Evaluation of the Ames Seralyzer for the determination of carbamazepine, phenobarbital, and phenytoin concentrations in saliva.

The performance of the dry-phase apoenzyme reactivation immunoassay system (ARIS) for the measurement of carbamazepine (CBZ), phenobarbital (PB), and phenytoin (PHT) concentrations in saliva was compared with fluorescence polarization immunoassay (FPIA). Blood and saliva samples were collected from 163 adult and pediatric epilepsy patients, then analyzed using both methods. Regressions between ARIS saliva CBZ, PB, and PHT concentrations, and FPIA unbound and total serum concentrations were highly correlated, but the ARIS technique was somewhat less precise than the FPIA. Valproic acid co-medication did not affect the relationships between ARIS and FPIA saliva concentrations and unbound serum concentrations of PHT, but did disrupt the relationship between ARIS and FPIA saliva PHT and total serum PHT. The sensitivity, specificity, predicted value positive (PV+) of a therapeutic concentration, and predicted value negative (PV-) of a concentration outside the therapeutic range for the ARIS saliva technique compared very well with FPIA for CBZ, PB, and PHT. The ARIS technique for CBZ, PB, and PHT saliva determination provides acceptable accuracy, precision, and sensitivity for therapeutic monitoring. In practice, the benefits of the ARIS saliva technique, including ease of collection, safety, patient/parent acceptance, and short analysis time, are striking.

Effects of enteral tube feeding on the absorption and pharmacokinetic profile of carbamazepine suspension.

In a randomized, two-period crossover clinical study, eight normal male volunteers received two separate 500-mg doses of carbamazepine (CBZ) suspension 1 week apart. One dose was administered orally after an overnight fast, and the other was administered by nasogastric feeding tube during a continuous enteral feeding infusion. Serial serum CBZ concentrations were determined by high-performance liquid chromatography (HPLC) to assess the effects of the enteral feeding on CBZ absorption. Noncompartmental methods were used to estimate pharmacokinetic data. One volunteer experienced a mild hypersensitivity reaction after his first CBZ dose and was withdrawn from the study. The other subjects tolerated both doses very well, although most experienced mild drowsiness or lightheadedness. Serum CBZ concentrations were lower during enteral feeding administration, but the differences were statistically significant only at 8 h (p = 0.044). Changes in pharmacokinetic data were not significant, although the decrease in maximum serum concentration approached significance (p = 0.052). The relative bioavailability of CBZ suspension with enteral feeding administration was 90.1% of that during fasting. There was a strong correlation between CBZ dose (mg/kg) and Cmax after oral administration (r = 0.97, Y = 1.88X - 4.49, p less than 0.001) but not during enteral feeding administration. Although absorption of CBZ suspension was generally slower and slightly diminished during nasogastric feeding, this interaction may lessen unwanted side effects.

Valproate metabolites and hepatotoxicity in an epileptic population.

Idiosyncratic hepatotoxicity, although rare, is of major concern when one is treating patients with valproate (VPA). Several clinical criteria are associated with an increased risk of developing this complication, but more specific predictors are needed. It has been postulated that 4-en-VPA or one of its further metabolites may be responsible for the hepatic toxicity and that under certain conditions the metabolism of VPA is shifted to this product. We postulated that measurement of serum concentrations of 4-en-VPA or another metabolite might be a simple technique that would be predictive of risk for developing idiosyncratic hepatotoxicity. Because this complication is rare, we chose to analyze our data by a multiple linear regression model, exploring associations between VPA or three of its metabolites and clinical risk factors for hepatotoxicity. 4-en-VPA correlated with older age and absence of encephalopathy. 4-en-VPA was only seen in patients receiving polytherapy; all patients were also receiving CBZ. 2-en-VPA correlated with poor nutritional status. We conclude that routine measurement of serum 4-en-VPA is unlikely to be a useful predictor of risk for developing fatal hepatotoxicity. Serum concentrations of 4-en-VPA may not reflect presence or effects in the liver as it may be metabolized to further intermediates or be bound to tissue. Thus, serum levels of 4-en-VPA do not reflect its important role in the pathogenesis of hepatotoxicity. This metabolite was detected only in patients receiving polytherapy, a potent risk factor for developing this rare complication.

