Metabolic effects of hypocaloric diets in management of gestational diabetes.

Although hypocaloric diets have been advocated for the management of the obese gravida and the obese mother with gestational diabetes, there is no general agreement on how severely calories should be restricted or on how this therapeutic approach compares with insulin therapy. The lack of consensus is in part because of the lack of studies comparing insulin management with the effects of different degrees of hypocaloric feeding and its effects on metabolism and glycemic status. We review the effects of 50 and 33% calorie restriction on glycemic status and intermediary fuel status in obese gestational diabetic subjects and compare the results with the administration of 20 U NPH and 10 U regular insulin every morning, a therapy of proven value in reducing macrosomia in gestational diabetes. When the two calorie-restriction regimens were compared after a 9-h overnight fast, glycemic status improved 10-20% on both. Ketonuria increased about twofold with 50% calorie restriction, but on average no increase in ketonuria was seen on the 33% calorie-restriction regimen. Both calorie-restriction programs led to a reduction in levels of plasma triglyceride, a correlate of infant birth weight. In contrast, the insulin regimen diminished ketonuria, but glycemic status improved little, and plasma triglyceride concentrations did not decline. Although more studies are needed to confirm these trends, the beneficial effect of 33% calorie restriction, which occurred without marked ketonuria, is consistent with previous studies in gestational diabetes. In addition, the simultaneous improvements observed in plasma glucose and triglyceride concentrations suggest that moderate calorie restriction may be valuable in preventing macrosomia in the offspring of the obese subject with gestational diabetes.(ABSTRACT TRUNCATED AT 250 WORDS)

Theophylline metabolism: variation and genetics.

Variation of theophylline metabolism in 54 healthy, nonmedicated adults (13 monozygotic [MZ] twin pairs, 11 dizygotic [DZ] twin pairs, and 6 single individuals) was assessed by kinetic study. Elimination rate constant, clearance (Cl), t1/2, and apparent volume of distribution, as well as urine excretion of unchanged theophylline and of the three major metabolites (1-methyluric acid, 3-methyl-xanthine, and 1,3-dimethyluric acid) were studied. Smokers and men had increased theophylline elimination rates compared to nonsmokers and women. Identical (MZ) twins resembled each other more closely than nonidentical (DZ) twins in the various kinetic parameters, but mean intrapair differences between MZ and DZ twins for all but one of the serum and urinary parameters examined (including t1/2) were not statistically significant. Correspondingly, estimates of heritability and of intrapair correlation coefficients showed a smaller contribution of genetic factors to variation in theophylline metabolism than had been reported for other drugs investigated by twin studies. Nevertheless, in the family of the individual with the longest theophylline t1/2, the operation of a rare major gene retarding theophylline metabolism could not be excluded. A father and two out of four children had very slow Cls. This finding would be consistent with, but does not prove, monogenic inheritance.

Diurnal variation in valproic acid clearance.

Diurnal variation in total and unbound valproic acid concentrations was measured at steady state in seven healthy men and three healthy women after 250-mg oral doses every 12 hr. Total average steady-state concentration (Css) during the morning dosage interval was 50.4 mg/l. During the evening dosage interval, total Css was 45.7 mg/l. Unbound Css was also less during the evening (2.9 and 3.4 mg/l). These changes were due to higher total and unbound clearance rates during the evening dosage interval. Total peak concentrations were lower (56.8 and 64.3 mg/l) and time of peak concentrations slightly longer (2.2 and 1.8 hr) during the evening. There was marked interindividual variability in all these changes. For best reproducibility of steady-state valproic acid concentrations, our results suggest that total and unbound levels be drawn at the same time of day.

Valproic acid clearance: unbound fraction and diurnal variation in young and elderly adults.

Six young (22 to 25 years old) and six elderly (60 to 88 years old) healthy adults took valproic acid, 250 mg by mouth, at 8 am and 8 pm for 5 days. On the fifth day, blood samples were drawn over each dosage interval. Both young and elderly subjects exhibited diurnal variability. Total and unbound clearances in the young and elderly subjects were about 10% and 15% higher during the evening. These changes led to lower total and unbound steady-state and peak concentrations during the nighttime dosage interval. There were no differences in total steady-state concentrations and kinetics computed from total concentrations between the young and elderly, but there were differences in unbound steady-state concentrations and kinetics. Unbound clearances were 65% lower, which resulted in unbound steady-state concentrations 67% higher in the elderly. The average unbound fractions in the elderly and young were 10.7% and 6.4%. To minimize the influence of diurnal variability, drug concentrations should be determined at the same time each day. Total valproic acid concentration data may be less useful in elderly patients; unbound concentrations may be more reliable in this population.

