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Biomedical subjects

R H Levy

Publications and source records attributed to R H Levy.

At least 55 records · Page 3Linked to original sources
PubMed1993

Recovery and elimination of the biotherapeutic agent, Saccharomyces boulardii, in healthy human volunteers.

Saccharomyces boulardii (Sb) is a nonpathogenic yeast used to treat intestinal illnesses such as pseudomembranous colitis and antibiotic associated diarrhea. The behavior of this biotherapeutic agent in humans was determined (1) in investigating the effect of dose on the steady-state level and recovery and (2) in quantitating the effect of ampicillin on the recovery and elimination profile. As the Sb dose increased, the mean steady-state concentration of Sb increased significantly. The percentage recovery was dose independent. When a single Sb dose was administered 24 hr after beginning a course of ampicillin, there was a significant increase (P < 0.01) in both the area under the concentration versus time curve and the maximum fecal concentration compared to values obtained without ampicillin. Ampicillin increased steady-state recovery of the drug about twofold (P < 0.05) and steady-state levels about 2.4 times (P < 0.01). These studies have shown that there is a relationship between the dose and the amount of Sb recovered and that perturbation of the GI flora by ampicillin increases steady-state levels of Sb.

Adult↗
PubMed1993

In vivo and in vitro correlation of microsomal epoxide hydrolase inhibition by progabide.

Progabide was investigated as a potential inhibitor of microsomal epoxide hydrolase as a result of reports of elevated levels of carbamazepine-10,11-epoxide after coadministration of progabide and carbamazepine to patients with epilepsy. The formation clearance of carbamazepine transdihydrodiol after administration of carbamazepine-10,11-epoxide to healthy volunteers was decreased 26% by progabide. Therapeutic concentrations of progabide inhibited S (+)-styrene oxide hydrolysis in human liver microsomes (inhibition constant [Ki] = 1.9 mumol/L) and purified human liver microsomal epoxide hydrolase (Ki = 4.4 mumol/L). A mixed competitive and noncompetitive mechanism of inhibition best described the effect of progabide on microsomal epoxide hydrolase; the most potent inhibition was competitive. A similar model described the inhibition by the acid metabolite of progabide, although inhibitory concentrations are higher than concentrations observed after progabide therapy. An excellent agreement between the in vivo and in vitro inhibitory potencies of progabide suggests that potential inhibitors of this important detoxification enzyme can be predicted in vitro.

Adult↗
PubMed1993

Measurement of in vivo microsomal epoxide hydrolase activity in white subjects.

An impairment or hereditary defect in microsomal epoxide hydrolase is considered a possible risk factor for drug and chemical toxicity. However, nothing is known about variability of in vivo epoxide hydrolase activity in humans. Our objectives were to develop and test a simple pharmacokinetic approach for measuring microsomal epoxide hydrolase activity in a population. After administration of carbamazepine-10,11-epoxide (100 mg), oral clearance showed a nearly linear relationship to the log (transdihydrodiol/epoxide) urine ratio in the 24- to 36-hour interval (log metabolic ratio). Intrasubject variability was assessed by administering the epoxide twice to 13 subjects (1- to 4-month interval); the log metabolic ratio did not change significantly (mean difference, 11%; paired t test, p = 0.79). In 110 healthy white adults, the log metabolic ratio ranged from 1.28 to 2.05 (mean +/- SD, 1.68 +/- 0.155). Outliers indicating enzyme-deficient phenotypes were not observed, and the frequency distribution was unimodal normal. The log metabolic ratio detected pronounced inhibition of epoxide hydrolase by valpromide (six subjects; median ratio, 0.91) and induction by phenobarbital/phenytoin (six subjects; median ratio, 2.42). We conclude that distribution of microsomal epoxide hydrolase activity in a study group can be measured pharmacokinetically by use of carbamazepine epoxide.

Adolescent↗
PubMed1992

Valproate hepatotoxicity syndrome: hypotheses of pathogenesis.

Therapeutic use of the anticonvulsant valproate (VPA) has been associated with a rare, but severe and often fatal hepatotoxicity. Cases usually present with lethargy, anorexia, and vomiting with rapid progression to coma. Liver histopathology is characterized by steatosis with and without necrosis. In some instances only necrosis was present. Several hypotheses of pathogenesis have been postulated. These deal mainly with biochemical systems that are known to be affected by VPA, or with the possible idiosyncratic production of toxic VPA metabolites, especially delta 4-VPA. At present, no hypothesis entirely explains the diverse characteristics of the disorder.

