Pharmacokinetic evaluation of erythromycin and caffeine administered with bromocriptine.

A study was performed to determine if the pharmacokinetics of bromocriptine is altered by factors that have been shown to interact with other ergot compounds. The effects on bromocriptine plasma concentrations by bromocriptine coadministration with caffeine and erythromycin were evaluated in five male volunteers. Serial blood samples were obtained during a 12-hour period after a single 5 mg oral dose of bromocriptine (alone and after 4-day treatments of either erythromycin estolate, 250 mg four times/day, or caffeine, 200 mg four times/day). There were no significant alterations of bromocriptine pharmacokinetic parameters after caffeine, although statistical power was very low. With the use of erythromycin, the bromocriptine area under the concentration-time curve standardized to body weight increased significantly by 268%, whereas peak bromocriptine plasma concentration (Cmax) increased to 4.6 times the Cmax from bromocriptine alone. Time to achieve Cmax was not altered by erythromycin. We conclude that erythromycin can markedly increase the systemic bioavailability of bromocriptine, which can lead to increased therapeutic or adverse effects, whereas the effects of caffeine require further study.

Dissociation between free and bound phenytoin levels in presence of valproate sodium.

A dissociation of free vs bound phenytoin levels is frequently observed in the presence of therapeutic doses of valproate sodium. This leads at times to symptoms and signs of phenytoin intoxication despite "therapeutic" plasma levels. The importance of supplementing bound levels with free levels is stressed when combined therapy of this type is used in epileptic patients.

Clorazepate therapy for refractory seizures.

We treated 61 patients with seizures refractory to conventional anticonvulsants by adding clorazepate to their regimen. There was some improvement of seizure control, but no overall improvement in the electroencephalogram. Improvement of seizure control was not significantly related to seizure type. No significant side effects, drug interactions, or laboratory abnormalities were noted with doses up to 3 mg per kilogram per day.

Pharmacodynamic modeling of concentration-effect relationships after controlled-release carbidopa/levodopa (Sinemet CR4) in Parkinson's disease.

Eight parkinsonian patients participated in a pharmacokinetic pharmacodynamic study of sequential doses of controlled-release carbidopa (CD)/levodopa (LD) at 4-hour intervals, with serial blood samples obtained before and after each dose. Effect measurements obtained with each blood sample included tapping and walking speed as well as a global assessment of motor function. Analysis of the data by extended least squares regression for linear, Emax, and sigmoid Emax pharmacodynamic models revealed that linear relationships do not provide the best fit between LD plasma concentrations and clinical effects after controlled-release CD/LD. The data are fit best to models that are curvilinear in nature. LD plasma concentrations greater than 2.0 micrograms/ml resulted in sustained effects on walking and global scores while the greatest rate of change in walking and global scores occurred at 0.9 micrograms/ml. LD plasma concentrations fluctuating around 0.9 micrograms/ml may result in the "on/off" effects seen in Parkinson's disease.

Controlled-release carbidopa/levodopa (Sinemet 50/200 CR4): clinical and pharmacokinetic studies.

Several controlled-release carbidopa/levodopa preparations have been formulated to achieve a more stable and extended antiparkinsonian action. The most effective is Sinemet CR (Sinemet CR4), with an erodible polymer matrix that retards release of levodopa. In 19 parkinsonians with prominent dose-by-dose fluctuations, double-blind crossover trials comparing 8-week regimens of standard carbidopa/levodopa (25/100) to Sinemet CR (50/200) showed comparable clinical outcomes, with mean daily dosing for optimal control reduced from 10.2 to 5.4 (although mean daily levodopa dosage increased from 1,340 to 1,781 mg/day). Most patients improved on the Sinemet CR regimen in hours "on" and in ratings of clinical state and disability. With pharmacokinetic studies correlated to clinical ratings, plasma levodopa was less variable during Sinemet CR treatment, and clinical responses showed greater uniformity. Compared to standard Sinemet 25/100, time to peak levodopa concentration (2.3 versus 1.1 hrs), onset of maximal clinical improvement (2.2 versus 1.1 hrs), and other indices were significantly delayed with Sinemet CR. Levodopa bioavailability and clearance were similar between formulations. Although onset of clinical response is slower, the Sinemet CR formulation lessens peak-dose and "wearing-off" responses occurring with conventional carbidopa/levodopa and offers substantial improvement for some parkinsonians.

Increased sensitivity of the elderly to the central depressant effects of diazepam.

The effects of diazepam on memory and psychomotor performance in healthy elderly (N = 12) and young (N = 12) individuals were examined. Diazepam was administered acutely in a single, oral 2.5 mg dose. Diazepam impaired memory, both immediate and delayed recall, and psychomotor performance in the elderly subjects. In addition, the drug caused an increase in self-reported sedation in elderly subjects but not in young subjects. These findings suggest an age-related increase in the sensitivity of elderly individuals to the central depressant effects of diazepam.

Maximizing the benefit of pharmacotherapy in Parkinson's disease.

