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Biomedical subjects

B E Gidal

Publications and source records attributed to B E Gidal.

51 records · Page 3Linked to original sources
PubMed1995

Evaluation of a potential enantioselective interaction between ticlopidine and warfarin in chronically anticoagulated patients.

Ticlopidine is a novel antiplatelet drug reported to cause significant inhibition of several drugs metabolized by the hepatic cytochrome P-450 enzyme system, including antipyrine and theophylline. Warfarin, a racemic mixture of two enantiomers (R and S), is extensively metabolized by the CYP-450 system. S-Warfarin is five to eight times as active as R-warfarin. The effects of ticlopidine on the pharmacokinetics and pharmacodynamics of warfarin were examined in nine elderly men (69 +/- 4 years) receiving long-term warfarin therapy. Steady-state warfarin enantiomer concentrations and International Normalized Ratios (INRs) were determined at baseline and after 14 days of treatment with oral ticlopidine, 250 mg twice daily. Warfarin enantiomer serum concentrations were determined by high-performance liquid chromatography after chiral derivitization. Ticlopidine co-medication resulted in a significant increase in mean R-warfarin concentrations (+25.7%, p < 0.05), while no significant difference in S-warfarin concentrations was noted (+0.8%). Mean INR values were not significantly different from the baseline (+8.3%), although substantial interindividual variability was noted. We conclude that ticlopidine co-medication does result in an enantioselective kinetic interaction with warfarin; however, this interaction is likely to be of minimal clinical significance in most patients.

Aged↗
PubMed1995

Relationship between valproic acid dosage, plasma concentration and clearance in adult monotherapy patients with epilepsy.

Significant variability has been reported in the plasma concentration-dose relationship for the anticonvulsant compound valproic acid (VPA). Several factors may contribute to this observed variability, including heterogeneous patient populations of children and adults, polytherapy, and timing of plasma concentration sampling. To optimally determine the relationship between trough VPA plasma concentration and dose, we evaluated a homogeneous group of adult ambulatory patients with epilepsy receiving VPA monotherapy. Furthermore, we sought to evaluate whether a relationship existed between VPA dosage and plasma clearance for both total and unbound or free drug. Steady-state trough plasma concentrations were determined in thirty-two patients. Mean VPA dose was 22.8 +/- 10.3 mg/kg/day. Mean total and unbound VPA plasma concentrations were 97.9 +/- 34.9 and 13.2 +/- 10.6 micrograms/ml, respectively. Significant correlations between VPA dose and total and unbound plasma concentrations were found (r = 0.82 and r = 0.85, P < or = 0.001, respectively). Significant relationships were also observed between VPA dose and clearance. A positive correlation was noted for dose and total plasma clearance (r = 0.61, P < or = 0.001), while an inverse correlation existed between dose and unbound VPA plasma clearance (r = -0.51, P < 0.01). Although a statistically significant correlation does exist between VPA dosage and both total and unbound plasma concentrations, significant interpatient variability still remains even under 'optimal' therapeutic drug monitoring conditions.

Administration, Oral↗
PubMed1995

Valproate in status epilepticus.

In patients with intractable status epilepticus who have not responded to therapy with benzodiazepines, phenytoin, and barbiturates, valproate may be a reasonable option. Extemporaneously prepared valproate rectal suppositories or retention enemas have been given in dosages of 200-1200 mg q6h in addition to phenytoin, phenobarbital, or both in adults. The pediatric dose used was 15-20 mg/kg, in addition to phenytoin and/or phenobarbital.

Animals↗
PubMed1995

Optimized method for determination of gabapentin in serum by high-performance liquid chromatography.

The anticonvulsant drug gabapentin and its heptaneacetic acid analog-used here as an internal standard--are isolated from serum (pH 9) with an octyldecyl (C-18) solid-phase sorbent column. To enhance analytical detection, trinitrobenzene derivatives of these extracted compounds are prepared quickly within 10 min. To further improve chromatographic selectivity, the derivatives are concentrated on a thin C-18 solid-phase membrane and interferences are washed away. The retained purified derivatives are eluted from the membrane with a small volume of solvent and the eluate is directly injected onto an Ultrasphere C-18 high-performance liquid chromatography column with quantification at 340 nm. No evaporation-concentration steps are necessary. Recoveries (extraction) of gabapentin and the internal standard are 94.2 +/- 2.9% and 98 +/- 2.0%, respectively. Analytical responses are linear from lower limit of sensitivity of 0.05 mg/L up to at least 10 mg/L. Between-run coefficients of variation (CV) range from 2.3 to 2.9% through the concentration range 0.5-4.0 mg/L. To illustrate the rationale for selection of test parameters for a robust method, we present optimization graphs for these processes. Moreover, we discuss the advantage of the packed cartridge and membrane sorbens as companion extraction devices.