Ammonia↗
PubMed1992

Comparative bioavailability and steady state fluctuations of Tegretol commercial and carbamazepine OROS tablets in adult and pediatric epileptic patients.

The comparative bioavailability and steady state fluctuations resulting from the administration of Tegretol 200 mg commercial tablets and carbamazepine OROS controlled delivery tablets were investigated in 22 adult and 12 pediatric epileptic patients. Tegretol commercial tablets were dosed according to previously established clinical regimens of 400 to 2000 mg daily doses divided into four equal or unequal intervals. Carbamazepine OROS was dosed every 12 h at the same corresponding daily dose. Comparisons of the pharmacokinetic parameters AUC, Cmax, Cmin, and tmax at steady state for the two dosage forms demonstrated definitively the bioequivalence of carbamazepine OROS with Tegretol commercial tablet over a 24-h treatment interval.

Adolescent↗
PubMed1992

Comparative anticonvulsant potency and pharmacokinetics of (+)-and (-)-enantiomers of stiripentol.

The anticonvulsant potency and pharmacokinetics of the enantiomers of stiripentol were compared using the intravenous pentylenetetrazol infusion seizure model in the rat. Enantioselectivity was observed with respect to both the anticonvulsant activity and elimination kinetics of this compound. (+)-Stiripentol was 2.4 times more potent than its antipode against pentylenetetrazol-induced clonic seizure (brain EC50 of 15.2 micrograms/ml versus 36.1 micrograms/ml). The (+)-enantiomer was eliminated more rapidly than the (-)-enantiomer, as reflected in a higher plasma clearance (1.64 l/h/kg versus 0.557 l/h/kg) and a shorter half-life (2.83 h versus 6.50 h). Parallel studies with the racemate of stiripentol indicated that the anticonvulsant potency of the racemate was between the potency of the two enantiomers, suggesting that the combined activity reflects the additive action of (+)- and (-)-stiripentol. However, a marked metabolic interaction between enantiomers was evident after racemate administration. These results point to the need for information on the differential pharmacokinetics of stiripentol enantiomers following racemic drug administration.

Animals↗
PubMed1992

The effect of valproate on the metabolism of phenobarbital in the rat.

Valproate has been shown to interact with all major antiepileptic drugs. The interaction with phenobarbital is the most clinically significant. The mechanism of the interaction was evaluated in the in vivo rat and in vitro liver perfusion system. Phenobarbital and parahydroxyphenobarbital (PbOH) were administered with and without valproate treatment. In vivo, after administration of PbOH, valproate caused a significant inhibition of both the renal clearance of unchanged PbOH (40%) and the formation clearance (ClF) of its glucuronide conjugate (44%). When coadministered with phenobarbital, valproate caused a significant decrease in the total plasma clearance of phenobarbital (95.4 +/- 29.0 to 65.8 +/- 20.2 ml/hr/kg), with no apparent effect on the phenobarbital renal clearance or the ClF of PbOH. Valproate did cause a significant inhibition (50%) of formation of a minor metabolite, metahydroxyphenobarbital. The largest effect of valproate appears to be on unknown pathways of phenobarbital elimination. In the isolated perfused rat liver, the ClF of PbOH and its glucuronide conjugate were determined. Valproate caused a small (10%) but significant decrease in the ClF of PbOH. As seen in vivo, the most significant effect of valproate was on the ClF of the PbOH glucuronide (66% decrease). In conclusion, inhibition of PbOH formation by valproate cannot account entirely for the increased plasma concentrations of phenobarbital that occur when valproate is added to therapy. A complete understanding of the mechanism will require a complete accounting of the phenobarbital dose in rat or in humans.

Animals↗
PubMed1992

Low and variable presence of valproic acid in human brain.

We studied the distribution of valproic acid (VPA) between brain (gray matter) and serum in 13 patients receiving chronic VPA therapy who underwent cortical resections for intractable seizures. Valproate concentration in cerebral cortex was remarkably low compared with either total or unbound valproate concentration in serum. The respective brain-to-serum partition ratios based on total and free drug in serum were 0.111 +/- 0.051 and 0.544 +/- 0.175. In comparison with other commonly used antiepileptic drugs, valproate has the distinction of exhibiting the lowest brain-to-blood partitioning. Moreover, the brain-to-serum concentration ratio varied over a four-fold range between patients. Some of this variability was related to variation in serum protein binding, as indicated by a modest correlation between the partition ratio and serum free fraction (r = +0.687). However, the brain-to-unbound concentration ratio still showed a three-fold variation. The variability in distribution of VPA between brain and blood is probably one of the underlying factors for the lack of a clearly definable therapeutic range of serum VPA concentration in epileptic patient populations.