Influence of long-term infusions on lidocaine kinetics.

Lidocaine kinetics were examined during continuous infusions in five healthy subjects using stable isotope lidocaine labeled with two deuterium atoms. During phase 1, lidocaine and stable isotope lidocaine (50 mg IV each) were given as a bolus to confirm that the two species were kinetically identical. Phase 2 consisted of a long-term (30 hr) lidocaine infusion designed to produce a steady-state concentration equal to 1.5 microgram/ml. Twenty-four hours into the infusion, stable isotope lidocaine (50 mg) was given as an intravenous bolus and kinetic parameters were calculated. Phase 3 differed from phase 2 in that target steady-state lidocaine concentration was 4 microgram/ml and the stable isotope lidocaine dose was reduced to 40 mg. A gas chromatograph-mass spectrometer was used to determine lidocaine and stable isotope lidocaine serum concentrations. Compared to phase 1, clearance decreased (P less than 0.05) and half-life increased (P less than 0.025) during phases 2 and 3. The volume of distribution at steady-state remained constant during all three phases. Lidocaine cumulated in serum during long-term infusions in all five patients; repeated decreases in infusion rate were necessary to avoid exceeding desired target concentrations in phases 2 and 3.

Ethosuximide kinetics: possible interaction with valproic acid.

Ethosuximide kinetics were determined in six normal healthy adults after a single dose (phase 1) and at steady-state (phase 2). After the completion of phase 2, valproic acid was added to the ethosuximide regimen (phase 3) to assess the possibility of drug interaction. Between phases 1 and 2 total clearance fell from 13.1 to 11.1 ml/hr/kg (P less than 0.05) and nonrenal clearance fell from 10.1 to 8.3 ml/hr/kg (P less than 0.05). When valproic acid was added (phase 3) there was no further change in total or nonrenal clearance (11.2 and 8.3 ml/hr/kg). To assess the possibility of nonlinear ethosuximide kinetics a review was conducted of patients who received ethosuximide as sole therapy for absence seizures. Of 106 patients, 10 met the required criterion that defined steady state. Data from seven of the 10 patients showed evidence of a nonlinear relationship when steady-state ethosuximide concentrations were plotted against dose.

Cimetidine clearance in the obese.

Six subjects with normal weight (mean weight = 62 kg) and six obese subjects (mean weight = 140 kg) were given a single intravenous cimetidine infusion of 600 mg over 10 to 15 minutes. Both groups of subjects had normal serum creatinine levels and were matched with respect to age, desirable body weight, height, renal function, and sex. Compared with subjects of normal weight, obese subjects had higher cimetidine systemic (1147 and 637 ml/min) and renal (808 and 318 ml/min) clearances. Volume of distribution at steady state was of the same order for the two groups (82 and 84 L), but the t 1/2 was shorter in the obese group (1.2 and 1.9 hr). Obese subjects had lower cimetidine sulfoxide serum concentrations and greater cimetidine sulfoxide renal clearance (856 and 509 ml/min). Cimetidine systemic clearance and cimetidine sulfoxide renal clearance values were of the same order in the two groups when normalized by the value of weight raised to the 0.76 and 0.5 powers. Under the assumptions of an average weight of 70 kg and that average serum concentrations produced by cimetidine, 300 mg iv every 6 hours, are appropriate, people with normal renal function and body weight usually receive 48 mg/day/weight0.76. This same dosage in obese individuals with normal serum creatinine values should result in the same average steady-state serum concentrations. In our obese subjects, the mean cimetidine dose would have been approximately 500 mg iv every 6 hours.

A case of nonneuroleptic malignant syndrome.

Neuroleptic malignant syndrome is a diagnosis that has been reported with increasing frequency in recent years. We report the case of a patient who was not treated with a neuroleptic but in whom a syndrome identical to neuroleptic malignant syndrome developed. The case highlights the overuse of and the confusion about the diagnosis of the syndrome.

The magnitude of acute and chronic alcohol abuse in trauma patients.