Acetates↗
PubMed1994

Decreased plasma protein binding of valproate in patients with acute head trauma.

1. One hundred and ten plasma samples were obtained from 50 patients treated with valproate for prophylaxis of post-traumatic head injuries. The samples were selected to include a wide range of albumin concentrations and were assayed for free and total valproate concentrations. Valproate binding parameters were determined from the Scatchard equation for one binding site using reweighted least squares analysis. 2. Plasma albumin concentrations were measured in 130 patients with head trauma. They started to decrease immediately after trauma, reaching a minimum at 5-7 days of approximately 24% of baseline value and did not return to normal until 1 month. 3. The free fraction of valproate varied six to seven-fold as albumin concentration ranged from 1.5 to 4.8 g 100 ml-1 (218-696 mumol l-1). The mean association constant for binding (Ka) was 0.008 mumol l(-1) and the mean number of binding sites (N) was 2.0. There values were similar to those reported for valproate in otherwise healthy patients with epilepsy. 4. Because of saturable protein binding of valproate, hypoalbuminaemia may necessitate the monitoring of free valproate concentrations to avoid toxicity when valproate is used in patients with acute head injury.

Acute Disease↗
PubMed1994

Potential pharmacokinetic interaction between felbamate and phenobarbital.

OBJECTIVE: To report a case of a potential pharmacokinetic interaction between felbamate and phenobarbital in a patient with epilepsy. CASE SUMMARY: A patient with a history of a mixed seizure disorder and static encephalopathy who was receiving sodium valproate 750 mg/d and phenobarbital 230 mg/d was initiated on felbamate (as part of a compassionate use program). Upon instituting felbamate, valproate dosage was reduced to 500 mg/d and phenobarbital to 200 mg/d. Felbamate dosage was titrated to approximately 50 mg/kg/d over three weeks. In this patient, plasma phenobarbital concentrations increased from 48 micrograms/mL to 68 micrograms/mL, at which point the patient was hospitalized because of clinically significant neurotoxicity. Phenobarbital dosage was subsequently reduced to 150 mg/d; this resulted in phenobarbital trough concentrations of 60 micrograms/mL. CONCLUSIONS: Felbamate has been shown previously to interact with multiple other anticonvulsant medications, including valproate, phenytoin, and carbamazepine. Felbamate appears to decrease the clearance of valproate, phenytoin, and carbamazepine epoxide to a significant extent, an effect that may be the result of inhibition of the metabolism of these compounds. Carbamazepine plasma concentrations have been demonstrated to decrease following administration of felbamate, suggesting metabolic induction. It is reasonable to suggest that based on these findings and the observations in our patient, felbamate comedication may result in clinically significant increases in plasma phenobarbital concentrations. It would seem prudent, therefore, when initiating or adjusting felbamate therapy in patients receiving this drug combination, to monitor phenobarbital plasma concentrations.

Adult↗
PubMed1993

Evaluation of the effect of fluoxetine on the formation of carbamazepine epoxide.

Fluoxetine has been reported to increase carbamazepine (CBZ) plasma concentrations and cause adverse effects. CBZ-10, 11 epoxide (CBZE), the major metabolite of CBZ, contributes to the clinical effect and toxicity of CBZ. The objective of the present study was to investigate the effect of fluoxetine and its major metabolite, norfluoxetine, on CBZE formation in isolated perfused rat liver, in vitro human liver (n = 5) microsomes, and patients (n = 14), after either CBZ monotherapy or polytherapy with fluoxetine. In isolated perfused rat liver, there was no effect of fluoxetine (n = 8) or norfluoxetine (n = 6) on the formation clearance of CBZE (12.8 +/- 5.3 and 11.7 +/- 3.8 ml/min, respectively) or the intrinsic metabolic clearance of CBZ (6.6 +/- 2.7 and 6.3 +/- 1.8 ml/min, respectively). Studies on human liver microsomes confirmed that neither fluoxetine or norfluoxetine inhibited formation of CBZE until concentrations were > 20 times those found clinically. In support of this, there was no difference in the ratio of CBZE to CBZ plasma concentrations in patients also receiving fluoxetine when compared to patients on CBZ monotherapy; however, there was a trend toward a decrease in the apparent plasma clearance of CBZ. In conclusion, increased plasma concentrations of CBZ found when fluoxetine is added are not due to decreased formation of CBZE. Clinically, if fluoxetine causes an increase in CBZ levels, CBZE plasma concentrations will increase proportionately and contribute to the toxicity.

