A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus.

BACKGROUND: It is uncertain whether the administration of benzodiazepines by paramedics is an effective and safe treatment for out-of-hospital status epilepticus. METHODS: We conducted a randomized, double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus. Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was given if needed. RESULTS: Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent) than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as compared with the placebo group. The rates of respiratory or circulatory complications (indicated by bag valve-mask ventilation or an attempt at intubation, hypotension, or cardiac dysrhythmia) after the study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for the diazepam group, and 22.5 percent for the placebo group (P=0.08). CONCLUSIONS: Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.

Impact of Parkinson's disease and its pharmacologic treatment on quality of life and economic outcomes.

The impact of Parkinson's disease (PD) and its pharmacologic treatment on health-related quality of life (HRQL) and economic outcomes is reviewed. PD is a chronic and progressive neurologic disorder characterized by specific motor deficits resulting from the degeneration of dopaminergic neurons in the substantia nigra. The cardinal symptoms are tremor, rigidity, bradykinesia, and loss of postural reflexes. PD markedly reduces HRQL and places an economic burden on society of up to $25 billion per year. Patients' inability to move freely and to perform everyday tasks restricts their independence and leads to increased reliance on caregivers and assistive devices. Emotional and psychosocial well-being is also negatively affected. As the disease progresses, the response to levodopa typically decreases and various motor complications develop; these are difficult to treat and result in further declines in HRQL. The economic costs of PD include both direct health care costs (for drugs, physician services, and hospitalization) and indirect costs (for lost worker productivity). Economic analyses of PD and its treatments can help guide effective allocation of health care resources. Various antiparkinsonian agents and formulations, such as extended-release levodopa-carbidopa and pramipexole, have been found to be cost-effective relative to other agents. The newest antiparkinsonian drugs, cathechol-O-methyltransferase inhibitors, also have the potential to improve HRQL and economic outcomes, although more study is needed to confirm this. The total impact of PD and its treatment can be fully appreciated only when HRQL and economic outcomes, in addition to clinical outcomes, are examined.

Maximizing the benefit:risk ratio of levodopa therapy in Parkinson's disease.

For over 30 years, levodopa has been the gold standard for managing the symptoms of Parkinson's disease. Treatment with levodopa has resulted in a marked decrease in disease-associated mortality and morbidity. However, one of its drawbacks is that many patients experience a shorter duration of response and increased motor fluctuations with disease progression and long-term levodopa therapy. These increased motor fluctuations, including dyskinesias, may be the consequence of oxidative stress or inability to store and regulate intrasynaptic dopamine concentrations with disease progression. Clinical investigations have demonstrated that continuous dopaminergic stimulation may widen the therapeutic window for levodopa and improve motor fluctuations. Strategies for providing continuous dopaminergic replacement include administration of levodopa by continuous infusion, controlled-release levodopa, long-acting dopamine agonists, and inhibitors of levodopa metabolism. The catechol-O-methyltransferase inhibitors that block a compensatory metabolic pathway for levodopa and prolong its duration may improve the consistency of the dopaminergic response.

Prehospital stability of diazepam and lorazepam.

Injectable benzodiazepines are commonly stocked on ambulances for use by paramedics. We evaluated the stability of lorazepam and diazepam as a function of storage temperature. Diazepam (5 mg/mL) and lorazepam (2 mg/mL) injectable solutions were stored for up to 210 days in clear glass syringes at three conditions: 4 degrees C to 10 degrees C (refrigerated); 15 degrees C to 30 degrees C (on-ambulance ambient temperature); and 37 degrees C (oven-heated). High-performance liquid chromatography (HPLC) analyses of syringe contents were performed at 30-day intervals. After 210 days, the reduction in diazepam concentration was 7% refrigerated, 15% at ambient temperature, and 25% at 37 degrees C. The reduction in lorazepam concentration was 0% refrigerated, 10% at ambient temperature, and 75% at 37 degrees C. Whereas diazepam retained 90% of its original concentration for 30 days of on-ambulance storage, lorazepam retained 90% of its original concentration for 150 days. The decrease in lorazepam concentration correlated with an increase in the maximum ambient temperature in San Francisco. These results suggest that diazepam and lorazepam can be stored on ambulances. When ambient storage temperatures are 30 degrees C or less, ambulances carrying lorazepam and diazepam should be restocked every 30 to 60 days. When drug storage temperatures exceed 30 degrees C, more frequent stocking or refrigeration is required.

Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease.

PURPOSE: The pharmacokinetic behavior of fosphenytoin (FOS), the water-soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. METHODS: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. RESULTS: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. CONCLUSIONS: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.

