Somatomedin: inhibiton of adenylate cyclase activity in subcellular membranes of various tissues.

Somatomedin in concentrations between 3 and 20 units per milliliter significantly inhibits the basal activity of adenylate cyclase in crude membrane preparations obtained from homogenates of fat cells, liver, and spleen lymphocytes of the rat, and from chondrocytes and cartilage of chick embryos. The enzyme activity measured in the presence of stimulating hormones (epinephrine, prostaglandin PGE(1), parathyroid hormone) is also inhibited in these preparations by somatomedin. These observations may be relevant in a general way to the mechanism of action of growth-prmoting substances and to the processes which normally regulate cell growth.

Pharmacokinetics of vigabatrin: implications of creatinine clearance.

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3-fold in the time to reach the maximum concentration, 2.7-fold in the maximum concentration, and 9.8-fold in the AUC; a twofold prolongation of the t1/2; and reduced urinary excretion of the biologically and pharmacologically active S(+)-enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactive R(-)-enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patient's renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients.

The interaction of hCG with rat adipose tissue: apparent lack of hCG--LH receptors.

The interaction of human chorionic gonadotropin (hCG) with rat adipose tissue was investigated by both metabolic and binding studies. Highly purified preparations of hCG did not affect the adenylate cyclase activity nor the lipolysis of rat adipocytes in the presence or in the absence of GTP. However, it was demonstrated that (a) the hCGs used were biologically active since they stimulated cAMP and testosterone production by rat Leydig cells, and (b) there are receptor sites on the rat ovary that bind [125I]hCG and recognize rat luteinizing hormone (LH). The lack of response cannot then be attributed to a loss of activity of the hormone preparation tested nor to a failure of the rat tissues to recognize an hormone of human origin, but rather to an absence of hCG--LH receptors on the fat cell membrane surface. It is suggested that results previously reported in other laboratories could be explained by the presence of contaminating amounts of lipolytic hormones in their preparations.

Hormonal regulation of membrane receptors and cell responsiveness: a review.

Hormone receptors are those components of target-cells that specifically bind hormones and convey the hormonal message to the intracellular machinery. Such receptors can be localized inside the cell, such as the nuclear receptors of thyroid hormones and the nuclear and cytoplasmic receptors of steroid hormones, or on the outer surface of the plasma membrane, such as the membrane-bound receptors of polypeptide hormones and neurotransmitters. Extensive studies during recent years have shown that the interaction between hormone and membrane-bound receptor can affect the receptor characteristics in at least two ways. Firstly, receptor occupancy can modify, by way of cooperativity, the affinity of homologue receptors for the given hormone. Secondly, the binding capacity of a target cell appears to vary as a function of the preexposure of the cell to the hormone. The latter phenomenon has been related to the so-called states of subsensitivity, desensitization, or refractoriness, and might be responsible for the physiologic regulation of the target cell sensitivity and for the hormone resistance which accompanies various metabolic disorders. In this review we attempt to describe the major findings related to hormone desensitization or resistance of these hormones that have plasma-membrane-bound receptors. Data from the literature are presented independently for each hormone and when applicable, conflicting results are discussed in each section. The various theories which might explain hormone desensitization are outlined in the last section of this paper.

Phase I study of methylacetylenic putrescine, an inhibitor of polyamine biosynthesis.