Animals↗
PubMed1993

Apparent valproic acid neurotoxicity in a hypoalbuminemic patient.

OBJECTIVE: To report a case of possible neurotoxicity caused by markedly elevated free valproic acid (VPA) plasma concentrations. CASE SUMMARY: A patient with a history of a mixed-type seizure disorder that had been treated with oral VPA 1000 mg four times daily for the previous two years was admitted to the neurology service with the chief complaint of increasing difficulty in walking and involuntary muscle jerks that were new in onset. The patient was hypersomnolent and dysarthric. The total plasma VPA concentration was 103 micrograms/mL, which was only slightly above the recommended therapeutic range (50-100 micrograms/mL). VPA free fraction and free plasma concentrations, however, were unexpectedly elevated (26 percent, 26.8 micrograms/mL, respectively). Further laboratory evaluation revealed a serum albumin concentration of 33 g/L. The neurologic symptoms resolved upon VPA dosage reduction. DISCUSSION: VPA displays concentration-dependent protein binding, resulting in disproportionate increases in drug free fraction with increasing drug concentration. This effect may be magnified in patients with decreased plasma protein-binding capacity. The plasma protein-binding kinetics of VPA are reviewed and the implications for therapeutic drug monitoring are discussed. CONCLUSIONS: It is likely that the markedly elevated free VPA plasma concentrations contributed to the neurologic symptoms displayed in this patient. In patients with decreased albumin concentrations, failure to recognize concentration-dependent protein binding, as well as exclusive reliance upon total drug concentrations, may lead to erroneous pharmacokinetic and therapeutic interpretations.

Adult↗
PubMed1993

Potential interaction between carbamazepine and loxapine: case report and retrospective review.

OBJECTIVE: To report a potential interaction between carbamazepine (CBZ), an anticonvulsant medication, and loxapine, an antipsychotic. CBZ is being increasingly used to treat a variety of psychiatric disorders. Because of this, the potential for multiple-drug therapy and subsequent drug interactions is increased. METHODS: We prospectively monitored plasma CBZ and carbamazepine epoxide (CBZE) concentrations in a single patient during and after withdrawal of loxapine comedication. Additionally, we retrospectively evaluated four patients who had received concomitant therapy with CBZ and loxapine. RESULTS: Plasma CBZE/CBZ ratios decreased from 0.76 to 0.18 following discontinuation of loxapine. Absolute CBZE plasma concentrations also decreased from 1.7 to 0.6 micrograms/mL after loxapine therapy was stopped. Retrospectively screened patients who were receiving concomitant loxapine-CBZ therapy all had unusually elevated CBZE/CBZ plasma concentration ratios (0.75-1.91). CONCLUSIONS: These cases suggest that an interaction occurs between loxapine and CBZ. Possible mechanisms include either induction of CBZ metabolism to its epoxide metabolite, or inhibition of the enzymatic metabolism of CBZE (epoxide hydrolase).

Adult↗
PubMedDate not supplied

Guidelines for nonemergency use of parenteral phenytoin products: proceedings of an expert panel consensus process. Panel on Nonemergency Use of Parenteral Phenytoin Products.

This document summarizes the proceedings of an expert panel consensus process addressing the nonemergency use of parenteral phenytoin products for management of seizures in pediatric and adult patients. The algorithm and consensus statements developed by the expert panel emphasize strategies for lowering the probability of adverse events associated with the use of parenteral phenytoin products. Specific patient characteristics are defined to guide administration and monitoring of parenteral phenytoin therapy. The algorithm provides a decision pathway for the selection of the product and the route of administration of phenytoin sodium or fosphenytoin sodium after it has been determined that a parenteral phenytoin product is appropriate. Key factors covered in the algorithm include a list of patient characteristics and considerations necessary to prevent parenteral phenytoin adverse effects during selection of administration route and recommendations for monitoring of parenteral phenytoin therapy once it has been initiated. Situations requiring rapid attainment of high phenytoin concentrations, such as in the management of acute seizures, are not addressed in these guidelines.

