Reduction of serum lactate by sodium dichloroacetate, and human pharmacokinetic-pharmacodynamic relationships.

Sodium dichloroacetate (DCA) or placebo, two infusions 30 min in duration and 8 h apart, was administered to healthy subjects under double-blind conditions. The objectives were to characterize accurately the tolerability of DCA, its pharmacokinetics, and the reduction of resting serum lactate concentration by DCA. A hybrid, one-compartment pharmacokinetic model fitted best, with zero-order elimination mean of 27.9 micrograms/ml/h at concentrations above about 80 to 120 micrograms/ml, and with first-order elimination (mean kelim = 0.54) at lower serum concentrations of DCA. Resting serum lactate was dose-independently, maximally reduced within 15 min of the end of all active infusions. The duration of suppression of resting serum lactate was dose-dependent, from 4.5 h (30 mg/kg) to > 8 h (100 mg/kg). Second infusions (15-50 mg/kg) again promptly and maximally reduced resting serum lactate. Hysteresis loops were asymmetrical for all doses but exhibited change in shape that was dose-dependent; no good pharmacokinetic-pharmacodynamic model could be fitted that was consistent between doses. Infusions were well tolerated, 100 mg/kg + 50 mg/kg being the highest doses. Somnolence, the only dose-related adverse event, was reported by 3 of 37 subjects at times corresponding to the highest serum DCA concentrations. This study demonstrates the tolerability of i.v. DCA, proposes a simple pharmacokinetic model for its elimination, characterizes the dose-response relationship in terms of time course of effect, shows the dissociation between elimination of DCA and offset of response and will guide further studies of DCA in patients with head injury or stroke.

Multicenter trial of L-carnitine in maintenance hemodialysis patients. I. Carnitine concentrations and lipid effects.

Previous studies have reported conflicting results of carnitine supplementation on plasma lipids in patients with chronic renal failure. We therefore performed a four center, double-blind placebo controlled trial to evaluate the effects of post-hemodialysis intravenous injection of L-carnitine in ESRD patients on maintenance hemodialysis. Thirty-eight patients received up to six months of L-carnitine infusions (20 mg/kg) post-dialysis and 44 patients received placebo infusions. In both groups of patients, baseline pre-dialysis plasma and red blood cell total carnitine levels were normal, but pre-dialysis plasma-free carnitine concentrations and free/total ratios were subnormal, and plasma acyl levels were elevated. Post-dialysis plasma free and total carnitine concentrations were also subnormal. Plasma and red blood cell total carnitine levels rose eightfold in carnitine recipients, but were unchanged from baseline in those receiving placebo. There were no significant changes observed in plasma triglycerides, HDL-cholesterol or other lipoprotein parameters in either the carnitine or placebo treated groups. We conclude that carnitine metabolism is altered in uremia. Furthermore, in a randomly-selected hemodialysis population, L-carnitine injection at the dose of 20 mg/kg results in significant increases in blood (and perhaps tissue) carnitine levels, but this is not associated with any major effects on lipid profiles.

Multicenter trial of L-carnitine in maintenance hemodialysis patients. II. Clinical and biochemical effects.

Since carnitine deficiency has been reported in some patients undergoing maintenance hemodialysis, we studied the effects of intravenous infusion of L-carnitine or placebo at the end of each dialysis treatment. The trial, which lasted seven months (one month baseline, 6 months treatment) was multicenter, double blind, placebo controlled, and randomized. Eighty-two long-term hemodialysis patients, who were given either carnitine (N = 38) or placebo (N = 44), completed this study. In each group, clinical and biochemical parameters during treatment were compared with baseline values. Intra-dialytic hypotension and muscle cramps were reduced only in the carnitine treated group, while improvement in post-dialysis asthenia was noticed in both carnitine and placebo groups. Maximal oxygen consumption, measured during a progressive work exercise test, improved significantly in the carnitine group (111 +/- 50 ml/min. P less than 0.03) and was unchanged in the placebo group. L-carnitine treatment was associated with a significant drop in pre-dialysis concentrations of serum urea nitrogen, creatinine and phosphorus (means +/- SEM, 101 +/- 4.5 to 84 +/- 3.9, 16.7 +/- 0.67 to 14.7 +/- 0.64, and 6.4 +/- 0.3 to 5.5 +/- 0.4 mg/dl, respectively, P less than 0.004). No significant changes in any of these variables were noticed in the placebo group. Mid-arm circumference and triceps skinfold thickness were measured in 11 carnitine and 13 placebo treated patients. Calculated mid-arm muscle area increased in the carnitine patients (41.37 +/- 2.68 to 45.6 +/- 2.82 cm2, P = 0.05) and remained unchanged in the placebo patients.(ABSTRACT TRUNCATED AT 250 WORDS)

