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Biomedical subjects

N M Graves

Publications and source records attributed to N M Graves.

At least 37 records · Page 2Linked to original sources
PubMed1991

Interaction between cyclosporine and fluconazole in renal allograft recipients.

To determine the effect of fluconazole on cyclosporine concentrations, we used a randomized, double-blind, placebo-controlled study design to evaluate 16 stable renal transplant recipients receiving a constant cyclosporine dose. The two groups of patients were given identical capsules of either placebo or fluconazole 200 mg daily for 14 days. Compliance with the protocol was ensured by watching each patient take all the drug doses. Frequent whole-blood cyclosporine trough concentrations, measured by high-performance liquid chromatography, and two area under the blood concentration time curves were determined before and after 14 days of fluconazole or placebo. The results show that cyclosporine trough concentrations, in patients given fluconazole, increased from a mean +/- SD of 27 +/- 16 to 58 +/- 28 ng/ml (P = 0.001) while patients given placebo did not change--35 +/- 26 vs. 37 +/- 35 ng/ml (P = 0.7). Mean cyclosporine AUC increased in the fluconazole patients from 2167 +/- 1039 to 3989 +/- 1675 ng.hr/ml (P = 0.02) while the placebo patients did not change, 3089 +/- 2439 vs. 2954 +/- 2216 ng.hr/ml (P = 0.9). The pre- and post-treatment cyclosporine AUC difference (day 16 minus day 2) for fluconazole vs. placebo was 1822 +/- 1083 vs. -134 +/- 831 ng.hr/ml (P = 0.001). Mean cyclosporine clearance decreased an average of 55% in the fluconazole patients from 1.2 +/- 0.5 to 0.7 +/- 0.4 ml/hr.kg (P = 0.03); the placebo patients did not change--1.4 +/- 1.1 vs. 1.7 +/- 2.3 ml/hr.kg (P = 0.07). During the study period, serum creatinine concentrations did not increase after fluconazole vs. placebo treatment; they were 1.4 +/- 0.3 vs. 1.3 +/- 0.3 mg% (P = 0.8) initially, and 1.4 +/- 0.2 vs. 1.3 +/- 0.3 mg% (P = 0.5) after 14 days. This study indicates that fluconazole 200 mg daily can slowly increase cyclosporine concentrations over two weeks of therapy, approximately doubling the cyclosporine trough concentrations. The management of this interaction requires prospective planning for adjustments in the cyclosporine dosage, guided by cyclosporine concentrations, while transplant recipients are receiving fluconazole.

Adolescent↗
PubMed1991

Antiepileptic medications in development.

Recently, there has been an increase in the research devoted to the study of investigational antiepileptic medications. This has led to extensive clinical trials of several new compounds. This review focuses on four of these antiepileptic medications in development: felbamate, gabapentin, lamotrigine, and vigabatrin. Each has a unique mechanism of action and great potential for the treatment of epilepsy.

Acetates↗
PubMed1991

Felbamate for partial seizures: results of a controlled clinical trial.

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Adult↗
PubMed1990

Simultaneous assay of felbamate plus carbamazepine, phenytoin, and their metabolites by liquid chromatography with mobile phase optimization.

Felbamate is an investigational antiepileptic drug (AED) in clinical trials. A high-performance liquid chromatographic method for the simultaneous analysis of felbamate, phenytoin (PHT), 5-(p-hydroxyphenyl)-5-phenylhydantoin, carbamazepine (CBZ), carbamazepine-10,11-epoxide, and carbamazepine-10,11-diol in serum was developed by a mobile phase optimization technique. Capacity factors for the compounds of interest and 12 other AEDs and metabolites were determined with mixtures of methanol, acetonitrile, or tetrahydrofuran and a 0.01 M ammonium phosphate buffer, pH 6.5, on a reversed-phase C8 column. An optimized mobile phase composition was determined that could separate the compounds of interest and three internal standards in less than 15 min. Serum was extracted with CH2Cl2/ethyl acetate (2:1) after addition of three internal standards. The method was validated for within-day and between-day precision and accuracy for the six compounds. Coefficients of variation were generally less than 10% at all concentrations and less than 5% in the typical therapeutic range for each compound. The lower limit of detection was estimated at 0.2 micrograms/ml for CBZ and its metabolites and 0.5 micrograms/ml for felbamate and PHT. For felbamate, the lowest point on the standard curve was 1.88 micrograms/ml with a between-day variability of 10.3%. The assay was used to determine the serum concentrations of PHT and CBZ and its metabolites in a subject before, during, and after felbamate therapy.

Carbamazepine↗
PubMed1990

Pharmacokinetics and safety of a phenytoin prodrug given i.v. or i.m. in patients.

ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phosphatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.