Correlates of systolic and diastolic blood pressure in men 40 to 59 years of age sampled from United States of America and Union of Soviet Socialist Republics Lipid Research Clinics populations.

The correlates of blood pressure (BP) were investigated in 2 samples using common protocols, one from a Union of Soviet Socialist Republics study in 2 locations and one from a United States of America study in 9 locations. Age, heart rate, Quetelet index, high density lipoprotein cholesterol, natural logarithm of triglycerides and fasting glucose were positively related to systolic BP in both samples. In diastolic BP, alcohol consumption, heart rate, Quetelet index and natural logarithm of triglycerides were positively associated, and number of cigarettes smoked was negatively related in both samples.

Prevalence of ischemic resting and stress electrocardiographic abnormalities and angina among 40- to 59-year-old men in selected U.S. and U.S.S.R. populations.

The prevalence of electrocardiographic (ECG) abnormalities and angina was investigated in 40- to 59-year-old men from two samples, one from a U.S.S.R. study in two locations and one from a U.S. study in nine locations. ECG abnormalities were defined by the Minnesota code and angina was defined by the Rose questionnaire. No differences were found in the prevalence of major Q waves and major or minor ischemia between the two samples, but differences were found in specific indicators of major ischemia. Major ischemic changes were more prevalent in older subjects in both samples. Estimated prevalence of angina was 50% less in the U.S. sample than in the U.S.S.R. sample, and this was consistent with the proportion of subjects excluded from the exercise test because of angina. In both samples, subjects with ECG abnormalities had higher systolic blood pressures. No difference in exercise test abnormalities was found between samples; however, more subjects with a history compatible with coronary artery disease were excluded from the U.S.S.R. sample.

Statistical and research quality of the medical and pharmacy literature.

The statistical and research quality of reports published in two U.S. medical journals and two U.S. pharmacy journals over a 12-month period was determined. A 50% random sample of issues of New England Journal of Medicine, Annals of Internal Medicine, American Journal of Hospital Pharmacy, and Drug Intelligence and Clinical Pharmacy published in 1979 was reviewed, and all citable items were classified as one of nine types of communications. Items classified as original evaluative research reports were evaluated for experimental design and research goals and rated for appropriateness of statistical testing and overall research quality according to a set of objective criteria. Reports that were not immediately classifiable were reviewed by one additional person, and classifications or ratings were assigned by mutual consent. Of a total of 1506 citable items, 120 met the criteria for original evaluative research reports. The two medical journals had the highest percentages of reports for which statistical methods were rated as correct but also had the most reports for which statistical methods could not be rated as a result of incomplete documentation or publication errors. Reports in the medical journals had conclusions based on a logical progression of hypothesis, methods, and analysis of results more frequently than did reports in pharmacy journals. Reports in the medical and pharmacy journals differed greatly according to research design and research goals. Improvement is needed in the statistical quality and research quality of original research reports published in the pharmacy literature.

U.S.S.R. and U.S. nutrient intake, plasma lipids, and lipoproteins in men ages 40-59 sampled from Lipid Research Clinics populations.

Correlates of high-density lipoprotein (HDL) cholesterol and other lipids and lipoproteins were studied in white men ages 40-59 who were part of the 15% random sample recalled to Visit 2 of the Lipid Research Clinics Program Prevalence Study. Standardized examinations were conducted by two U.S.S.R. and nine U.S. clinics. Mean plasma lipid and lipoprotein cholesterol levels differed significantly between the two countries, with the U.S.S.R. subpopulations having higher mean total plasma and HDL cholesterol levels and HDL/total cholesterol ratios and lower mean triglyceride levels and low-density lipoprotein (LDL)/HDL cholesterol ratios than the U.S. subpopulations. Small, but statistically significant, differences were found in some dietary components. The U.S.S.R. sample had a significantly higher intake of saturated fatty acids, carbohydrates, complex carbohydrates, and kilocalories/kilogram body weight and a significantly lower intake of total fat, polyunsaturated fatty acids, protein, and polyunsaturated/saturated fat ratio. The multiple regression models tested were not major predictors for total plasma cholesterol or LDL cholesterol. Characteristics associated with higher HDL cholesterol levels in both countries were lean body mass, ethanol consumption, abstinence from cigarette smoking, and lower dietary consumption of carbohydrates.