In a phase I clinical trial, nine patients with advanced malignancies not amenable to alternative therapy received alpha-methyl-delta-acetylenic putrescine (MAP), an enzyme-activated, irreversible inhibitor of ornithine decarboxylase (ODC). MAP was given orally in increasing doses to successive groups of three patients as follows: 375 mg, 750 mg and 1500 mg/day, given as three equally divided doses for 4 weeks. Doses of 375 and 750 mg/day were well tolerated, with no detectable toxicity. Of three patients receiving 1500 mg/day, two experienced moderate to severe myelosuppression; one of these also became anuric, requiring the discontinuation of therapy after 9 days. Both effects were reversible after treatment was stopped. No objective responses were observed, with five patients having stable disease and four, progressive disease during the study period. In the seven patients in whom it could be calculated, the plasma elimination half-life t1/2 of MAP measured on the last day of treatment was between 3.9 and 9.2 h in six patients (mean, 5.6 h) and 26.1 h in the seventh. Mean steady-state trough concentrations of MAP were 2.3 mumol after the 375 mg/day dose, 7.1 mumol after 750 mg/day and 16.6 mumol after dosing with 1500 mg/day for 4 weeks, the levels after each treatment schedule being sufficient to inhibit ODC as demonstrated by increases in the urinary excretion of decarboxylated S-adenosylmethionine (dc-SAM). MAP treatment was associated with mean maximal increases in the urinary excretion of dc-SAM of 2.6-, 9.3- and 17.9-fold after 375, 750 and 1500 mg/day for 4 weeks, respectively, but no consistent changes in the urinary excretion of the polyamines, putrescine, spermidine or spermine were observed. Thus, the 24-h urinary excretion of dc-SAM may be used as a conveniently accessible marker of ODC inhibition in cancer patients.

[Effects of gamma-vinyl GABA per os in 5 cases of hebephreno-catatonic schizophrenia]. / Effets du gamma-vinyl GABA per os dans cinq cas de schizophrénie hébéphréno-catatonique.

gamma-Vinyl GABA, an irreversible inhibitor of GABA transaminase, was administered orally to five patients with catatonic or hebephreno-catatonic schizophrenia. Improvement of psychiatric symptoms was observed in four cases. The results are discussed in relation to previously reported attempts to increase the CNS gabaergic function of patients with schizophrenia.

[Therapeutic trial of gamma-vinyl GABA, an inhibitor of GABA transaminase, in tardive dyskinesias induced by neuroleptics]. / Essai thérapeutique du gamma-vinyl GABA, un inhibiteur de la GABA-transaminase, dans les dyskinésies tardives induites par les neuroleptiques.

Oral gamma-vinyl GABA, an irreversible inhibitor of GABA-transaminase, was given to 10 patients with neuroleptic-induced tardive dyskinesia (7 chronic simple schizophrenics and 3 chronic paranoid schizophrenics). Dyskinesia was reduced in 8 of 10 cases. Aggravation of dyskinesia and major psychomotor sedation was observed in two elderly patients with senile dementia. In addition, with regard to schizophrenic symptoms, gamma-vinyl GABA appeared to have beneficial effects on affective withdrawal and retardation, while hallucinations seemed to be aggravated.

[African trypanosomiasis in children treated with eflornithine. A case]. / Trypanosomiase africaine de l'enfant traitée par éflornithine. Un cas.

We report the case of a 14-year old African girl presenting with late-stage African T. gambiense trypanosomiasis. She was treated with eflornithine, an ornithine decarboxylase inhibitor which is a key enzyme in the biosynthesis of polyamine. Polyamines are essential to the multiplication of trypanosomes. Two treatment courses were necessary to achieve an apparent cure after one year; however, a longer follow up will be required to confirm whether or not the cure is permanent. Determination of drug concentrations in plasma and cerebrospinal fluid was performed during the second treatment course. Side-effects were easily controlled.

[A trial treatment with eflornithine of trypanosomiasis caused by Trypanosoma brucei gambiense in the Peoples Republic of the Congo]. / Essai de traitement de la trypanosomiase à Trypanosoma brucei-gambiense par l'eflornithine en République Populaire du congo.

In a multiclinic trial in Brazzaville, Congo, 14 patients with late-stage Trypanosoma brucei gambiense trypanosomiasis were treated with eflornithine. All cases had previously been treated with one or several courses of melarsoprol. Eflornithine treatment consisted of 400 mg/kg/day intravenously for 14 days followed by 300 mg/kg/day orally for 21 days. After treatment all patients had a disappearance of trypanosomes from cerebrospinal fluid (CSF), a normalization of CSF WBC count, and, where present prior to study, a clear, rapid and lasting amelioration of neurological signs. Neither clinical nor biological adverse effects necessitated modifying or discontinuing treatment. These encouraging results in melarsoprol-refractory cases demonstrate, despite certain logistical problems, the interest of eflornithine in the treatment of human African trypanosomiasis.