Adult↗
PubMed1989

Absorption of valproic acid suppositories in human volunteers.

The absorption of valproic acid administered by rectal suppository was studied in six male volunteers. Valproic acid was incorporated into a synthetic lipid base in our pharmacy. Each subject received 500 mg of valproic acid by rectal suppository and 500 mg of oral valproate sodium syrup one week apart; 13 blood samples were drawn to determine serum concentrations over 48 hours after administration of each formulation. Significant differences were evident in the amount absorbed, maximum serum concentration, and time to achieve maximum serum concentration between the oral and rectal formulations. Mean absorption after rectal suppository was 80%. Maximum serum concentration was 43.4 mg/L after oral administration and 29.2 mg/L after rectal suppository. The time to achieve maximum serum concentration was 1.0 hour after oral syrup and 3.1 hours after rectal suppository. Absorption of the rectal suppository was consistent and complete within 3 hours. The use of valproate sodium in rectal suppository form can be a more convenient and satisfactory method of administering valproic acid when the oral route is impossible. Dosage increases may be necessary, and serum concentrations should be monitored.

Administration, Oral↗
PubMed1989

Pharmacokinetics of felbamate, a novel antiepileptic drug: application of mixed-effect modeling to clinical trials.

Felbamate is a novel antiepileptic drug currently undergoing clinical trials in the United States. Serum felbamate concentration data from a phase II safety and efficacy trial were analyzed using NONMEM. A one-compartment, open model with first-order absorption and elimination was used. Body weight, sex, concurrent folic acid therapy, and phenytoin dose and dose:concentration ratio did not affect the estimates for felbamate clearance (Cl). Carbamazepine dose and dose:concentration ratio (CDCR) led to significant improvements in the objective function. The final models for felbamate clearance and volume of distribution (Vd) were as follows: Cl(L/hr) = 2.43 + 0.429*CDCR/240, Vd (L) = 51. The coefficient of variation of clearance was only about 12%, which may be indicative of the highly selective patient population. The clearance estimates are similar to those obtained in healthy volunteers and in patients receiving lower dosages of felbamate. The volume of distribution estimate, however, is slightly smaller than that reported previously. Valuable pharmacokinetic information can be obtained from the routine monitoring of serum concentrations during safety and efficacy trials.

Adolescent↗
PubMed1989

Phenytoin prodrug: preclinical and clinical studies.

The currently available phenytoin (PHT) solution has many disadvantages stemming from poor aqueous solubility of PHT. A novel approach to solve the problem has been the synthesis of a phosphate ester of PHT (PHT prodrug ACC-9653). This water-soluble compound is metabolized rapidly into PO4 and PHT. A four center open-label, baseline-controlled study of 43 patients with epilepsy maintained on oral twice-daily PHT monotherapy was performed to evaluate the safety and pharmacokinetic profile of the prodrug. Patients received an i.v. or i.m. dose of ACC-9653 at a dose equivalent to the patients' morning dose of PHT. Intravenous dosages were infused at a rate of 75 mg/min, and i.m. dosages were given as one or two injections. After a period of 6 days, during which patients were again maintained with oral PHT, they were given a dose of ACC-9653 via whichever route they had not yet received. The Tmax of the prodrug averaged 5.7 and 36 min (0.095 and 0.606 h) after i.v. and i.m. administrations, respectively. The elimination half-life of ACC-9653 (conversion from prodrug to PHT) after i.v. and i.m. administration was 8.4 and 32.7 min (0.140 and 0.545 h), respectively, and both were independent of the dose. The plasma clearance of ACC-9653 was not dependent on dose or route of administration and averaged 19.8 +/- 1.16 and 17.8 +/- 0.83 L/h after i.v. and i.m. administrations, respectively. The area under curve ratio of PHT after i.m. and i.v. ACC-9653 was 1.17 +/- 0.13 which was not significantly different from 1.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Compliant populations: variability in serum concentrations.

Safety and efficacy studies of new antiepileptic drugs require strict adherence to prescribed dosage regimens. Therefore, they provide a unique opportunity to investigate the variability in serum concentrations that are seen in a compliant group of motivated patients. Phenytoin and carbamazepine serum concentrations from two safety and efficacy trials were evaluated for coefficient of variation, difference from baseline concentration, and percent difference. Coefficient of variation for phenytoin was usually less than 20% and was not influenced by baseline serum concentration or frequency of administration. There was no relationship between serum concentration and frequency of administration on carbamazepine coefficient of variation which was less than 25% in most cases. Most PHT differences from baseline were within 5 micrograms/ml, whereas most CBZ differences were within 2 micrograms/ml. Most PHT concentrations were within 30% of each other whereas most CBZ concentrations were within 40% of each other. Data from this study provide information regarding the variability of phenytoin and carbamazepine concentrations under ideal conditions and can be used to set limits for fluctuations of concomitant antiepileptic drugs in safety and efficacy trials or ideal patient care settings.

