Search PubMed⌕ Search

Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 235 records · Page 13Linked to original sources
PubMed1988

Kinetics of drug action in disease states. XXVI: Effect of fever on the pharmacodynamics of theophylline-induced seizures in rats.

This investigation was designed to determine the effect of fever on the neurotoxicity of theophylline as reflected by the concentrations of this drug that cause convulsions in experimental animals. Fever was produced in male, inbred, adult Lewis rats (approximately 180 g) by sc injection of brewer's yeast; an elevation of body temperature of 1.2 +/- 0.4 degrees C (mean +/- SD) was achieved at the time of the pharmacodynamic measurements. Theophylline was infused iv at a rate of 1.03 mg/min until the onset of maximal seizures. Drug concentrations in serum, serum water, brain, and cerebrospinal fluid (CSF) at that time were determined by high-performance liquid chromatography. Compared with the control group, the group of febrile rats had statically significantly lower serum protein concentrations, decreased serum protein binding of theophylline, and slightly increased theophylline concentrations in the CSF at the onset of seizures. Inasmuch as theophylline concentrations in the CSF reflect the concentrations of this drug in the biophase, the results of this study show that fever does not increase the sensitivity of the central nervous system to the neurotoxic effects of theophylline in rats. In fact, a statistically significant positive correlation between theophylline concentrations in the CSF and body temperature was found in this investigation, suggesting a decreased sensitivity of the animals to the neurotoxic effects of theophylline at higher body temperature.

Animals↗
PubMed1988

Caffeine as a potential risk factor for theophylline neurotoxicity.

Theophylline can cause life-threatening seizures when administered in excessive doses. The plasma concentrations associated with this neurotoxic effect vary widely among patients. To determine the reasons for the wide variation, an animal model of theophylline-induced seizures was developed and has now been used to determine the effect of pre-exposure to caffeine on theophylline-induced neurotoxicity. Male adult rats received an iv infusion of either caffeine citrate or sodium citrate solution for 15 min. Theophylline was then infused at a relatively rapid rate until onset of maximum seizures. A third group of rats received a rapid infusion of caffeine only until onset of seizures. Samples of blood, brain, and cerebrospinal fluid were obtained at that time for determination of caffeine and theophylline concentrations by HPLC. Prior exposure to caffeine was associated with a statistically significant reduction in the total amount of theophylline required to produce seizures and caused theophylline concentrations at all sampling sites to be significantly lower than in controls. Caffeine alone required a larger total dose and higher concentrations than theophylline alone to produce seizures. It is concluded that acute exposure to caffeine can increase the risk of theophylline-induced neurotoxicity.

Animals↗
PubMed1988

Assay of inorganic sulfate in biologic fluids by nonsuppressed (single-column) ion chromatography.

An assay using nonsuppressed (single-column) anion chromatography was developed to determine the concentration of inorganic sulfate in biologic fluids. A conventional HPLC system with an anion-exchange column and conductimetric detector interfaced with an automatic injector and integrator was used. The mobile phase for the chromatography of urine and serum samples is 4 mM potassium hydrogen phthalate, pH 4.5, and potassium iodide is used as the internal standard. For cerebrospinal fluid samples, the mobile phase is modified by addition of 10% of a 4 mM phthalic acid solution. Results of the HPLC assay were found to correlate well (r = 0.991 and 0.999) with those of two commonly used spectrophotometric methods for urine and serum inorganic sulfate determinations. However, the concentrations determined by ion chromatography were 2.5 to 10% lower, possibly due to less assay interference by other substances following chromatographic separation of sulfate. Anion chromatography using a single-column system is a convenient and relatively inexpensive method with sufficient sensitivity for the determination of inorganic sulfate concentrations in urine, serum, and cerebrospinal fluid.

Animals↗
PubMed1988

Pharmacodynamics of zoxazolamine and chlorzoxazone in rats.

Zoxazolamine is used for the pharmacologic assessment of possible changes in oxidative enzyme activity (paralysis time test) in rodents, whereas one of its metabolites, chlorzoxazone, is used clinically as a skeletal muscle relaxant. In this investigation, the pharmacodynamics of the two compounds were characterized in normal adult rats to determine their suitability for studies of the kinetics of drug action in disease states. Upon i.v. infusion 5 min beyond the onset of loss of the righting reflex (LRR) and concomitant blood sampling, serum concentrations of either drug were higher at the onset than at the offset of LRR, suggestive of a distribution disequilibrium. When zoxazolamine was infused at three different rates to onset of LRR, the pharmacologic end point was reached in 10 to 53 min. Drug concentrations in serum and brain at onset of LRR increased with increasing infusion rate, whereas drug concentrations in cerebrospinal fluid (CSF) were infusion rate independent and essentially identical to CSF concentrations at offset of LRR. Similar experiments (five infusion rates) with chlorzoxazone revealed drug infusion rate dependence even of CSF concentrations at the onset of LRR; only at very slow infusion rates (onset of effect in greater than or equal to 50 min) were onset concentrations in CSF essentially equal to offset concentrations. Neither drug produced measurable metabolite concentrations in the CSF. It is concluded that zoxazolamine but not chlorzoxazone distributes rapidly between CSF and the biophase, metabolites of either drug do not contribute measurably to the pharmacologic effect, and neither drug is subject to development of functional tolerance under the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Rapid development of functional tolerance to caffeine-induced seizures in rats.