Levodopa is one of the principal agents administered to treat patients with Parkinson's disease (PD). Several pharmacologic strategies can limit its side effects and enhance its activity. Although certain exceptions apply, dosage adjustments and drug changes should be instituted slowly. Levodopa is typically introduced in the form of carbidopa-levodopa, with upward dosage titration weekly until symptoms improve. A dopamine agonist may be added when the dosage of levodopa reaches 300-500 mg/day Dopamine agonists are used to control symptoms of PD, decrease or delay motor fluctuations, and allow lower dosages of levodopa to be administered. These agents are also being prescribed early in treatment before carbidopa-levodopa therapy is begun. Addition of a catechol-O-methyltransferase inhibitor can increase the duration of levodopa's effect and may prove especially valuable for patients who experience early wearing off of levodopa. Patients with PD require close monitoring for drug toxicity. Because most of them are treated with several agents to provide maximum improvement and also receive treatment for comorbid conditions, drug-drug interactions are possible. Frequently, clinically significant interactions are associated with agents that block D2 receptors or deplete dopamine stores in the brain.

Pharmacokinetic and pharmacodynamic modeling of L-dopa plasma concentrations and clinical effects in Parkinson's disease after Sinemet.

Eleven parkinsonian patients participated in a pharmacokinetic/pharmacodynamic study in an attempt to model levodopa (L-DOPA) plasma concentrations to clinical effect. Carbidopa 25 mg/L-DOPA 100 mg (Sinemet 25/100) was given orally, and blood samples were obtained before and serially for 4 hours after the dose. Effect measurements were obtained with each blood sample and included tapping score, timed walking, and global assessment of motor function. Mean L-DOPA plasma concentrations were fitted to a one-compartment pharmacokinetic model. A time-wise plot of modeled plasma L-DOPA concentrations versus mean effect measurements revealed a counter-clockwise hysteresis. Effect compartment concentrations were determined by a least squares approach, which determined elimination rate constants by minimizing hysteresis. Half-times for the equilibration between plasma and the effect compartment were 0.39 h for tapping, 0.36 h for walking, and 0.34 h for the global score. Pharmacodynamic data were fit best with an Emax model with baseline effect for tapping (Emax = 53.2 taps/60 s, EC50 = 0.58 microgram/ml) and global score (Emax set at 5.0 by limits of scale, EC50 = 2.53 micrograms/ml). A linear model best described the relationship between predicted effect site concentration and timed walking. L-DOPA plasma concentrations after oral Sinemet did not correlate well with clinical response because clinical response lags behind plasma concentrations. Half-times for equilibration between plasma and the effect site were similar for all of the effects measured.

Accuracy of serum anticonvulsant measurements. A comparison of enzyme multiplied immunoassay technique and gas-liquid chromatography.

An enzyme multiplied immunoassay technique is compared with a gas-liquid chromatographic technique for the measurement in blood serum of the anticonvulsants phenytoin, carbamazepine, phenobarbitone, primidone, and ethosuximide. The correlation between results obtained by each method was excellent, and both systematic and random errors were well within acceptable limits.

Effect of a consultant pharmacist on medication use in an institution for the mentally retarded.

The effect of a consultant pharmacist on medication use in an institution for the mentally retarded was studied. One year after hiring the consultant pharmacist and the implementation of a multidisciplinary approach to patient care at institution A, a previous medication survey was repeated for 715 patients. Medication use at a nearby mental retardation institution (institution B) with 1049 patients was surveyed once. The overall percentage of patients receiving antipsychotics or anticonvulsants in institution A was not different in the two surveys. There was a significant increase in the percent of patients receiving single drug entities in the second survey (for antipsychotics, 4.9% versus 9.1%; for anticonvulsants, 2.7% versus 15.1%). The use of long-term medications decreased from 76.1% to 56.8% of the population, and the use of individual antipsychotic agents changed significantly. The survey at institution B, a similar facility with less direct pharmacy involvement, showed significantly more use of antipsychotics than at institution A (34.2% versus 16.8%) and fewer patients receiving no long-term medications (29.2% versus 43.2%). The results suggest that the direct clinical involvement of skilled pharmacists in cooperation with other health professionals can significantly alter the patterns of medication use in a long-term care facility for the mentally retarded.

Post-traumatic epilepsy following head injury.

The occurrence of post-traumatic epilepsy (PTE) was studied in 164 consecutive closed head injury patients, each of whom had been unconscious and amnestic for at least one hour. The overall incidence of PTE was found to be 25%, significantly higher than previously reported. Analysis of data revealed PTE was not related to the presence or absence of a hematoma, but rather to the duration of the coma. The incidence of PTE was found to be 35% among patients comatose for three weeks or more.

Diminished mephobarbital anticonvulsant action following diphenhydramine pretreatment.

Diphenhydramine and other antihistamines produce biphasic effects on drug disposition and lower seizure threshold, thereby potentially diminishing the efficacy of anticonvulsants such as mephobarbital. Accordingly, the influence of diphenhydramine (50 mg/kg, IP) pretreatment on the anticonvulsant activity of mephobarbital (50 mg/kg, IP) was determined in adult female Swiss-Webster mice given pentylenetetrazol (SC). Diphenhydramine lowered the pentylenetetrazol convulsive dose (CD50) by 60%. Administration of diphenhydramine in combination with mephobarbital produced a 65% decrease in the CD50 of pentylenetetrazol in comparison with that of animals given mephobarbital plus pentylenetetrazol. Pharmacokinetic evaluation of mephobarbital blood level data indicates that the mechanism responsible for the observed interaction between diphenhydramine and mephobarbital involves a decrease in mephobarbital uptake from the administration site.