Anticonvulsants↗
PubMed1987

Effect of progabide on serum phenytoin and carbamazepine concentrations.

Progabide (PGB) is a gamma-aminobutyric acid (GABA)-agonist drug undergoing clinical evaluation for the treatment of spasticity, movement disorders, and epilepsy. Drug interactions were studied during a randomized, double-blind, crossover trial of the efficacy and toxicity of PGB in patients with partial seizures taking phenytoin (PHT) and carbamazepine (CBZ). In twenty-two of 32 patients (69%) receiving PGB, PHT dosage was reduced, while only four patients (12%) had their dosage reduced during placebo treatment (p less than 0.001). Carbamazepine dosage was decreased in five of 32 patients (16%) during the active treatment, while two patients (6%) had a dosage reduction when receiving placebo (p greater than 0.75). The mean PHT concentrations at the end of baseline, PGB, and placebo treatments were significantly different: 17.5, 20.4, and 16.8 mg/L, respectively (p less than 0.05). Nevertheless, careful adjustment of PHT dosage maintained serum concentration within +/- 25% of target values in both the PGB and placebo periods. Among patients who first received PGB and then placebo, PHT concentrations remained elevated relative to dose suggesting that PGB exerts a prolonged effect on PHT disposition. The addition of PGB to regimens including PHT results in a significant increase in serum PHT concentrations. This drug interaction most likely occurs as a result of PGB mediated inhibition of hepatic microsomal enzymes.

Adult↗
PubMed1986

Phenytoin clearances in a compliant population: description and application.

The saturable elimination kinetics of phenytoin (PHT) makes accurate dosing difficult. A simple equation has been derived to predict dosing requirements if one dose--steady-state serum concentration pair is known [new dose = first dose X Cpss (desired)0.2 X Cpss (achieved)-0.2]. This equation is based on an exponential relation between 177 pairs of PHT clearance and steady-state serum concentrations from 59 compliant patients. To evaluate this population clearance method (PCM), patients were drawn from two independent populations (Minnesota and Iowa, U.S.A.). Predicted doses obtained from PCM were compared with predictions from Bayesian, average Vmax, and average Km methods. The Bayesian method was the most precise and least biased of all methods, under- and overpredicting doses in equal frequency. PCM was biased to produce underpredictions. However, clinically achievable doses can be obtained by consistently rounding the calculated dose upward. The mean underprediction for the Bayesian method was 6 mg, for PCM 46 mg, for average Vmax 21 mg, and for average Km 11 mg. PCM is relatively precise, somewhat biased, and very easy to use.

Bayes Theorem↗
PubMed1983

Bioavailability of rectally administered carbamazepine suspension in dogs.

The relative bioavailability of an investigational carbamazepine suspension was studied following rectal administration in dogs. Doses of carbamazepine, 20 mg/kg, were given to six dogs. The routes of administration were oral tablet, oral suspension, and rectal suspension. There was no significant difference (p greater than 0.05) in total absorption, as indicated by the area under the serum concentration-time curve between the oral and rectal suspensions. The notable differences between the oral suspension and the rectal suspension were in the maximum serum concentration achieved and the time to achieve this maximum serum concentration. This is due to a prolonged absorption of carbamazepine given rectally, which may limit the ability to achieve therapeutic serum concentrations rapidly. Carbamazepine suspension given rectally may be a satisfactory alternative when administration by the oral route is not possible.

Animals↗
PubMedDate not supplied

Absorption and safety of rectally administered phenytoin.

Parenteral phenytoin solution (Dilantin) was given rectally three times a day for three days to two beagle dogs. This was well tolerated, with no evidence of mucosal irritation noted either on endoscopic nor on rectal mucosal biopsy. When given in this manner, phenytoin is absorbed to a limited degree in canines. Parenteral phenytoin solution can be safely administered rectally, despite a pH of 12. Further study in normal volunteers is needed to assess the usefulness of this route of administration in situations in which the oral and/or parenteral route of administration is unavailable.

Administration, Rectal↗
PubMedDate not supplied

Rectal administration of antiepileptic drugs in children.

This article reviews the current literature describing the use of rectally administered antiepileptic drugs. Individual antiepileptic drugs are discussed in regard to efficacy, toxicity, and rate of absorption. Absorption occurs through passive diffusion; therefore, solutions are absorbed most quickly. Paraldehyde, diazepam, secobarbital, and valproic acid are used when rapid effect for termination of prolonged or serial seizures is desired. Valproic acid, lorazepam, carbamazepine, and phenytoin all can be used for maintenance therapy.

Administration, Rectal↗