Plasma levels of the partial dopamine agonist, terguride, were measured by RIA in healthy volunteers after a single i.v. dose of 50 micrograms and on the first and seventh day of an oral treatment with 250 micrograms, 500 micrograms and 750 micrograms b.d. Basal and releasing hormone (TRH, GHRH, CRF, LHRH)-stimulated pituitary hormone secretion (PRL, TSH, GH, FSH, LH) and cortisol were also determined by RIA. Following the i.v. injection, plasma terguride levels declined biphasically, with half-lives of 0.2 and 1.5 h; total clearance was 17 ml.min-1.kg-1. The oral bioavailability of terguride over all doses was about 20%. Basal and TRH-stimulated prolactin levels were dose-dependently depressed, but the secretion of other hormones remained unaffected. Tolerance of terguride was excellent and there was no negative effect on performance or mood, nor on mixed-function oxygenase activity, assessed as urinary 6 beta-OH cortisol.

The effects of benzonal on the course of neonatal hemolytic disease due to the Rhesus factor-conflict was studied in comparison with that of phenobarbital. Dynamic follow-up of infants in the early neonatal period showed benzonal to produce a more pronounced hypobilirubinemic effect which was manifested as a prompter disappearance of skin jaundice and lower percentages of complications. By depressing the activity of organospecific enzymes and lowering the serum biliary acid levels, benzonal promotes normalization of the metabolic shifts present in neonatal hemolytic disease. The findings make it possible to recommend the new inductor of microsomal liver enzymes benzonal as part of the combined therapy of neonatal hemolytic disease.

Twenty-four healthy volunteers were divided in three groups who were randomly assigned different treatments for 13 days: group I received 400 mg/day of a defined Ginkgo biloba extract (GBE), group II 300 mg/day of phenytoin and group III a placebo. The elimination half-life of antipyrine was measured with a high performance liquid chromatographic technique initially and on the last day of the administration of the treatments. The results show that the half-life of antipyrine was not affected by GBE and placebo treatments, whereas it was significantly decreased (p less than 0.05) frm 12.2 to 6.8 h after phenytoin control treatment. This study demonstrates that GBE has no effect on the hepatic microsomal drug oxidation system.

A placebo-controlled, double-blind crossover study was carried out in 11 non-insulin-dependent (type 2) diabetic patients to find out the effects of a hepatic enzyme inducer (phenobarbital, 100 mg/day for 2 months) on the metabolic control, plasma C-peptide, insulin, serum, and lipoprotein lipid levels. Phenobarbital induced a significant increase in hepatic antipyrine metabolizing activity, but no significant changes were found in fasting or postload blood glucose, plasma C-peptide, or insulin levels during the study. There was a significant increase in serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, as well as in serum total and very low-density lipoprotein triglycerides, during phenobarbital treatment as compared with placebo.

The effects of hepatic microsomal enzyme inducing (phenobarbitone and flumecinol), and inhibiting (cimetidine) drugs, and placebo treatment on insulin mediated glucose metabolism (M) were investigated in 29 healthy volunteers. Phenobarbitone (50 mg for 10 days) increased M (30%), metabolic clearance rate of glucose (MCRg), and antipyrine clearance rate (33%). Fasting immunoreactive insulin (IRI) decreased while fasting blood glucose (BG) remained unaltered. Flumecinol, another inducer, tested in two doses (200 mg and 600 mg for 6 days), did not alter glucose or antipyrine metabolism. Fasting IRI reduced on treatment with 600 mg of flumecinol, but not with the smaller dose. Cimetidine (600 mg for 6 days) decreased M (19.5%), MCRg (26%), and antipyrine clearance rate (20%). The placebo did not alter glucose or antipyrine metabolism. The results indicate that the insulin mediated glucose disposal rate can be altered by drugs influencing hepatic microsomal enzyme activity.

To know the intensity of liver enzyme induction during a treatment with anticonvulsant, the authors have measured gamma GT before and at the 7th, 30th, 60th days after a treatment by one of the 4 major anticonvulsant as phenobarbital, diphenylhydantoin, carbamazepine and sodium valproate. All alcoholic patients, and all the patients having a liver disease have been eliminated. The results show that diphenylhydantoin is the most important inductor of gamma GT with an elevation that can reach 312% of basal level, followed by phenobarbital, when sodium valproate and carbamazepine are the weakest inductors. More, induction by carbamazepine in women is more weak than in man. Age takes a place in intensity of induction with a major induction observed between 30 and 50 years old for phenobarbital, and above 50 years old for sodium valproate. These effects are not dependent of an hepatitis. The knowledge of the upper levels of gamma GT induction by anticonvulsant appear to us usefull for several reasons: carbamazepine and sodium valproate being the weakest inductors, they must be chosen in priority in women under contraceptive treatment. Any abnormal elevation of gamma GT need to look of an alcoholic intoxication, an hepatitis or a liver cancer.

Zixoryn, (3-trifluoromethyl-alfa-aethyl-benzhydrole) is a new product of the Hungarian Chemical Works of Gedeon Richter Ltd. It induces the mixed function oxydase enzyme system of the endoplasmic reticulum of the liver and has no other pharmacological effects. We have studied the effect of Zixoryn on early hyperbilirubin-aemia. 42 neonates were studied, 21 of them were randomly assigned to be treated and the others served as control group Zixoryn treatment consisted of drops containing 10 mg Zixoryn per ml in a single 20 mg/kg body weight dose through a gastric tube. Results are summarized in Fig. 2. It shows the mean se bi levels during the first six days of life. It is remarkable that the decline of se bi level was much faster in the treated than in the control group. On the third day the difference between the two groups was significant. We may conclude that after Zixoryn administration the se bi level of otherwise healthy newborns decreased significantly faster than that of untreated neonates. No side-effects what so ever were observed. The administration is easy, a single oral dose has a satisfactory effect.