High calorie essential amino acid parenteral therapy in acute renal failure.

Analysis of data from a heterogenous, acutely ill series of 192 patients with acute renal failure confirmed earlier reports of diminished BUN and serum potassium, magnesium, and phosphorous in association with hypertonic dextrose and essential amino acid intake suggesting urea reutilization and decreased catabolism. Based on serum creatinine levels, renal function appeared to improve somewhat, but mortality appeared to be little changed by treatment. Comparison of these results with the dramatic effects on survival and renal function reported earlier suggests that infusion of hypertonic dextrose and essential amino acids may result in earlier return of renal function and a greater chance of survival in selected patients with few complications and potentially reversible acute renal failure.

Factor VIII preservation following collection into commercial plasmapheresis systems.

The two-stage method of Pool and Robinson was used in determining plasma Factor VIII activity following contact with four commercially available plastic blood and pooling bag films. Employing a two-arm double plasmapheresis technique, it was shown that Factor VIII activity in whole blood initially drawn into BB-69 and PL-130 blood bags decreased only slightly from in vivo levels for activity in PL-130 blood bags (t equal 3.2317, p. less than 0.01). Factor VIII activity fell to 98 and 90 per cent preservation levels from an initial 104 per cent in vivo activity, for BB-69 and PL-130 respectively. Factor VIII activity in plasma collected in Ellay and PL-146 pooling bags, both decreased significantly to 85 and 86 per cent, respectively, after three hours storage at room temperature (24 to 25.5 C). Following five weeks storage (-30 C) in Ellay and PL-146 pooling bags, Factor VIII activity significantly (p less than 0.005) fell to 79 and 77 per cent, respectively. No significant differences were observed when Factor VIII activity levels were compared in BB-69 versus PL-130 or Ellay versus PL-146 plastic film systems.

Comparison of two lidocaine preparations by in vivo assay methods.

An in vivo study was conducted to determine if there were differences in local anesthetic potency between two commercial brands of lidocaine. The two preparations were evaluated in terms of onset of action, peak effects and duration of action using a double-blink technique. Both products were tested at concentrations of 0.25%, 0.50% and 1%. Each were evaluated for conduction (in rats), topical (in rabbits) and in filtration (in guinea pigs) anesthesia. No clinically significant differences between the two commercial preparations were found.

The effect of a single or double dose of dexamethasone on granulocyte collection with the continuous flow centrifuge.

A total of 33 leukaphereses were performed with the IBM continuous flow centrifuge on 28 normal healthy donors for the purpose of obtaining increased yields of granulocytes for infusion into leukopenic recipients. The pretreatment of donors within a 10- to 12-hour period prior to pheresis with a double dose of dexamethasone and the addition of hydroxyethyl starch to the input line of the continuous flow centrifuge, significantly increased the total quantity and efficiency of granulocyte collected as compared to a donor group receiving a single dose of dexamethasone in addition to hydroxyethyl starch. A mean of 25.5 times 10-9 total granulocytes were collected in addition to an efficiency of 2.11 times 10-9 granulocytes harvested per liter of blood processed in the double-dose-treated donors, in contrast to 19.6 times 10-9 total granulocytes collected and an efficiency of 1.82 times 10-9 granulocytes harvested per liter of blood processed in the single dose donor group. The results of the present study demonstrate that elevated quantities of granulocytes can be collected from normal donors by scheduling a double dose of dexamethasone prior to the pheresis procedure.