Biomedical subjects
Publications and source records attributed to F Bochner.
Three patients with impaired renal function suffered complications of hyperkalaemia within 10 days of beginning therapy with hydrochlorothiazide and amiloride combination (Moduretic). The possible relationship between hyperkalaemia and this diuretic is discussed.
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Described here is a young woman with intermittent Cushing's disease associated with psychotic disturbance. On five occasions, over a period of four years, she became severely depressed and had acne, amenorrhea, hirsuties and moon facies. On each of the first four occasions the symptoms lasted from two to three months and disappeared spontaneously. Biochemical investigations, including plasma ACTH estimations during the last two episodes, indicated that the adrenocortical overactivity was pituitary-dependent. During the fifth relapse the patient experienced a very severe, depressive psychosis, necessitating bilateral adrenalectomy, which resulted in complete remission.
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The pharmacokinetics of methylphenobarbitone and phenobarbitone were studied following the administration of methylphenobarbitone on a chronic basis in 77 patients, and after a single dose to each of 4 subjects who had received no other drugs and 4 subjects who had been pretreated with various anticonvulsants and other agents. At steady-state, plasma phenobarbitone concentrations correlated better with methylphenobarbitone dose than did plasma methylphenobarbitone concentrations. In this group the ratio of plasma phenobarbitone level to plasma methylphenobarbitone level was in the range of 7 to 10:1. In the single dose studies, mean values of elimination rate constant (0.0155h) and clearance (1.85L/h) for untreated subjects were different from those for the pretreated subjects (0.0375h and 5.10L/h), while the apparent volumes of distribution did not differ significantly between the two groups (120.3L vs 140.8L). The data are interpreted as most probably indicating induction of hepatic microsomal enzymes in the pretreated group.
The relationship between the plasma concentration of glutethimide (G) and the change from baseline of the standard error of the mean (deltaSDE) of a tracking test was determined in 7 volunteers. There was excellent positive correlation (r = 0.91) between log G and log deltaSDE and good correlation between log G and deltaSDE (r = 0.77). The metabolite, 4 hydroxyglutethimide, did not contribute significantly to the effect of G administered in therapeutic doses. No trend in performance versus level was found with 5 other tests (finger tapping, card sorting, digit substitution, subtraction, and subjective perception of drowsiness). Although the numbers were small, when the volunteers were divided into smokers (3) and nonsmokers (4) G decreased tracking ability to a greater extent in smokers than in nonsmokers.
A new oral digoxin formulation, a digoxin-hydroquinone complex (99% dissolution at 5 min), was evaluated in 12 healthy human volunteers with reference to bioavailability and extent and time of peak serum digoxin levels. This preparation was compared with a commercial digoxin tablet (26% dissolution at 5 min), digoxin elixir, and a parenteral digoxin solution. Bioavailability was assessed by the 24-hr area under the serum digoxin-time curve and 48-hr digoxin excretion in urine. The bioavailability of the complex was similar to that of the elixir but not statistically different from that of the tablet. The tablet was less bioavailable than the elixir. There was less interindividual variation in bioavailability with the complex than with the elixir. Peak serum digoxin levels were higher with the complex than the tablet and were achieved more quickly.
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The binding of carbamazepine to the proteins of human plasma has been studied using ultrafiltration techniques. In vitro studies at 37 degrees C showed the relation between concentration of unbound drug and total drug to be linear through the range of total concentration of 5 to 50 mug/ml. The per cent unbound drug increased slightly as concentration increased. There was little difference between the extent of binding at 4 degrees C and 20 degrees C, but more carbamazepine was unbound at 37 degrees C. Under in vitro conditions, 6 other anticonvulsants, and aspirin, were tested individually, each at high therapeutic or toxic concentration, and shown not to displace carbamazepine from plasma proteins to a significant degree. The extent of binding of carbamazepine in vivo was determined in a total of 54 plasma samples collected from treated patients; 26.9 plus or minus SD 9.4 percent of the drug was unbound. In blood samples from 23 of these patients, the red cell concentration of carbamazepine averaged 38.3 plus or minus SD 17.9 percent of the plasma concentration. The effects of hepatic and renal diseases on the carbamazepine binding capacity of plasma proteins were assessed by comparing the binding capacity of plasma from disease persons with that from normal subjects. There was no significant difference in binding capacity between plasma from patients with renal disease and that from normal subjects. However, the plasma from patients with hepatic disease bound a slightly lower percentage of carbamazepine than did normal plasma (p smaller than 0.05). This alteration did not correlate with changes in any of 15 biochemical parameters measured in these patients. The clinical significance of these results is discussed.
A 48 year old man with normal hepatic function presented with abnormally prolonged bleeding following orally administered warfarin. Warfarin and diphenylhydantoin are known to be hydroxylated in the liver. To investigate the possibility of the patient having a metabolic (hydroxylating) defect, his ability to metabolize diphenylhydantoin was studied, as it would have been unethical to administer warfarin again. Parallel studies were carried out on two healthy subjects as a basis for comparison. On three separate occasions the elimination half-life for diphenylhydantoin in the patient (158, 87, 72 hours) was significantly longer than those obtained in the normal subjects (31 and 32 hours). This difference was most probably due to decreased hydroxylation of diphenylhydantoin to 5-(p-hydroxy-phenyl)-5-phenylhydantoin since his urinary elimination of this substance was demonstrated to be significantly less than that of the normal subjects. The results suggest that this patient had a reduced capacity to hydroxylate diphenylhydantoin, and this defect in liver hydroxylation may explain his increased sensitivity to warfarin.
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