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Biomedical subjects

I M Ramzan

Publications and source records attributed to I M Ramzan.

At least 19 recordsLinked to original sources
PubMed1995

Pharmacokinetics of alcuronium in children with acyanotic and cyanotic cardiac disease undergoing cardiopulmonary bypass surgery.

The aim of this study was to determine the pharmacokinetic parameters for alcuronium in children with cyanotic or acyanotic congenital cardiac disease undergoing cardiopulmonary bypass surgery and to compare these parameters with previously reported values in children and adults with normal cardiac function. Seven children with acyanotic disease and seven with cyanotic disease were studied. Alcuronium (base) was administered in an initial dosage of 0.25 mg.kg-1 with additional doses as needed to maintain paralysis. Using time averaged data, cyanotic children had lower mean clearance, elimination half-life and volume of distribution at steady state than the acyanotic children; none of these differences was, however, statistically significant. In this study, children with acyanotic and cyanotic cardiac disease undergoing bypass, had a diminished clearance (P < 0.05) and a smaller volume of distribution (P < 0.05) than normal children and a shorter elimination half-life (P < 0.05) than adults. Onset of cardiopulmonary bypass caused an immediate marked decrease in alcuronium plasma concentrations which remained low in the acyanotic children at the completion of bypass.

Adjuvants, Anesthesia↗
PubMed1993

Delayed onset of alcuronium effect in children with cyanotic congenital heart disease.

The effect of alcuronium dichloride (0.3 mg/kg) was studied in seven normal children (Group A), nine with acyanotic congenital heart disease (Group B) and eight with cyanotic disease (Group C). The onset of action was recorded using an integrated electromyograph and blood samples taken for later estimation of plasma concentrations of the drug. The mean time (SD) taken to 75% suppression of twitch height was 1.3(0.8), 1.7(1.0) and 3.8(2.8) minutes, respectively, in each of the three groups. This was significantly slower in Group C compared with both other groups (P < 0.05). While six of the Group A patients and seven from Group B reached 95% paralysis within ten minutes, only two of the cyanosed children achieved this level of relaxation. However, if times to 95% relaxation were extrapolated, there was no significant difference between the groups at 4.5(3.9), 5.8(5.7) and 10.9(6.5) minutes respectively. There was a weak but statistically significant relationship between haematocrit and time to 75% blockade. Maximum twitch depression was similar in all three groups with plasma concentrations at this time being 1.6(0.7), 1.8(0.5) and 2.3(1.4) micrograms/ml respectively. Again, there was no statistically significant difference between these values. These results confirm that the clinical onset of relaxation is delayed in children with cyanotic congenital heart disease, possibly because of delayed distribution of alcuronium.

Alcuronium↗
PubMed1989

Intravenous ranitidine antagonizes intense atracurium-induced neuromuscular blockade in rats.

The neuromuscular action of ranitidine, an H2-receptor antagonist, was investigated by determining its effect on atracurium-induced neuromuscular blockade in urethane-anesthetized and mechanically ventilated male Sprague-Dawley rats. An intravenous bolus and an infusion of atracurium were administered to produce a stable 93 +/- 5% (n = 11) neuromuscular blockade as judged by tibialis anterior muscle twitch response. Ranitidine administered as a 1, 5, or 10 mg/kg normal body weight IV bolus during continuous atracurium infusion produced marked antagonism of neuromuscular paralysis. The percentage of antagonism (25 +/- 9%; n = 4; 53 +/- 19%, n = 4; and 79 +/- 9%, n = 3, respectively) was linearly related to the dose of ranitidine (r = 0.86, P less than 0.05). These results suggest that IV ranitidine has a significant anticholinesterase action against atracurium-induced neuromuscular blockade.

Animals↗
PubMed1987

Kinetics of drug action in disease states. XIX. Effect of experimental liver disease on the neurotoxicity of theophylline in rats.

There are pronounced interindividual differences in the neurotoxicity of theophylline in humans as reflected by the wide range of plasma theophylline concentrations associated with the occurrence of life-threatening, generalized seizures in patients treated with this widely used bronchodilator. The variability indicates that there may be a number of as yet unrecognized risk factors for theophylline neurotoxicity. After the development of an animal model of theophylline-induced seizures, renal failure was identified as one such risk factor. This investigation was designed to determine if experimental liver disease will alter the neurotoxic effect of theophylline. Studies were performed on rats with extrahepatic cholestasis produced by bile duct ligation and with hepatic necrosis induced by carbon tetrachloride administration and on respective controls. Theophylline was infused i.v. at 1.03 mg/min until the onset of maximal seizures. Theophylline and theophylline metabolite concentrations at that time were determined in serum (unbound and total drug), brain and cerebrospinal fluid. Extrahepatic cholestasis was associated with small increases in unbound theophylline concentration in serum, theophylline concentration in brain and serum free fraction in serum at onset of seizures. The concentrations of theophylline metabolites were negligible. There were no apparent effects of extrahepatic cholestasis or hepatic necrosis on theophylline concentrations at onset of seizures in cerebrospinal fluid, the fluid that was shown in a preceding study to be the best indicator of the theophylline concentration at the site of the neurotoxic effect. It is concluded that experimental liver disease had no apparent effect on the neurotoxicity of theophylline under the conditions of this investigation.