The concentration and time dependence of caffeine-induced neurotoxicity was determined by infusing rats intravenously with caffeine at a rate of about 5, 12.5, and 25 mg kg-1 min-1 until the onset of generalized seizures which occurred at about 82, 28, and 11 min, respectively. The concentration of caffeine in the serum, brain, and cerebrospinal fluid at onset of seizures increased with decreasing infusion rate; the concentrations of caffeine metabolites were negligible and serum protein binding was not affected by the infusion rate. In another experiment, one group of rats was infused with caffeine for 60 min at about 2.2 mg kg-1 min-1 whereas another group was infused with solvent only. Both groups were then immediately infused with caffeine at about 22 mg kg-1 min-1 until onset of seizures. Caffeine concentrations at that time in serum, brain, and cerebrospinal fluid were significantly higher in the caffeine-pretreated animals than in the solvent-pretreated controls. The same pretreatment 17 hr before the fast infusion of caffeine had no apparent effect on caffeine concentrations at onset of seizures. These results show that functional tolerance to the seizure-inducing effect of caffeine in rats develops within minutes and that it is reversible within hours or less.

Animals↗
PubMed1988

Kinetics of drug action in disease states. XXV. Effect of experimental hypovolemia on the pharmacodynamics and pharmacokinetics of desmethyldiazepam.

It has been reported that hypovolemia secondary to extensive blood loss alters the functionality of the central nervous system and is associated with changes in the dose requirements or intensity of action of various central nervous system depressants, including a benzodiazepine. To investigate the mechanism(s) of this effect, the influence of experimental hypovolemia on the pharmacodynamics, receptor binding and pharmacokinetics of a benzodiazepine drug was determined. Adult male Sprague-Dawley rats were made hypovolemic by removal of about 30% of their blood over 30 min. An i.v. infusion of desmethyldiazepam (DDZP) was started 30 min later and continued until the animals lost their righting reflex. Compared to results obtained with normal controls, the hypovolemic rats required about one-half the dose of DDZP to produce loss of righting reflex and had significantly lower DDZP concentrations in serum and cerebrospinal fluid at that time. This effect of substantial blood removal could not be reversed by prompt return of the removed blood to the animals. Experimental hypovolemia had no apparent effect on the in vitro binding of tritiated diazepam to benzodiazepine receptor sites in the cerebral cortex of rats. The plasma clearance of DDZP was decreased significantly and the biological half-life was increased in hypovolemic rats compared to normal animals when both received a 30-mg/kg dose by i.v. infusion over 10 min. It is concluded that acute hemorrhagic hypovolemia increases the sensitivity of the central nervous system to the depressant effect of DDZP and decreases the body clearance of that drug in rats. Thus, the pharmacodynamics as well as the pharmacokinetics of a benzodiazepine are altered by hypovolemia.

Animals↗
PubMed1988

Kinetics of drug action in disease states. XXIV. Pharmacodynamics of diazepam and its active metabolites in rats.

The purpose of this investigation was to determine the relative contribution of diazepam and its active metabolites (desmethyldiazepam, oxazepam and temazepam) to the hypnotic activity of this benzodiazepine drug and to assess the role of rate of drug administration as a determinant of the relative concentrations of diazepam and its active metabolites in serum and in the central nervous system at the onset of a predefined pharmacologic endpoint. Rats were given i.v. infusions of diazepam to onset of loss of righting reflex. Samples of cerebrospinal fluid (CSF), blood (for serum) and brain were obtained at that time and were analyzed for diazepam and its active metabolites. Based on the results of six experiments on groups of 6 to 14 rats performed at the same time of day over 11 months, the pharmacologic response of the animals was found to be relatively consistent, with little variation between rats and between experiments in body weight-normalized effective dose and in diazepam serum and CSF concentrations. All three active metabolites of diazepam were found in serum, CSF and brain; they were relatively more prominent in CSF than in serum. Variation of the diazepam infusion rate (four rates between 0.10 and 0.34 mg/min per approximately 200-g rat) was associated with changes in average onset time (50 to 10 min) and dose (26 to 17 mg/kg) required to produce the pharmacologic effect. The drug and metabolite concentrations in CSF determined in these experiments, together with corresponding concentrations obtained by infusion of each active metabolite individually, yielded estimates of their relative hypnotic potency that were unaffected by differences in serum protein binding and tissue distribution.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

[Intravenous thrombolysis in myocardial infarction. Influence of the quality of the anticoagulation on the early recurrence rate of angina or infarction].