Thirty-two fit patients scheduled for explorative arthrotomy of the knee were allocated randomly to either halothane/oxygen anesthesia or spinal anesthesia with bupivacaine 0.25 mg X kg-1. The day before and 1, 10, and 21 days after surgery, the aminopyrine breath test (ABT) was performed. The day before and 5, 10, and 21 days after surgery, the antipyrine clearance (APcl) was measured by the single sample saliva technique. The ABT as well as the APcl were increased significantly postoperatively (P less than 0.01). The day after surgery the ABT was increased by 13 +/- 21% in the spinal anesthesia group only, whereas a late increase by 14 +/- 31% was found in the halothane group. Five days after surgery, the APcl was increased by 36 +/- 45% in the spinal anesthesia group and by 21 +/- 28% in the halothane group. Both tests returned to base line values within 3 weeks postoperatively. In five volunteers following the same sampling scheme but receiving bupivacaine 0.25 mg X kg-1 im without surgery, no change in the ABT or the APcl was observed. The authors conclude that surgery may cause microsomal enzyme induction regardless of the anesthetic agent or technique used. The mechanism of this induction remains to be elucidated.

Pronase digestion of IRBP yielded one major glycopeptide (IRBP-GP1) of approximate Mr 2,500 IRBP-GP1 was heterogeneous by anion exchange chromatography, an observation that was attributed to the presence of varying numbers of sialic acid residues. Asialo-IRBP-GP1 was also heterogeneous by gel-filtration chromatography, possibly because of varying degrees of fucosylation. A minimum of four (possibly five) concanavalin A-binding glycopeptides was generated by cyanogen bromide cleavage of IRBP. These findings, in conjunction with earlier observations, suggest that bovine IRBP contains 4-5 N-linked oligosaccharide chains. These chains appear to have the same basic complex biantennary structure. They contain galactose, mannose and N-acetylglucosamine, in addition to sialic acid and fucose. Nearly all of the IRBP secreted by bovine retinas incubated with (3H)-leucine in the presence of tunicamycin was nonglycosylated and did not bind to concanavalin A. On SDS polyacrylamide gels non-glycosylated IRBP had an Mr that was 5,000-6,000 below that of the glycosylated protein. Non-glycosylated IRBP had an Mr of 250,000 on gel-filtration columns, a value that was identical with that of glycosylated IRBP. It is concluded that the oligosaccharide has little influence on the molecular conformation of IRBP, which is believed to be responsible for the anomalously high Mr seen on these columns. When mixed, the glycosylated and nonglycosylated forms of IRBP appeared to associate as stable aggregates. Bovine retinas incubated with (14C)-leucine and (3H)-fucose in the presence of castanospermine, an inhibitor of glucosidase I, secreted IRBP that appeared to have a reduced number of fucose residues. Swainsonine, an inhibitor of mannosidase II, effected only a marginal reduction in the degree of fucosylation of secreted IRBP.

The effects of local glucocorticosteroid treatment on collagen biosynthesis and basement membrane components were studied in suction blisters in human abdominal skin. Pretreatment with clobetasol-17-propionate, applied three times a day for 4 days, did not affect the activity of galactosylhydroxylysyl glucosyltransferase (GGT) in fresh blisters but post-blistering treatment for 3 days with the steroid markedly inhibited the increase of this enzyme activity during the initial phases of re-epithelialization. The GGT activity was over 50% lower in steroid-treated blisters compared with control values. Protein concentrations and blister fluid volumes were also significantly decreased in healing 3-day blisters after steroid treatment. These results suggest that local glucocorticosteroid decreases either the synthesis of GGT or its release from the tissue into the blister fluid. The treatment did not affect the blister histology nor the early process of re-epithelialization. Immunohistochemically, type IV and V collagens and laminin of the basement membrane zone were similarly located in blisters of steroid-treated and placebo-treated skin, suggesting that local glucocorticosteroid does not affect the integrity of the basement membrane.

1 The disposition kinetics of lignocaine and antipyrine were compared in eight normal subjects and in eleven patients receiving chronic therapy with antiepileptic drugs. The urinary excretion of D-glucaric acid (D-GA) was measured in 16 subjects. 2 In patients treated with antiepileptic drugs antipyrine clearance and D-GA excretion were significantly increased, whereas lignocaine biovailability was significantly reduced. 3 When all the subjects included in the study were considered, a significant positive correlation could be found between the apparent oral clearance of lignocaine (Dose/area under the blood concentration curve) and both antipyrine clearance (r = 0.73) and D-GA excretion (r = 0.74). 4 When normal subjects and epileptic patients were considered separately, a significant positive correlation could be confirmed between the apparent oral clearance of lignocaine and both antipyrine clearance (r = 0.71) and D-GA excretion (r = 0.76) in normal subjects, and between antipyrine clearance and D-GA excretion (r = 0.75) in epileptic patients. 5 These results suggest that the reduction of the oral availability of lignocaine in epileptic patients is secondary to induction of first-pass metabolism of the latter drug.