Acute Kidney Injury↗
PubMed1987

Kinetics of drug action in disease states. XVIII. Effect of experimental renal failure on the pharmacodynamics of theophylline-induced seizures in rats.

Theophylline, the bronchodilating agent, can cause life-threatening, generalized seizures when plasma concentrations exceed the usual therapeutic concentration range. However, the plasma concentrations of theophylline associated with this neurotoxic effect vary widely between patients. To determine the reasons for the wide variation, and thereby to facilitate prevention or early treatment of theophylline-induced neurotoxicity, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of experimental renal failure on the concentrations of theophylline that cause convulsions. Adult female rats were subjected to bilateral ureteral ligation or injected with uranyl nitrate to produce renal failure or dysfunction. Sham-operated and saline-injected rats, respectively, served as controls. Theophylline was infused i.v. at either 1.03 or 2.06 mg/min until the onset of maximal seizures. Renal failure due to ureter ligation was associated with a substantial reduction of the dose of drug required to produce seizures, the concentrations of total and free (unbound) theophylline in serum and the concentrations of theophylline in the brain and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were very low and did not account for the enhanced neurotoxicity. No apparent change in the neurotoxicity of theophylline was observed in rats with uranyl nitrate-induced renal dysfunction. The results of the investigation on ureter-ligated rats are consistent with recent clinical findings of a higher incidence of theophylline-induced neurotoxicity in azotemic patients. The experimental methodology may therefore be suitable for the prospective identification of other potential clinical risk factors for theophylline neurotoxicity.

Animals↗
PubMed1986

Chronic theophylline administration has no apparent effect on theophylline concentrations required to produce seizures in rats.

Theophylline, the widely used antiasthmatic drug, can cause life-threatening, generalized seizures when administered in excessive doses. The plasma concentrations of theophylline associated with these seizures vary widely among patients, thereby complicating efforts to prevent seizures by timely initiation of appropriate treatment. Some investigators suspect that chronic administration increases the neurotoxicity of theophylline but others have suggested the opposite. We have studied this problem in an animal model of theophylline-induced seizures. Osmotic pumps containing theophylline solution or drug-free solvent (for the surgical control group) were implanted in adult female Lewis rats, yielding almost constant serum theophylline concentrations of about 14 mg/liter for 7 days in the treated group. On the seventh day, theophylline was administered by much more rapid iv infusion to the two groups of animals and to one nonimplanted (nonsurgical) control group until onset of maximal seizures. There were no statistically significant differences between the three groups with respect to the concentrations of theophylline in serum, serum water, brain, and cerebrospinal fluid at onset of seizures. The concentrations of theophylline metabolites were either very low or undetectable. Under the experimental conditions, preexposure of rats for 7 days to theophylline in the human therapeutic concentration range had no apparent effect on the acute neurotoxicity of the drug.

Animals↗
PubMed1986

Kinetics of drug action in disease states. XVI. Pharmacodynamics of theophylline-induced seizures in rats.

Seizures, often with fatal outcome, are a manifestation of pronounced theophylline intoxication. The purpose of this investigation was to characterize the relationship between theophylline concentrations and theophylline-induced convulsions and to develop an animal model suitable for exploring conditions that might predispose theophylline-treated individuals to seizures. Female Lewis rats (approximately 170 g) received an i.v. infusion of theophylline (as aminophylline) at one of three different rates (1.03-5.1 mg/min/rat) until the animals exhibited a maximal seizure (which occurred after 11 +/- 1 to 42 +/- 3 min of infusion). The total dose, the serum concentration (both total and unbound drug) and the brain concentration of theophylline at onset of seizures increased with increasing infusion rate. The theophylline concentration in cerebrospinal fluid at onset of seizures (mean +/- S.D., 232 +/- 17 mg/l, n = 41) was not affected by the infusion rate. The theophylline metabolites 1-methyluric acid and 1,3-dimethyluric acid were found in serum but at very much lower concentrations than those of theophylline. 1-Methylxanthine and caffeine were not detected in any serum sample, 3-methylxanthine was present in low concentrations in only some serum samples and 1-methyluric acid and 3-methylxanthine were found in the brain in low concentrations (less than 10 mg/kg). Theophylline metabolites were not detected in cerebrospinal fluid. Direct i.v. infusion of either 1-methyluric acid, 1,3-dimethyluric acid or 3-methylxanthine did not produce seizures despite high concentrations in serum. Ethylenediamine infusions also did not cause seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Kinetics of drug action in disease states. XV: Effect of pregnancy on the convulsive activity of pentylenetetrazol in rats.