OBJECTIVE: To assess the incidence of acute alcohol intoxication and the proportion of trauma patients with evidence of chronic alcohol abuse. DESIGN: Prospective cohort study. SETTING: Regional level I trauma center. PARTICIPANTS: Patients aged 18 years and older admitted with blunt or penetrating trauma. MAIN OUTCOME MEASURES: Admission blood alcohol concentrations (BACs), the Short Michigan Alcohol Screening Test (SMAST), and biochemical markers for chronic alcohol abuse. RESULTS: Of the 2657 patients enrolled, 47.0% had a positive BAC and 35.8% were intoxicated (BAC > or = 100 mg/dL) on admission to the emergency department. Intoxicated patients were more likely to be 25 to 34 years old, male, and nonwhite; the highest proportion of intoxicated patients was among victims of stab wounds. Three fourths of acutely intoxicated patients had evidence of chronic alcoholism as indicated by a positive SMAST, and 25% to 35% of acutely intoxicated patients had biochemical evidence of chronic alcohol abuse. CONCLUSIONS: The high prevalence of both acute intoxication and chronic alcoholism in trauma patients indicates the need to diagnose and appropriately treat this pervasive problem in trauma victims.

The pharmacokinetics of thiabendazole and its metabolites in an anephric patient undergoing hemodialysis and hemoperfusion.

The pharmacokinetics of thiabendazole and its metabolites were determined after the first dose and during hemodialysis and hemoperfusion in an anephric female patient treated for a strongyloides infection. The half-live, volume of distribution, and clearance for thiabendazole were 1.17 hour, 2.76 liters/kg, and 27.2 ml/min . kg, respectively. While thiabendazole and the 5-OH metabolite did not accumulate during multiple dosing, the glucuronide and sulfate esters accumulated extensively despite hemodialysis and hemoperfusion. Hemodialysis clearances for all compounds were poor. Hemoperfusion removal was much better but declined rapidly after the first hour. If rapid removal of thiabendazole and its metabolites is required, the hemoperfusion column should be changed hourly.

Correlation of the "EMIT" antiepileptic drug assay with a gas liquid chromatographic method.

Many methodologies have been developed for determining anticonvulsant drug levels in human serum. Unfortunately, most procedures are either time consuming or subject to a variety of interferring substances. The "Enzyme Multiplied Immunoassay Technique" (EMIT) system has been evaluated for its speed, sensitivity, accuracy, and precision. When compared with a gas-liquid chromatographic procedure, the EMIT assay appeared to yield results which were statistically comparable for the drugs diphenylhydantoin, phenobarbital, and primidone. The EMIT assay also demonstrated no significant interference when challenged with extraordinarily high levels of potentially cross reacting drugs. Results obtained with the EMIT assay correlated well with GLC data and rank it as an attractive alternative to many of the existing procedures now being used.

Mitral valve abnormalities and catecholamine activity in anxious patients.

We studied 38 anxiety disorder patients, 19 of whom had evidence of mitral valve abnormalities by two-dimensional echocardiography. The presence or absence of mitral valve abnormalities was not related to 3-methoxy-4-hydroxyphenylglycol/creatinine excretion, platelet and plasma monoamine oxidase-type activity, or autonomic arousal as measured by blood pressure and resting heart rate. These findings fail to support the hypothesis that mitral valve abnormalities identify a specific subpopulation of anxious patients with differences in catecholamine function.

Can oral midazolam predict oral cyclosporine disposition?

Effective cyclosporine therapy is confounded by large interindividual differences in oral bioavailability and a narrow therapeutic window. Because cytochrome P450 (CYP) 3A-mediated first-pass metabolism contributes to this unpredictable bioavailability, an in vivo oral CYP3A phenotyping probe could be a valuable tool in optimizing cyclosporine therapy. Based on similarities in the metabolic kinetics of cyclosporine and midazolam by the liver and intestinal mucosa, we evaluated whether midazolam oral clearance would predict cyclosporine oral clearance when the two drugs were administered to 20 medically stable kidney transplant recipients. Despite earlier findings in liver transplant recipients who displayed a strong correlation between the systemic clearances of midazolam and cyclosporine, there was a weak correlation between their oral clearances in the current group of subjects (r(s)=0.50, P=0.03). Differing extents of intestinal first-pass metabolic extraction between the two drugs, inhibition of midazolam metabolism by cyclosporine at the level of the intestine, and/or P-glycoprotein-mediated intestinal efflux of cyclosporine (but not midazolam) may account for this poor correlation. We conclude that although oral midazolam is unlikely to be clinically useful as a probe for cyclosporine disposition, its utility in the prediction of other orally administered CYP3A substrates cannot be out ruled.