Adolescent↗
PubMedDate not supplied

Pharmacologic management of epilepsy in the elderly.

OBJECTIVE: To review the epidemiology and pharmacologic management of epilepsy in elderly patients. DATA SOURCES: Controlled trials, case studies, and review articles identified via MEDLINE using the search terms epilepsy, seizures, elderly, phenobarbital, primidone, phenytoin, carbamazepine, valproic acid, felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide. Recently published standard textbooks on epilepsy were also consulted. DATA SYNTHESIS: Epilepsy is a common neurologic disorder in the elderly. Cerebrovascular and neurodegenerative diseases are the most common causes of new-onset seizures in these patients. Alterations in protein binding, distribution, elimination, and increased sensitivity to the pharmacodynamic effects of antiepileptic drugs (AEDs) are relatively frequent, and these factors should be assessed at the initiation, and during adjustment, of treatment. Drug-drug interactions are also an important issue in elderly patients, because multiple drug use is common and AEDs are susceptible to many interactions. In addition to understanding age-related changes in the pharmacokinetics and pharmacodynamics of AEDs, clinicians should know the common seizure types in the elderly and the spectrum of AED activity for these seizure types. AEDs with activity against both partial-onset and generalized seizures include felbamate, lamotrigine, levetiracetam, topiramate, valproic acid, and zonisamide. Other AEDs discussed in this review (carbamazepine, gabapentin, phenobarbital, phenytoin, primidone, and tiagabine) are most useful for partial-onset seizures. CONCLUSION: The provision of safe and effective drug therapy to elderly patients requires an understanding of the unique age-related changes' in the pharmacokinetics and pharmacodynamics of AEDs as well as an appreciation of common seizure types and the drugs that are effective for the specific types seen in the elderly.

Absorption↗
PubMedDate not supplied

Lorazepam-valproate interaction: studies in normal subjects and isolated perfused rat liver.

Valproate (VPA) has been shown to interact with all the major antiepileptic drugs (AEDs) through two mechanisms of action: displacement from albumin binding sites and inhibition of drug metabolism. More recently, evidence showed that VPA inhibits the elimination of drugs metabolized by glucuronide conjugation. Lorazepam (LZP), which is primarily eliminated by conjugation with glucuronic acid, is administered concurrently with VPA both in treatment of epilepsy and in patients treated with VPA for psychiatric disorders. Therefore, a significant drug interaction is likely. We investigated such interaction both in in vitro isolated perfused rat liver (IPRL) and in normal subjects. LZP [2 mg, intravenous (i.v.) bolus] was administered to 8 normal volunteers before and after chronic dosing with VPA. In 6 of 8 subjects, VPA significantly decreased LZP plasma clearance by an average of 40% (p < 0.05) and increased LZP concentrations by decreasing formation clearance of the LZP glucuronide. In the IPRL studies, VPA also significantly decreased formation of LZP glucuronide (from 0.72 +/- 0.14 to 0.22 +/- 0.15 ml/h/kg, p < 0.05), indicating that IPRL is a useful tool for evaluation of the effect of VPA on drugs eliminated by glucuronide conjugation.

Adult↗
PubMedDate not supplied

Evaluation of a rat model of valproate-induced obesity.

Long-term treatment with the anticonvulsant valproate (VPA) leads to well-documented weight gain and obesity in humans. In an attempt to develop an animal model of this condition, adult rats were given VPA 20 g/kg (high-dose) or 2 g/kg (low-dose) in their daily feeding or orally 120 mg/kg body weight/day in two divided doses, and food intake and body weight were assessed. Valproate resulted in lower body weights in all protocols. Food intake was lower (p<0.001) for rats receiving high-dose VPA than for controls. Feed efficiency (change in weight divided by cumulative food intake for that period) was lower than that of controls for both high (p<0.0001) and low doses (NS). Metabolic rate and physical activity were not different between control and VPA animals, although decreased food intake would be expected to decrease metabolic rate. Valproate failed to produce obesity in rats in any treatment period. For reasons that are unclear, rats do not appear to be suitable as a model to study this adverse side effect of VPA in humans with epilepsy.

Animals↗