In this retrospective study the data of 70 patients treated with streptokinase in the acute phase of myocardial infarction were reviewed in search of a possible relation between recurrent ischaemic events and degree of anticoagulation. All patients had received a 30 mn infusion of streptokinase 1.500.000 units within a mean 175 mn period from the initial symptoms. They were followed up clinically (signs of angina or infarction), angiographically (coronary arteriography within 5.5 days on average) and biochemically (daily measurements of TCA values and blood fibrinogen concentrations). Fifteen recurrent ischaemic events (21.4 p. 100), including 6 attacks of angina and 9 myocardial infarctions, were observed. Angiography showed that the artery responsible for the initial infarction was occluded in 23.6 p. 100 (13/55) of patients without recurrent ischaemic accident. This figure rose to 46.6 p. 100 in patients who suffered a new anginal attack (7/15; NS) and up to 77 p. 100 in those who developed a new myocardial infarction (7/9; p less than 0.01). Biochemical data showed that 13 recurrent ischaemic accidents occurred when the APTT values were lower than 1.5 (176 measurements), as against 2 when these values were higher than 1.5 (359 measurements) (p less than 0.01). These two recurrent ischaemic accidents took place when fibrinogen concentrations abruptly rose above 1 g/litre. These results demonstrate that poor quality anticoagulation is responsible for the occurrence of recurrent ischaemic events within days of thrombolysis for acute myocardial infarction. They prompt the authors to recommend anticoagulation with heparin started at an early stage and carefully adjusted by means of repeated biochemical essays.

Adult↗
PubMed1988

Kinetics of drug action in disease states. XXVII. Effect of experimental renal failure on the pharmacodynamics of zoxazolamine and chlorzoxazone.

The purpose of this investigation was to determine whether the pharmacodynamics of the centrally acting skeletal muscle relaxants zoxazolamine (ZOX) and chlorzoxazone (CZX) are altered in renal failure. Male Lewis rats with renal failure due to bilateral ligation of ureters and sham-operated controls (ZOX and CZX), as well as rats with uranyl nitrate-induced renal dysfunction and saline-injected controls (ZOX only), received an infusion of ZOX or CZX until onset of loss of righting reflex. Drug concentrations in serum, brain and cerebrospinal fluid at that time were substantially lower in animals with renal failure or dysfunction than in normal controls. The ZOX concentrations in the cerebrospinal fluid correlated negatively with indices of renal function (serum creatinine and urea concentrations). Administration of a concentrated dialyzate of serum from rats with uranyl nitrate-induced renal dysfunction to normal animals also decreased the concentrations of ZOX at onset of loss of righting reflex. Thus, the sensitivity of the central nervous system of rats to the depressant action of ZOX and CZX is significantly increased by renal failure. This effect appears to be mediated, at least in part, by an endogenous, dialyzable substance that accumulates in the blood of rats with impaired renal function.

Acute Kidney Injury↗
PubMed1988

[First heterotopic ovarian autotransplantation in the female].

Treatment of subdiaphragmatic Hodgkin's disease with combined radio and chemotherapy results in castration of more than 80% women treated, despite oophorepexy. Several types of oophorepexy (lateral and medial transposition), have been described in the literature. None warranted sufficient schelter to avoid frequent alteration of ovarian function and fertility. We suggest a news technique of subcutaneous ovarian grafting which provides full protection against irradiation. To be successful, this technique requires the creation, prior to grafting, of a receptive cavity, two surgical teams working together, and the use of an operative microscope during transplantation. A mature oocyte was collected by puncture of the ovary containing cavity one year after the operation. Two years later, ovarian cycles remain regular, and follicle growth occurs normally each second of third cycle on the transplanted ovary.

Adolescent↗
PubMed1988

Nonlinear pharmacokinetics of aspirin in rats.

Rats are frequently used as an animal model for studies of the antithrombotic action of aspirin. The purpose of this investigation was to explore factors that influence the systemic exposure to unhydrolyzed aspirin after oral and systemic administration of the drug to adult male Sprague-Dawley rats. The experiments were performed according to a crossover design, and drug concentration measurements were made on whole blood. Intravenous injection and oral administration of aspirin (200 mg/kg) showed that the drug is eliminated rapidly (total clearance approximately 45 ml/min/kg; half-life approximately 8 min), that only about one-fourth of the dose is absorbed intact, and that the systemic availability of the oral dose is highly variable (coefficient of variation approximately 60%). A 40 mg/kg i.v. dose was cleared almost twice as rapidly as a 200 mg/kg i.v. dose. Injection of salicylic acid to yield concentrations similar to those obtained after injection of the large dose of aspirin (approximately 400 mg/l) reduced the total clearance of a 40 mg/kg i.v. dose of aspirin by about one-third, suggesting product inhibition of ester hydrolysis. The systemic availability of aspirin infused into the portal circulation was about 80% over a wide range of infusion rates, showing that presystemic hydrolysis of the drug occurs mainly in the gut. As in humans, absorption of orally administered aspirin affects the exponential decline of aspirin concentrations in blood, resulting in an apparent half-life substantially longer than the actual biologic half-life of the drug after i.v. injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