Monotherapy In Subjects Research Articles

Phenytoin versus valproate monotherapy for partial onset seizures and generalized onset tonic-clonic seizures.

Phenytoin and valproate are commonly used antiepileptic drugs. It is generally believed that phenytoin is more effective for partial onset (simple partial, complex partial and secondary generalized tonic-clonic seizures) seizures whilst valproate is more effective in generalized onset seizures (generalized tonic-clonic seizures, absence, myoclonus) although there is no evidence from randomized controlled trials to support this belief. The use of individual patient data meta-analysis enabled us to examine time to event outcomes which are important in epilepsy monotherapy trials, and also to examine treatment-covariate interactions. To review the best evidence comparing phenytoin and valproate when used as monotherapy in subjects with partial onset seizures, or generalized onset tonic-clonic seizures with or without other generalized seizure types. Our search strategy included: (i) the Cochrane Epilepsy Group trial register, (ii) MEDLINE 1966-2000, (iii) hand-searching relevant journals, (iv) the pharmaceutical industry, and (v) researchers in the field. Randomized controlled trials in children or adults with partial onset seizures or generalized onset tonic-clonic seizures. Trials must have included a comparison of phenytoin monotherapy with valproate monotherapy. This was an individual patient data review. Outcomes were time to (i) withdrawal of allocated treatment, (ii) 12 month remission, (iii) six month remission, and (iv) first seizure post randomization. Data were analysed using stratified logrank analysis with results expressed as hazard ratios (HR) and 95% confidence intervals (95% CI), where a HR>1 indicates an event is more likely on phenytoin. A test for interaction between treatment and seizure type (partial onset versus generalized onset) was also undertaken for each outcome. Data were available for 669 subjects from five trials, representing 60% of the subjects recruited into the eleven trials that met our inclusion criteria. One important limitation of these data is that in four of the five trials, for patients classified as having generalized onset seizures, tonic-clonic seizures were the only seizure types recorded at follow up, despite the fact that some patients will have been experiencing other generalized seizure types such as absence or myoclonus. Their results for the generalized seizures therefore relate only to generalized onset tonic-clonic seizures. The main overall results were as follows (HR(95% CI), HR>1 indicates a clinical advantage for phenytoin for both remission outcomes and a clinical advantage for valproate for the outcomes time to withdrawal and time to first seizure) (i) time to withdrawal of allocated treatment 1.10(0.79-1.54), (ii) time to 12 month remission 1.04(0.78-1.38), (iii) time to six month remission 0.89(0.71-1.11), and (iv) time to first seizure 0.92(0.74-1.14). The results suggest no overall difference between drugs for these outcomes. The test for an interaction between treatment and seizure type (generalized versus partial onset) was non significant for all outcomes. We have not found evidence that a significant difference exists between phenytoin and valproate for the outcomes examined in this review. As generalized seizures such as absence and myoclonus were counted in only one trial, results do not address the treatment of these seizure types. We found no unequivocal evidence to overthrow or support the policy of using valproate in generalized onset tonic-clonic seizures and phenytoin in partial onset seizures.

HIV-1 reverse transcriptase codon 215 mutation in plasma RNA: immunologic and virologic responses to zidovudine. The AIDS Clinical Trials Group Study 175 Virology Team.

Treatment of HIV infection with zidovudine (ZDV) may select for changes in the genetic sequence of the viral reverse transcriptase (RT) that imparts drug resistance. The presence of a 2-bp mutation at codon 215 of RT (from threonine to phenylalanine or tyrosine) was assessed in plasma viral RNA in 85 subjects treated with ZDV in the AIDS Clinical Trials Group (ACTG) 175 virology substudy. Median CD4 cell numbers, HIV plasma RNA levels, and infectious titers of virus were significantly different over 56 weeks of treatment among 58 subjects with the wild-type threonine at codon 215 virus at study entry compared with the 27 subjects with mutations to phenylalanine or tyrosine (MUT) virus. Thirty percent (13 of 44 subjects) with wild-type virus at study entry developed a new codon 215 mutation. Genotypic resistance at codon 215 in plasma HIV RNA is associated with the subsequent immunologic and virologic failure of ZDV monotherapy in subjects with 200 to 500 CD4 cells/mm3.

Efficacy of Insulin and Sulfonylurea Combination Therapy in Type II Diabetes

Numerous studies demonstrate the efficacy of the combination therapy of insulin and sulfonylurea in subjects with type II diabetes mellitus. However, two recent meta-analyses of randomized trials during the last decade provided inconsistent conclusions and failed to resolve the controversy. To assess the efficacy of insulin and sulfonylurea combination therapy in type II diabetes mellitus by performing meta-analysis of only the controlled studies selected according to specific strict criteria. A computerized literature survey was conducted using the MEDLINE database from January 1980 through March 1992 with the search headings of "sulfonylurea" and "insulin" and "combination therapy in diabetes mellitus. "A manual search was also performed using references from each retrieved report. Case reports, review articles, editorials, and citations reported in non-English-language journals without English translations were excluded. Forty-three citations were obtained. Four strict inclusion criteria were used to select studies: randomized, placebo-controlled trials (oral agent plus insulin vs placebo plus insulin); homogeneous target population (subjects with type II diabetes); intervention using the same sulfonylurea agent in a combination therapy; and uniform outcome measures to evaluate efficacy such as body weight; values for serum glucose, glycohemoglobin, and C peptide; daily insulin dosage; and lipid concentrations. More stringent qualitative subcriteria were then used to eliminate bias in the final unanimous selection by two blinded reviewers. Data were pooled and analyzed using Student's t test and Winer's combined test. Sixteen studies satisfied the inclusion criteria. Metabolic control improved with the combination therapy as reflected by a significant lowering of fasting serum glucose values (P < .01) and glycohemoglobin concentrations (P < .025). Moreover, improved metabolic control was achieved with a significantly smaller daily insulin dose (P < .01) and without a significant change in body weight. Finally, the combination therapy enhanced the endogenous insulin secretion as expressed by an increase in fasting serum C peptide concentration (P < .05). Combination therapy with insulin and sulfonylurea may be a more appropriate and a suitable option to insulin monotherapy in subjects with non-insulin-dependent diabetes in whom primary or secondary failure to sulfonylurea developed. It may also be a more cost-effective way of long-term management in this group of subjects, especially in the elderly.

Effect of benazepril monotherapy in subjects with hypertension associated with renal dysfunction.

Nine hypertensive patients with mild to moderate renal dysfunction were entered into a protocol to assess the blood pressure, humoral and renal effects of the angiotensin converting enzyme inhibitor, Benazepril (CGS14824A, 2 to 20 mg twice daily) in patients with hypertension and moderate renal insufficiency (mean creatinine clearance 56 ml/min/1.73 m2). Specifically monitored, prior to and following 12 weeks of Benazepril monotherapy, were plasma renin activity and plasma aldosterone, the clearances of creatinine, Tc99m-diethylenetriaminepentaacetic acid (TC99m-DTPA) and para-amino-hippurate, and the 24-hour urinary excretion of protein. Blood pressure was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed. Mean serum potassium increased from 3.9 to 4.2 mEq/L. Benazepril monotherapy had no adverse renal hemodynamic effect. Benazepril appears to be an effective antihypertensive agent in hypertensive patients with moderately impaired renal function.