Entacapone, a catechol-O-methyltransferase inhibitor for treating Parkinson's disease: review and current status.

Levodopa, a dopamine precursor administered with a decarboxylase inhibitor, is the principal therapy for treating the symptoms of Parkinson's disease. Unfortunately, after approximately 2-5 years, it frequently loses its beneficial effects as evidenced by motor fluctuations. Entacapone (Comtan) is a selective, reversible catechol-O-methyltransferase inhibitor that dose-dependently increases the peripheral bioavailability of levodopa and prolongs its duration of action. Early studies confirmed that treatment with entacapone resulted in increased striatal uptake of levodopa after iv. administration of [18F] levodopa. Preclinical studies confirmed decreased formation of COMT-dependent metabolites, including 3-O methyldopa and homovanillic acid. Clinical studies performed in patients with motor fluctuations have shown that entacapone prolonged the duration of motor response by an average of 1-1.3 h. Parkinsonian patients receiving therapeutic doses of dopamine agonists and selegiline also experienced an incremental improvement in 'on' time when entacapone was added to their drug regimen. At present, there are no published safety studies beyond six to twelve months in duration, or studies in nonfluctuating patients. Based on the clinical trial data available, entacapone is well-tolerated in the majority of patients. Dopaminergic-related adverse effects include dyskinesias, nausea and dizziness. Non-dopaminergic adverse effects include diarrhoea, abdominal discomfort and discoloration of urine. Diarrhoea is occasionally severe and may require discontinuation of therapy. Of 406 entacapone-treated subjects, there was one incidence of elevated liver transaminases, although this was attributed to an underlying disorder. In the US, Phase III trials have been completed and a New Drug Application (NDA) has been filed. In Europe, the drug received a favourable review and is currently available.

New pharmacotherapy for Parkinson's disease.

OBJECTIVE: To summarize the development, pharmacology, pharmacokinetics, efficacy, and safety of five investigational antiparkinsonian drugs that are in or have recently completed Phase III trials: three dopamine agonists, pramipexole, ropinirole, and cabergoline; and two catechol-O-methyltransferase (COMT) inhibitors, entacapone and tolcapone. The pathophysiology and the role of dopamine in Parkinson's disease are also reviewed. DATA SOURCES: A MEDLINE search of relevant English-language literature, clinical studies, abstracts, and review articles pertaining to Parkinson's disease was conducted. Manual searches of 1996/1997 meeting abstracts published by the American Academy of Neurology and the Movement Disorders Society were also performed. Manufacturers provided unpublished Phase III trial efficacy and pharmacokinetic data. STUDY SELECTION AND DATA EXTRACTION: Clinical trial investigations selected for inclusion were limited to human subjects. Interim analyses after 6 months for long-term clinical studies in progress were included. Pharmacokinetic data from animals were cited if human data were unavailable. Statistical analyses for all studies were evaluated. DATA SYNTHESIS: By selectivity targeting D2 receptors, the newer dopamine agonists (i.e., cabergoline, pramipexole, ropinirole) may delay the introduction of levodopa and thus the occurrence of levodopa-induced dyskinesias. In addition, they are efficacious as adjunctive therapies in patients with advanced Parkinson's disease. Unlike the currently available dopamine agonists, pramipexole and ropinirole are non-ergot derivatives and do not cause skin inflammation, paresthesias, pulmonary infiltrates, or pleural effusion. The COMT inhibitors, tolcapone and entacapone, improve the pharmacokinetics of levodopa by preventing its peripheral catabolism and increasing the concentration of brain dopamine; thus, these agents may reduce the incidence of "wearing-off" effects associated with the short half-life of levodopa and the progression of Parkinson's disease. CONCLUSIONS: Interim 6-month analyses of pramipexole, ropinirole, and cabergoline for symptomatic treatment of early Parkinson's disease have shown these drugs to be efficacious and relatively well-tolerated when used as monotherapy. Their role in delaying the development of motor fluctuations and delaying the addition of levodopa is the subject of long-term clinical studies. In advanced stages of Parkinson's disease, these medications were also efficacious; however, the main adverse effects included dyskinesias, somnolence, and hallucinations. The COMT inhibitors, entacapone and tolcapone, have also demonstrated efficacy in improving on-time in patients with stable disease. Tolcapone has also demonstrated efficacy in patients with motor fluctuations. Both drugs are relatively well-tolerated, with the exception of dyskinesias that require reduction of the levodopa dosage and occasional diarrhea.