Vidmantas A. Raisys

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.

Drug use in trauma victims

We examined the prevalence and characteristics of drug use in a large sample of fatally and nonfatally injured trauma victims. Routinely collected urine specimens from 452 emergency room patients and 160 persons autopsied at the Medical Examiners Office (MEO) were analyzed for the presence of marijuana, cocaine, opiates and benzodiazepines using EMIT enzyme immunoassays. Blood alcohol levels were also measured. Tests were positive for at least one drug in 40.3% of the ER and 18.7% of the MEO samples. Marijuana was the most commonly detected drug in both groups. Specimens were more likely to be positive in younger persons and in males, and in victims of assaults and traffic accidents. Alcohol was present in the blood in more than one third of ER and MEO samples. Only 39.8% of ER samples and 52.3% of MEO samples were negative for both alcohol and drugs.

Hypocaloric diets and ketogenesis in the management of obese gestational diabetic women.

The extent to which given levels of caloric restriction will improve glycemic status but increase plasma ketone bodies in gestational diabetic women has received little attention. After reviewing the underlying physiology, we present data on two feeding studies investigating the question. In the first, a weight-maintaining approximately 2400-kcal/day diet was fed on a metabolic ward to 12 gestational diabetic women for 1 week. In the second week, subjects were randomized to a continuation of the 2400-kcal/day diet or to a 1200-kcal/day diet. Twenty-four-hour mean glucose levels remained unchanged in the control group but declined in the calorie-restricted group (6.7 mM or 121 mg/dl in week 1 vs 5.4 mM or 97.3 mg/dl in week 2) (p less than 0.01). Nine-hour overnight fasting plasma insulin also declined but oral glucose tolerance did not improve with caloric restriction. Fasting plasma beta-hydroxybutyrate rose in the calorie-restricted group, along with an increase in ketonuria, but not in the control group. A second study compared the impact of a 33% calorie-restricted diet or insulin to a full-calorie diet in a similar 2-week experimental design and measured hepatic glucose output and insulin sensitivity with dideuterated glucose before and during an insulin clamp. Diet in three subjects improved fasting and 24-hr mean glucose by 22 and 10%, respectively, whereas prophylactic insulin in three subjects produced 0 and 4% reductions, respectively. On average, ketonuria after a 9-hr fast declined to an equivalent degree with both treatments. Hepatic glucose output and insulin sensitivity were not statistically significantly altered by gestational diabetes or the therapeutic interventions compared to nondiabetic normal weight or obese pregnant controls. In conclusion, 50% caloric restriction improves glycemic status in obese women with gestational diabetes but is associated with an increase in ketonuria, which is of uncertain significance. An intermediate 33% level of caloric restriction (to 1600-1800 kcal daily) may be more appropriate in dietary management of obese woman with gestational diabetes mellitus and more effective than prophylactic insulin. Further studies are required to confirm these findings.

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 μg/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 the target steady‐state lidocaine concentration was 4 μg/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 < 0.05) and half‐life increased (P < 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 subjects; repeated decreases in infusion rate were necessary to avoid exceeding desired target concentrations in phases 2 and 3.

Coating of Oral Beclomethasone Dipropionate Capsules With Cellulose Acetate Phthalate Enhances Delivery of Topically Active Antfinflammatory Drug to the Terminal Ileum

Selective delivery of orally administered topically active antiinflammatory drugs to the terminal ileum and ascending colon could be potentially useful for patients with inflammatory bowel disease involving these sites. Because topical beclomethasone dipropionate (BDP) enemas have been used successfully in the treatment of distal idiopathic colitis, oral formulations of this drug were studied. Enteric-coated or uncoated capsules containing BDP were administered in a single-dose protocol on separate days to 6 healthy volunteers with postcolectomy ileostomies. Ileostomy effluent was collected for a minimum of 8 h and analyzed by high-performance liquid chromatography for BDP, its pharmacologically active derivative beclomethasone monopropionate (BMP), and inactive beclomethasone alcohol. Cellulose acetate phthalate coating of oral BDP capsules significantly increased the mean percentage recovery of BDP + BMP in ileal effluent (43.0% +/- 24.1%) compared to uncoated BDP capsules (13.5% +/- 8.5%, p less than 0.05, Students paired t-test). We conclude that oral cellulose acetate phthalate-coated BDP capsules may merit clinical trial in Crohns ileitis and ileocolitis or in conjunction with BDP enemas for topical treatment of ulcerative colitis involving the whole colon.

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. A clinical trial to test this hypothesis is warranted.

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 (CI), t½, 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 t½) 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 t½, 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.

Tricyclic Antidepressant-Specific fab fragments alter the distribution and elimination of desipramine in the rabbit: A Model for overdose treatment

The effects of tricyclic antidepressant (TCA)-specific Fab fragments (Fab) on total and free desipramine (DMI) levels in serum and urine of DMI-treated rabbits were studied to determine the feasibility of using these Fab for antidotal treatment of TCA overdoses in humans. Serial samples of blood and urine were collected from two 3 kg rabbits after arterial injection of 2 mg 3H-DMI and, about 1.5 hr later, after injection of approximately 1 g Fab (prepared from sheep total IgG). Protein-free filtrates of serum and urine samples were obtained by ultrafiltration; concentrations of apparent total and apparent free DMI (apparent DMI, aDMI = DMI + metabolites) were calculated based on the radioactivity in the sample and ultrafiltrate, respectively. Treatment with Fab induced significant changes in the absolute and relative concentrations of free and total aDMI in both serum and urine. Changes in the serum included increases in the total and free aDMI levels. Changes in the urine included the appearances of a protein-bound aDMI fraction and Fab, and an increase in the percent of unmetabolized DMI. These results demonstrate that TCA-specific Fab influence the distribution and elimination of desipramine in DMI-treated rabbits and suggest that further studies on the use of TCA-specific Fab for antidotal treatment of TCA overdose are warranted.

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 t½ 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.

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.