% reversal was 2.9 +/- 0.1 mg/kg, and this reversal was associated with a ranitidine serum concentration of 5.2 +/- 0.3 micrograms/mL. Ranitidine administered alone (and without gallamine) did not alter twitch tension at either 2.5 or 20 mg/kg. In addition, ranitidine did not alter either the gallamine neuromuscular blocking concentration in serum or the serum clearance of gallamine. Ranitidine reverses the neuromuscular action of gallamine, and this effect of ranitidine is not due to a pharmacokinetic interaction between ranitidine and gallamine.

Animals↗
PubMed1993

Interaction between famotidine and neuromuscular blockers: an in vivo study in rats.

The effect of histamine 2-antagonist famotidine on neuromuscular paralysis induced with either nondepolarizing or depolarizing neuromuscular blocking drugs was examined in anesthetized and mechanically ventilated rats. Neuromuscular paralysis, as judged by tibialis anterior muscle twitch tension in response to sciatic nerve stimulation, was maintained at about 50% with intravenous bolus and infusion regimens of either atracurium, gallamine, succinylcholine, or decamethonium. Famotidine, 0.1, 1, and 4 mg/kg, intravenously, were then administered at 5-min intervals as the infusion of the neuromuscular blocker was continued. Famotidine at any of these three doses failed to alter the steady state neuromuscular paralysis produced with either atracurium (prefamotidine versus final postfamotidine paralysis (mean +/- SE depression of twitch tension, n = 6, 49.8 +/- 2.8 vs 51.5 +/- 2.6%), gallamine (47.8 +/- 1.6 vs 47.6 +/- 3.0%), succinylcholine (49.2 +/- 1.8 vs 49.4 +/- 2.0%), or decamethonium (50.3 +/- 2.1 vs 51.5 +/- 2.0%). Intravenous famotidine at human therapeutic doses, fails to alter neuromuscular function in vivo in rats.

Animals↗
PubMed1992

Myoclonus in the decerebrate cat produced by gallamine.

After intravenous infusion maintaining a neuromuscular blocking concentration very little gallamine enters the cerebrospinal fluid (CSF) of the intact anesthetized cat even after several days. After a similar intravenous infusion in the decerebrate cat gallamine enters the CSF slowly over 4 days eventually reaching a concentration similar to that in the plasma. This procedure is accompanied by very strong twitching in many muscles and the occurrence of slow waves in the inferior olive in synchrony with the twitches. A large dose (4 mg) of gallamine triethiodide injected directly into the cisterna magna of an intact anesthetized cat produced twitching within 1 min and slow waves in the inferior olive in good synchrony with the twitches; the effects lasted at least 43 h. Injection of a quantity of gallamine triethiodide (about 130 micrograms) sufficient to mimic the concentration in the CSF obtained after 3-4 days of neuromuscular block in the decerebrate cat (50-120 micrograms/ml gallamine) had extremely weak effects lasting for at most 1 h. However, this weak effect is probably due to the anesthetic because injection of a similar quantity into an (unanesthetized) decerebrate cat at any time after decerebration had strong effects. After intracisternal injection of gallamine the concentration in the CSF reaches very low levels within 12 h but twitching and activity in the inferior olive persists for 1-2 days. The reasons for this prolonged action are now being investigated. The effects of gallamine are compared with the condition of reticular reflex myoclonus.

Animals↗
PubMed1992

Interaction between succinylcholine and cimetidine in rats.

The hypothesis that histamine H2 receptor blockade adversely affects neuromuscular function was tested, in vivo, in rats anaesthetised with urethane during mechanical pulmonary ventilation. Succinylcholine was administered as a bolus and constant-rate infusion to maintain 49.2% (+/- 1.5 SEM) twitch suppression in 19 rats. Cimetidine iv, 3.2, 7.5, 10, 17.8, 23.7, 31.6, or 56.2 mg.kg-1 was then administered in groups of two to three rats. Cimetidine produced an immediate potentiation of twitch suppression followed by a transient reversal and then a continued potentiation. Peak potentiation occurred within 19.0 (+/- 2.7) sec and was maintained in 11 rats at steady-state. Reversal was evident 4.1 (+/- 0.4) min after cimetidine administration. There was a good relationship between peak potentiation and serum cimetidine concentration with 50% potentiation occurring at 46.5 (+/- 4.6) micrograms.ml-1. Potentiation at steady-state was not correlated to serum cimetidine concentration but there was a weak relationship between reversal and serum cimetidine concentration. These results support reports from patients of an interaction between cimetidine and succinylcholine.

Anesthesia, Intravenous↗
PubMed1992

Influence of cimetidine on gallamine-induced neuromuscular paralysis in rats.

1. The effect of cimetidine on gallamine-induced neuromuscular paralysis was evaluated in urethane-anaesthetized and mechanically ventilated rats. 2. Intravenous cimetidine (between 3.2 and 100 mg/kg) produced an immediate and sustained potentiation of gallamine-induced neuromuscular paralysis. 3. Intravenous calcium (0.35 mmol/kg) completely reversed the cimetidine-induced potentiation of gallamine's effect. 4. Cimetidine alone did not produce neuromuscular paralysis. 5. Cimetidine did not alter either the serum concentration or the total serum clearance of gallamine. 6. Cimetidine thus potentiates the action of gallamine via a pharmacodynamic and not a pharmacokinetic mechanism.