Drug-specific Fab therapy in drug overdose.

The use of digoxin-specific fragments, antigen-binding (Fab) for antidotal therapy of severe digitalis intoxication is rapidly becoming a treatment of choice. Furthermore, studies with this mode of drug-specific therapy using Fab specific for desipramine and for phencyclidine suggest that this treatment may be applicable to a variety of other drugs or drug classes. As Fab technology has advanced, so have laboratory methods for monitoring the efficacy of treatment.

The reliability of laboratory data from blood samples collected through pulmonary artery catheters.

Blood samples obtained through quadruple-lumen Swan-Ganz catheters in ten critically ill patients provided reliable results after withdrawal of a total of 2.2 mL (including 1.2 mL of dead space) for hematocrit tests and 3.2 mL (including 1.2 mL of dead space) for plasma sodium tests.

Analysis of digoxin concentrations in serum by fluorescence polarization immunoassay: an evaluation.

The Abbott TDx fluorescence polarization immunoassay was evaluated for the determination of serum digoxin concentrations. Within-assay precision was less than 4% coefficient of variation (CV) for concentrations ranging from 0.64 to 3.75 ng/mL. Between-assay precision was 14.5% CV at 0.75 ng/mL, 5.7% CV at 1.50 ng/mL, and 4.9% CV at 3.48 ng/mL. Sensitivity to 0.2 ng/mL digoxin was confirmed. Correlation of 86 patient specimens assayed by radioimmunoassay (RIA) with the TDx showed the following: correlation coefficient r = 0.94, slope = 0.93, intercept = 0.11, and Sy/x = 0.19. Recovery from serum at concentrations of 0.97 ng/mL and 4.50 ng/mL averaged 98%. No significant interference from lipemia, icteria, or hemolysis was observed. Spironolactone showed no cross-reactivity with the antibody, while digitoxin exhibited significant cross-reactivity. Compared to the RIA procedure, the TDx assay was more rapid, reliable and, in this clinical situation, more cost effective.

The analysis of cocaine and benzoylecgonine in meconium.

We describe an assay for measuring cocaine and benzoylecgonine in meconium of infants born to mothers suspected of using cocaine during their pregnancy. The assay involves the use of fluorescence polarization immunoassay (FPIA) to screen for benzoylecgonine in a methanolic extract of the meconium. The FPIA is sensitive to 0.6 microgram benzoylecgonine per gram meconium. Confirmation of the presence (or absence) of benzoylecgonine and cocaine in meconium samples was performed by solid phase extraction of a second methanolic extract of the meconium, derivatizing using BSTFA, followed by a gas chromatographic/mass spectrometric (GC/MS) analysis, which can detect both cocaine and benzoylecgonine. The GC/MS confirmation was sensitive to less than 0.25 microgram cocaine or 0.5 microgram benzoylecgonine per gram meconium. FPIA, which is commonly used in many toxicology laboratories, is advantageous because it precludes the need to use radioimmunoassays for the initial screen. The confirmation step provides greater certainty for the presence of cocaine and/or benzoylecgonine in meconium.

Death following accidental sodium azide ingestion.

Two college students developed symptoms of poisoning following ingestion of a salt solution during a college physiology laboratory exercise. Symptoms included nausea, vomiting, diarrhea, and altered consciousness. The ingested solution was identified as isotonic buffered saline containing sodium azide in a concentration of 1.0 g/L. The solution was commercially prepared for instrumentation use only and was used inadvertently for the exercise instead of freshly preparing sodium chloride in water. One student drank three sips of the solution and survived. The other student drank 700 to 800 mL and over several days became progressively ill, suffering myocardial damage and cardiac dysrhythmias, and, finally, died. Toxicologic studies confirmed the presence of azide in an antemortem urine sample from the deceased. Sodium azide is an uncommon but potent poison which can cause serious illness and death.

Substance abuse testing of urine by GC/MS in scanning mode evaluated by proficiency studies, TLC/GC, and EMIT.

Using GC/MS in scanning mode as a screening and definitive identification methodology for substance abuse testing, 4500 urine samples have been analyzed. The accuracy and sensitivity of this method was evaluated by the results of 92 proficiency sample analyses, reanalyses by TLC screening with GC confirmation of 125 samples from forensic sources and reanalysis by EMIT screening for seven groups of drugs confirmed by GC/MS of 590 samples from industrial and treatment sources. The results of these studies are presented.