Adolescent↗
PubMed1992

Clinical and experimental studies linking oxidative metabolism to phenytoin-induced teratogenesis.

The research presented in this article concerns the proposed mechanism of phenytoin-induced teratogenicity that focuses on oxidative metabolites as sources of reactive species in clinical studies and by testing paradigms in animal models. The clinical aspect involved determining whether at-risk fetuses could be detected prenatally on the basis of low or deficient epoxide hydrolase activity. In 19 pregnancies monitored by amniocentesis, we predicted an adverse outcome in four infants on the basis of low enzyme activity. When examined neonatally, all four infants had the dysmorphic features of the "fetal hydantoin syndrome." In an animal model of phenytoin-induced teratogenesis, the level of fetal exposure to oxidative metabolites was decreased by coadministration of the cytochrome P-450-inhibiting antiepileptic drug stiripentol, which significantly reduced the incidence of phenytoin-induced congenital malformations in two of the three inbred mouse strains, thus providing support for the hypothesis that oxidative metabolites are critical in mediating phenytoin teratogenesis.

Abnormalities, Drug-Induced↗
PubMed1991

Influence of antibiotics on the recovery and kinetics of Saccharomyces boulardii in rats.

Saccharomyces boulardii (SB) is a yeast that is used for the prevention and treatment of antibiotic-associated diarrhea and for the treatment of pseudomembranous colitis. Since SB will most commonly be used when the bacterial flora of the gastrointestinal tract have been disrupted by antibiotic treatment, the influence of different antibiotics on the kinetics and recovery of SB in feces was investigated in rats. Following a single oral dose, SB concentrations in feces were measured for periods of 1 to 6 days. Although SB is eliminated exclusively in the feces, less than 3% of the dose is recovered as viable yeast. When rats were treated with neomycin, which is active against gram-negative aerobic bacteria but not against anaerobes, no change was observed in recovery of SB when compared with recovery from untreated rats. Also, there was no change in the rate at which SB concentrations declined in feces. In contrast, treatment with clindamycin and the broad-spectrum antibiotic ampicillin, which are active against anaerobes, produced an increase in the recovery of SB of up to seven times that of controls and slowed the rate of decline of SB concentration in the feces. This antibiotic effect on SB disposition was also found when SB was administered in multiple doses. An eightfold increase in the steady-state output of SB was observed from ampicillin-treated animals. Analysis of the recovery and kinetic data showed that the primary effect of these antibiotics was to reduce the destruction of SB, probably in the cecum and colon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Stereoselectivity in pharmacokinetics: a general theory.

Stereoselectivity in pharmacokinetics may be characterized by a measurable difference between enantiomers in a pharmacokinetic parameter. We propose that pharmacokinetic parameters may be classified according to three levels of organization in the body and that the hybrid character of parameters increases with the level of organization that they represent. At the molecular level are intrinsic metabolite formation clearances and fraction of drug unbound in plasma, reflecting the selectivity of an endogenous macromolecule for the enantiomers of a chiral drug molecule. At the organ level, pharmacokinetic parameters represent the combined effects of stereoselectivity in each of their component parameters within an organ. As a result, these parameters are of intermediate hybrid character. Parameters with the highest degree of hybrid character describe the pharmacokinetic behavior of a drug in the whole body. The stereoselectivity associated with each of the component parameters could either amplify or dampen the resultant stereoselectivity in hybrid parameters. The hypothesis that kinetic differences between enantiomers are inversely correlated with the degree of hybrid character was examined for four drugs: warfarin, verapamil, mephenytoin, and propranolol. By classifying pharmacokinetic parameters according to both the level of organization that they characterize and their hybrid nature, it becomes possible to account for stereoselectivity in drug distribution and elimination.

Humans↗
PubMed1991

In vitro and in vivo investigations of dihydropyridine-based chemical delivery systems for anticonvulsants.