Animals↗
PubMed1991

High-performance liquid chromatographic assay for laudanosine in biological fluids and tissue for neurotoxic studies in rats.

A procedure for the determination of laudanosine, the central nervous system active metabolite of the neuromuscular blocking drug atracurium, in serum, cerebrospinal fluid and brain is described. The method uses a readily available internal standard, ethavrine, and a single-step protein precipitation with acetonitrile followed by high-performance liquid chromatographic separation with ultraviolet detection. Norlaudanosine, the major metabolite of laudanosine, can also be quantified. Linearity of detector response was obtained between 1 and 25 micrograms/ml or micrograms/g and the method is suitable for determining neurotoxic concentrations of laudanosine in experimental animals.

Animals↗
PubMed1990

Theophylline neurotoxicity is unaffected by glycerol-induced renal failure.

Glycerol acute renal failure (ARF) was examined to see if it alters theophylline (Th) neurotoxicity in rats. Concentrations of Th in serum, cerebrospinal fluid and in brain at seizure onset were similar in control and ARF rats infused with Th. Thus, glycerol ARF fails to alter Th neurotoxicity, an effect similar to that noted previously with uranyl nitrate but not with ureter ligation.

Acute Kidney Injury↗
PubMed1989

Kinetics of drug action in disease states. XXXIII: Disparate effects of pentylenetetrazol in rats as a function of renal disease model and pharmacologic endpoint.

The purpose of this investigation was to determine if the pharmacodynamics of the central nervous system stimulant pentylenetetrazol (PTZ) are altered in renal dysfunction. Female rats subjected to bilateral ureteral ligation (with sham-operated controls) or injected with uranyl nitrate (with saline injected controls) were infused intravenously with PTZ until the onset of either a minimal (myoclonic jerk) or maximal (tonic hindlimb extension) seizure. Neither chemically nor surgically induced renal dysfunction caused a change in the concentrations of PTZ in CSF, serum, or brain at onset of minimal seizures. When PTZ was infused to onset of maximal seizures, the rats with chemically induced renal dysfunction required higher concentrations, whereas the ureter-ligated rats convulsed at lower concentrations of PTZ than did the corresponding control animals. Thus, the effects of experimental renal dysfunction on the convulsant action of PTZ are dependent on both the disease model and the endpoint used for the pharmacodynamic measurement. Apparently, renal dysfunction did not affect the PTZ-induced seizure threshold, but inhibited the spread of seizures. The increased sensitivity of ureter-ligated rats may be due to their pronounced retention of water, since water loading is known to increase seizure susceptibility.

Animals↗
PubMed1989

Relationship between concentration and anticonvulsant effect of phenytoin against electroshock-induced seizures in rats: comparison of sampling sites for concentration determinations.

The purpose of this investigation was to determine the optimum sampling site for phenytoin concentration measurements in the context of pharmacodynamic studies of the anticonvulsant effect of phenytoin. Determination of drug concentrations in the serum, serum water, brain, and cerebrospinal fluid (CSF) of rats as a function of time after iv injection of a 6-mg/kg dose revealed a significant disequilibrium between brain and serum water for 15 min and between CSF and serum water for 5 min after injection. The concentrations of phenytoin in serum water 1 min after injection of 3 mg/kg (0.371 +/- 0.054 microgram/mL) and 45 min after injection of 8 mg/kg (0.399 +/- 0.049 microgram/mL) were not significantly different, but drug concentrations in the CSF and brain were appreciably higher after the latter dose. There was no protection against electroshock-induced seizures 1 min after the 3-mg/kg dose, but there was complete protection 45 min after the 8-mg/kg dose. At 15 min after drug injection, phenytoin concentrations in CSF and serum water were essentially identical over a wide concentration range. Fifty female Lewis rats weighing approximately 225 g, that consistently exhibited maximal electroshock-induced seizures in three preliminary trials on separate days, received 1, 2, 4, 6, or 8 mg/kg of phenytoin by iv injection. Electroshock was applied 15 min later, the percentage of animals protected from seizure by each dose was determined, and drug concentrations in serum, serum water, brain, and CSF were measured by gas chromatography. The relationship between anticonvulsant activity and drug concentration could be described by a Hill-type equation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Proconvulsant effect of papaverine on theophylline-induced seizures in rats.

1. The effects of papaverine, an adenosine uptake inhibitor, were tested against theophylline-induced seizures. 2. Rats were infused with a constant intravenous infusion of theophylline at 10.3 mg/min immediately following intraperitoneal pretreatment with either papaverine 35 mg/kg or saline vehicle. 3. Papaverine produced a potent proconvulsant effect towards theophylline seizures, reducing the onset time and cumulative dose to seizure and theophylline concentrations in arterial serum, cerebrospinal fluid and brain, respectively, at onset of maximal seizures.

Animals↗