Hepatic and renal contributions to valproic acid-induced hyperammonemia.

Valproic acid (VPA) consistently and reproducibly elevates arterial ammonia in rats injected with an amino acid load. The extent of the hyperammonemia is dependent on the dose of VPA injected or VPA plasma concentration and the amino acid dose. Bilaterally nephrectomized rats injected with VPA and an amino acid load also develop hyperammonemia, which overall approximates 75% of that achieved in non-nephrectomized animals. In non-nephrectomized animals injected with an amino acid load, valproic acid produces a marked reduction in baseline and activated hepatic mitochondrial carbamyl phosphate synthetase I activity. Our results suggest that VPA-induced hyperammonemia after an amino acid load results from inhibition of hepatic intramitochondrial citrullinogenesis with only a limited contribution from the kidneys.

Sodium valproate-induced hyperammonemia without clinical hepatic dysfunction.

Three adults on unrestricted protein diets receiving valproic aci (VPA) developed gastrointestinal symptoms with encephalopathy and/or deteriorating seizure control associated with arterial hyperammonemia and normal liver function tests. The signs and symptoms did not directly correlate with VPA dosage and the arterial ammonium levels did not correlate with serum VPA concentrations. Two of the three patients had phenobarbital concentrations above the therapeutic range, but remission of neurologic or gastrointestinal symptoms was dependent on a reduction of the VPA concentration. In one case, rechallenge with VPA reproduced hyperammonemia.

The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: plasma and ventricular CSF L-dopa levels and clinical responses.

We monitored the motor response and plasma and ventricular CSF (CSFv) concentrations of L-dopa during IV infusions of L-dopa in two patients with advanced Parkinson's disease. Concentrations of L-dopa in CSFv mirrored, but lagged behind, those in plasma. In the fasting state, the duration, but not the magnitude, of the motor response was greater with increasing plasma and CSFv levels of L-dopa. During IV infusions of L-dopa following oral administration of phenylalanine, a large neutral amino acid that shares a transport system into the brain with L-dopa, the duration of the motor response was markedly attenuated despite undiminished CSFv levels of L-dopa. These observations suggest that either L-dopa entry into CSFv and the brain are differentially affected by phenylalanine or that phenylalanine affects other steps in the motor response. These observations demonstrate that, except in the fasting state, L-dopa in CSFv is not a reliable predictor of motor response.

Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

A comparison of minoxidil and hydralazine in non-azotemic hypertensives.

In 36 patients with normal renal function receiving hydrochlorothiazide and propranolol, lying diastolic blood pressure remained above 95 mmHg. In a double-blind trial, Step 3 therapy with 5-40 mg/day of minoxidil reduced blood pressure somewhat more effectively than 25-200 mg/day of hydralazine. The percentage of patients with lying diastolic blood pressure below 90 mmHg was 69 versus 35% at four weeks, and 55 versus 40% at 28 weeks. Transient falls in blood pressure within 4 h of any dose were greater with hydralazine which usually needed to be given in divided daily doses. Minoxidil caused tachycardia, and more adverse effects. Minoxidil is more effective, produces more consistent blood pressure control throughout the day, and may often be administered once daily.

Heparin-induced thrombocytopenia. What is its real frequency?

A prospective study of 104 patients was undertaken to determine the frequency of severe heparin-induced thrombocytopenia in patients receiving either bovine lung or porcine mucosal heparin. One of 54 patients randomized to receive bovine heparin and two of 50 patients randomized to receive porcine heparin developed heparin-induced thrombocytopenia (platelet count less than 100,000/microliters). Although three previous studies suggest a remarkably high frequency of bovine heparin-induced thrombocytopenia, or a high frequency compared to porcine heparin, our study supports other evidence that clinically important, severe heparin-induced thrombocytopenia (platelet count less than 100,000/microliters) occurs in 10 percent of patients or less receiving heparin, and that there is no significant difference of occurrence between bovine and porcine heparin.

Pharmacy participation in pharmaceutical representative displays in a large teaching hospital.

The Department of Pharmacy in a 1200-bed private teaching hospital was seeking additional ways to inform the medical staff of pharmaceutical services and decided to participate as an exhibitor in an established pharmaceutical representative display. The format for the display consisted of three different exhibitors twice weekly in a centrally located area with catering provided. Topics presented by the Pharmacy Department, bi-monthly, included patient medication teaching sheets, drug information services, drug use evaluation results, Additive Room services, formulary content and use, as well as kinetics.

Emergency department medication and drug interaction evaluation.

The emergency department evaluation had two primary objectives: 1) to determine the accuracy of the oral medication history given at arrival at the emergency department and 2) to determine how often the emergency department physician may prescribe medications which when taken with current medications, may cause a potential drug interaction. Data were collected from 228 emergency department visits of clinic patients 65 years old and older. The average number of medications reported by the patients' medication history was 3.0 +/- 2.3 (range 0-13). The number of medications the patient "forgot" was 1.3 +/- 1.8 (range 0-9). A complete medication history was given by 50.4% of patients. There was an upward trend that correlated with an increased chance for an incomplete medication history as the total number of current medications increased. The rate of a potentially significant drug interaction between a newly prescribed medication in the emergency department and current medications was 3.4% for patients receiving a new medication.