Role of basal insulin in the regulation of protein kinetics and energy metabolism in septic patients.

We have investigated the role of basal insulin concentration on leucine kinetics (determined by means of 1-[13C]leucine) and energy metabolism (determined by indirect calorimetry) in eight septic patients by reducing insulin (and glucagon) secretion by somatostatin infusion. Basal glucagon concentration was elevated (744 +/- 381 pg/mL), and insulin concentration was normal (10 +/- 4 microU/mL). Basal resting energy expenditure (REE) was 151 +/- 8% that of predicted basal energy expenditure, and leucine appearance (Ra), oxidation, and nonoxidative disposal rates were all elevated above the normal ranges. Somatostatin infusion reduced insulin concentration by 52% and glucagon concentration by 64%. This resulted in a significant increase in the rate of leucine oxidation from 0.96 +/- 0.08 to 1.18 +/- 0.14 mumol/kg/min (p less than 0.01), and nonoxidative leucine disposal decreased from 2.95 +/- 0.18 to 2.67 +/- 0.17 mumol/kg/min (p less than 0.01). Somatostatin infusion also caused significant increases in REE and fat oxidation from 1310 +/- 100 to 1505 +/- 128 kcal/m2/day (p less than 0.05) and from 1.72 +/- 0.24 to 2.41 +/- 0.41 mg/kg/min, respectively, and a slight decrease of carbohydrate oxidation from 1.51 +/- 0.49 to 1.31 +/- 0.49 mg/kg/min. These metabolic responses can be attributed to the reduction in insulin concentration, because they are in the opposite direction of changes that would occur as a consequence of a reduction in glucagon concentration. We conclude that the basal insulin plays an important role in attenuating net protein loss and energy expenditure.     

Cylindrical spirals of myofilamentous origin associated with exertional cramps and rhabdomyolysis

We describe the presence of cylindrical spirals on muscle biopsy from a 31-year-old man who developed rhabodomyolysis following a long run. He had a prior history of exertional cramps and myoglobinuria. His maternal grandfather had similar symptoms. Transmission electron micrographs demonstrated continuity between the lamellae of the cylindrical spirals and native myofilaments. Whether these unusual structures confer a derangement in myofilament function is uncertain.     

The Effect of Flurbiprofen on Steady-State Plasma Lithium Levels

Study Objective . To evaluate the effects of flurbiprofen therapy on the pharmacokinetics of lithium. Design . Placebo-controlled, single-blind, crossover study. Setting . University-affiliated hospital. Patients . Eleven healthy women with bipolar disorder. Interventions . The subjects received therapeutic doses of lithium administered as an immediate-release capsule every 12 hours. In addition, they received one placebo tablet every 12 hours during phase I and flurbiprofen 100 mg every 12 hours during phase II of the study. Measurements and Main Results . Steady-state pharmacokinetic parameters were measured for each phase. Lithium trough plasma concentration (C_min) and area under the curve were statistically significantly increased (p<0.05) when patients received flurbiprofen. Flurbiprofen also caused decreases in lithium clearance and 24-hour lithium urine excretion, although the changes did not reach statistical significance. Clinically significant increases in C_min appeared to be associated with a greater than 1000-μg/24 hour decrease in urinary excretion of prostaglandin E₂. Conclusion . Patients with clinically normal renal function may experience an increase in lithium levels with the initiation of flurbiprofen therapy.     

Disposition of Tablet and Capsule Formulations of Digoxin in the Elderly

Study Objective . To compare digoxin tablets and liquid-filled capsules with respect to excretion of the drug and its metabolites in urine and feces at steady state. Design . A randomized, crossover trial, each period lasting 3 weeks, with no washout period. Setting . A university hospital. Patients . Six patients, five of whom were elderly, with histories of gastrointestinal disorders, such as hypochlorhydria, intestinal bacterial overgrowth, and inflammatory bowel disease. Interventions . The patients received digoxin once/day in either tablet or capsule form for 3 weeks, and then were switched to the other formulation. Total urinary and fecal excretion from the last 3 days of each regimen were analyzed for the drug and metabolites. Measurements and Main Results . No statistically significant differences were found between tablets and capsules in recovery of digoxin or its metabolites in urine or feces (p=0.05). One subject had a 4-fold increase in urinary drug excretion and 50% decrease in fecal excretion after taking the capsules compared with tablets. Intersubject variability in extent and type of metabolite excretion was greater than intrasubject variability. Conclusions . Fecal analyses may be an accurate way to classify patients as formers of digoxin reduction products.     

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.