The purpose of this investigation was to determine whether the pharmacodynamics of the central nervous system stimulant pentylenetetrazol (1) are altered in advanced pregnancy. Lewis rats that were 20 days pregnant and nonpregnant rats of the same age and strain received either a relatively fast or a relatively slow intravenous infusion of 1 until the onset of a maximal seizure, which occurred after about 11 or 31 min, respectively, of infusion. The concentrations of 1 at that time in serum, cerebrospinal fluid, (CSF) and brain were independent of the infusion rate and did not differ significantly between pregnant and nonpregnant animals. The ratio of concentrations of 1 in the cerebrospinal fluid to that in serum was unity in all groups, consistent with negligible serum protein binding and indicative of rapid penetration of 1 into the central nervous system. It is concluded that advanced pregnancy has no apparent effect on the response of the central nervous system of rats to the convulsive activity of 1.

Animals↗
PubMed1985

Kinetics of drug action in disease states. XIV. Effect of infusion rate on pentylenetetrazol concentrations in serum, brain and cerebrospinal fluid of rats at onset of convulsions.

The purpose of this investigation was to develop a method which can be used to determine the effect of various diseases on the concentration-pharmacologic activity relationship of the central nervous system stimulant pentylenetetrazol (PTZ, Metrazol) in a manner that excludes or accounts for pharmacokinetic variables. Adult female rats (approximately 170 g) received an i.v. infusion of PTZ at one of four different rates (0.155-1.53 mg/min) until the animals exhibited the first myoclonic jerk. This occurred after an average of 4.9 to 52 min of infusion. The PTZ concentrations in serum, brain and cerebrospinal fluid at this pharmacologic endpoint were independent of infusion rate. Other groups of rats were infused at three different rates (0.155-1.53 mg/min) to the onset of maximal seizures. Again, the PTZ concentrations in serum, brain and cerebrospinal fluid were not significantly affected by the rate of infusion of the drug. The average (+/- S.D.) PTZ concentration in cerebrospinal fluid was 46 +/- 5 mg/l (n = 22) at the onset of the first myoclonic jerk and 109 +/- 13 mg/l (n = 12) at the onset of maximal seizure. PTZ concentrations in brain and serum were similar to those in cerebrospinal fluid. The total serum clearance of a 20-mg/kg i.v. bolus dose of PTZ was 5.36 +/- 0.34 ml/min/kg, the terminal half-life was 116 +/- 25 min and the apparent volume of distribution was 896 +/- 134 ml/kg (all values are mean +/- S.D.). Serum protein binding was negligible (less than 10%).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Gallamine disposition in open-heart surgery involving cardiopulmonary bypass.

Kinetics of gallamine, a neuromuscular blocker, were investigated in 22 adult patients undergoing surgery involving cardiopulmonary bypass (CPB). Approximately 60 min before CPB, 11 patients received 480 mg gallamine IV; the other 11 patients received an initial dose of 240 mg IV, followed by another 240 mg through the pump priming fluid at the start of CPB. In 14 of our patients, the time course of gallamine concentrations in the plasma before, during, and after CPB was similar to that in normal surgical patients, indicating little or no effect of cardiac disease or CPB. In the remaining patients, perturbations were not observed before CPB, but with its onset there were varying changes, typically, rises in gallamine concentration ranging from an alteration during the period of CPB only or during the elimination phase, to an alteration at all times after starting CPB. Although the mechanism for this rise in gallamine plasma concentrations during and after CPB is not known, computer simulations suggest that it is due to a contraction in blood volume or decreased tissue perfusion during the period of extracorporeal circulation. Gallamine disposition differed only moderately in our patients from that in control patients. Therefore, from a kinetic viewpoint, provided that renal function is not impaired, gallamine is not contraindicated in CPB surgery.

Adult↗
PubMed1981

Pharmacokinetics and pharmacodynamics of gallamine triethiodide in patients with total biliary obstruction.

Pharmacokinetics and pharmacodynamics of gallamine were assessed in seven patients undergoing surgery for correction of total biliary obstruction. Results were compared to those obtained in a previous study of 17 patients without obstruction. A significant increase in the steady-state volume of distribution of gallamine was noted in patients with biliary obstruction as compared to the group without obstruction, but no significant differences between the groups were apparent for the biologic half-life and total clearance of the drug. Duration of action of gallamine and rate of recovery together with onset characteristics were similar in both patient groups. Slight accumulation of gallamine was noted in two of the four patients with biliary disease receiving multiple doses of gallamine, but this was also characteristic of data obtained in the patients without obstruction. At completion of surgery to relieve the biliary obstruction all patients showed a measurable degree of recovery from paralysis, and no difficulties were experienced in the reversal of relaxant effect. Contrary to the observed "resistance" of patients with liver disease to the action of d-tubocurarine no such finding was apparent in this study with gallamine. Gallamine may be the relaxant of choice for surgery to relieve total biliary obstruction provided no complicating renal pathology is also present.

Adult↗