A dihydropyridine-based chemical delivery system (CDS), intended to improve drug delivery to the brain, was investigated with a series of analogues of the anticonvulsant striripentol. In vitro experiments demonstrated that the rates of hydrolysis of the corresponding pyridinium conjugates were influenced markedly by small changes in the structure of the drug moiety to be released. Thus, allylic esters were hydrolyzed rapidly to drug in all aqueous media, while the analogous saturated esters and an allylic amide derivative were almost totally stable. The mechanism of hydrolysis, which is particular to this series of CDS conjugates, appeared to occur via ionization to a resonance-stabilized carbocation intermediate. The same CDS compounds were investigated in vivo and compared to the corresponding drugs after intravenous administration. Only those CDS compounds that were found to hydrolyze in vitro released appreciable amounts of drug in vivo. Prolonged release of the drug from the CDS in the brain could be demonstrated for these compounds, but the gain in the ratio of brain-to-plasma AUC when the CDS was administered depended on the innate distribution characteristics of the drug. Thus, the drug D3, which had a high brain-to-plasma AUC ratio, did not show an improvement in this ratio when administered as CDS3. In contrast, stiripentol with a poor brain-to-plasma AUC ratio showed a two- to threefold increase in this ratio when administered as a CDS. These investigations highlight the need for a thorough understanding of the mechanism of drug release and the importance of the pharmacokinetic properties of the drug in designing a carrier system for delivery of drugs to the brain.

Animals↗
PubMed1990

Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid.

The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA), formed by a cytochrome P450-mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4-ene-VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4-ene-VPA was increased twofold in the valproic acid-carbamazepine and valproic acid-phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4-ene-VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4-ene-VPA, in humans. The increased formation of 4-ene-VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid-related hepatotoxicity during polytherapy with P450 inducers.

Adult↗
PubMed1990

Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine.

The effect of valproic acid (VPA) on the disposition of carbamazepine-10,11-epoxide (epoxide) was studied in five epileptic patients on chronic carbamazepine (CBZ) therapy. The individual pharmacokinetic parameters influencing epoxide disposition were determined in the presence and absence of VPA. VPA significantly decreased the clearance of unbound epoxide (an in vivo index of epoxide hydrolase activity), but did not appear to affect epoxide formation. VPA also increased the free concentrations of both CBZ and epoxide.

Adolescent↗
PubMed1989

Application of thermospray liquid chromatography-mass spectrometry to the simultaneous quantification of tracer concentrations of isotopically labelled carbamazepine epoxide and steady-state levels of carbamazepine and carbamazepine epoxide.

A thermospray high-performance liquid chromatography-mass spectrometry method for the separation and quantification of tracer concentrations of isotopically labelled carbamazepine epoxide ([15N, 13C]CBZE) in the presence of steady-state levels of the anticonvulsant carbamazepine (CBZ) and its epoxide metabolite (CBZE) has been developed. The technique does not require derivatization, demonstrates little or no thermal degradation of the analytes, provides increased specificity not available from conventional high-performance liquid chromatography, and has a detection limit of 500 pg for CBZE on-column. The method, incorporating d4-CBZ and d4-CBZE as internal standards, allows precise and accurate determination of the analytes with good reproducibility and stability.

Carbamazepine↗
PubMed1989

Quantitative metabolic profiling of valproic acid in humans using automated gas chromatographic/mass spectrometric techniques.

An automated gas chromatographic/mass spectrometric assay is described for the antiepileptic drug valproic acid (VPA) and 14 of its metabolites in plasma or urine. Quantitative analysis of the parent drug and its biotransformation products was carried out with the aid of trimethylsilyl derivatives, and was performed by selected ion monitoring gas chromatography/mass spectrometry (normally of [M-CH3]+ species) using an HP 5790 mass selective detector (MSD) quadrupole mass spectrometer. The analysis was fully automated, in that simple injection, data acquisition, integration, quantification and report functions were carried out during unattended operation by an HP 59970C ChemStation computer system. The method exhibits good accuracy and high precision, with correlation coefficients greater than 0.990 for all standard curves. Replicate analyses of pooled plasma samples over a 4 month period exhibited an inter-day variation of less than 15% for the parent drug and ten of its metabolites. Moreover, the high dynamic range of the MSD instrument permitted quantification of VPA and minor metabolites thereof (e.g. the hepatotoxic terminal olefin, delta 4-VPA) at levels as disparate as 260 micrograms ml-1 (VPA) and 14 ng ml-1 (delta 4-VPA) in a single analysis. The high stability and sensitivity of the assay, combined with the fully automated features of the instrumentation, make the method ideally suited to expanded clinical studies and for the routine monitoring of potentially high-risk patients on VPA therapy.

Gas Chromatography-Mass Spectrometry↗