Insulin-like activity of concanavalin A and wheat germ agglutinin--direct interactions with insulin receptors.

Concanavalin A and wheat germ agglutinin are as effective as insulin in enhancing the rate of glucose transport and in inhibiting epinephrine-stimulated lipolysis in isolated adipocytes. These lectins, also like insulin, inhibit basal as well as epinephrine-stimulated adenylate cyclase activity of membranes obtained from homogenates of fat cells. Low concentrations of wheat germ agglutinin enhance the specific binding of insulin to receptors of fat cells and liver membranes. Higher concentrations of this plant lectin, as well as of concanavalin A, competitively displace the binding of insulin to receptors in these tissues. These effects are equally apparent in insulin-binding proteins solubilized from membranes, indicating that the plant lectins interact directly with insulin receptors. All of the effects observed with the plant lectins are reversed by simple sugars that bind specifically to these plant proteins. Agarose derivatives of the plant lectins effectively adsorb solubilized insulin-binding proteins, and these can be eluted with buffers containing specific simple sugars. The possible implications of these findings to certain biological properties (mitogenicity) of these lectins and to the mechanism of action of other growth-promoting substances are considered.

Guanosine 3':5'-cyclic monophosphate and the action of insulin and acetylcholine.

Low concentrations of insulin (120 muunits/ml) and of carbamylcholine (1 muM) increase cyclic GMP content in isolated fat cells by 350%. The maximal amount of cyclic GMP, achieved within 2 min after addition of insulin or carbamylcholine, falls rapidly for insulin and much more slowly for carbamylcholine. 10 pM Acetylcholine can also augment the content of fat-cell cyclic GMP, but by 5 min (37 degrees ) the amount falls to that of unstimulated cells. Atropine abolishes the effects of carbamylcholine and acetylcholine but does not modify that of insulin, indicating that the ability of insulin to regulate cyclic GMP levels is not mediated by cholinergic receptors. Insulin and carbamylcholine increase the concentration of cyclic GMP in rat-liver slices by 400%; the effects of both agents occur rapidly and are relatively transient. Insulin does not alter cyclic GMP concentrations in purified human peripheral lymphocytes or in rat-spleen lymphocytes, cells which possess few insulin receptors and which are insensitive to the metabolic effects of the hormone. Carbamylcholine, however, causes a substantial increase in the cyclic GMP content of these lymphocytes. The data support the view that close and reciprocal relationships may exist between the concentrations and actions of cyclic AMP and cyclic GMP, as well as between the enzymes responsible for biosynthesis and degradation of these nucleotides.

Effects on migraine headache of MDL 72,222, an antagonist at neuronal 5-HT receptors. Double-blind, placebo-controlled study.

MDL 72,222 (1 alpha H, 5 alpha H-tropan-3 alpha-yl 3,5-dichlorobenzoate), a novel agent with antagonist activity at neuronal 5-HT receptors, was tested as an acute treatment for migraine pain under double-blind, placebo-controlled conditions. Forty-seven patients with common (n = 29) or classical (n = 8) migraine or mixed type with or without a psychogenic component (n = 10) received 20-40 mg MDL 72,222 (n = 24) or placebo (n = 23) intravenously during the headache phase of a migraine attack. MDL 72,222 was consistently superior to placebo in rapidly alleviating the migraine pain. The treatment was remarkably well tolerated. The results are consistent with the hypothesis that the pain of migraine is related to activation of neuronal 5-HT receptors and suggest that compounds such as MDL 72,222, which block neuronal 5-HT receptors, could be useful new therapeutic agents for the management of migraine.

Double-blind, placebo-controlled study of vigabatrin (gamma-vinyl GABA) in drug-resistant epilepsy.

Vigabatrin (GVG) (3 g/day) and placebo were compared as an add-on to standard therapy in therapy-resistant epileptic patients using a double-blind crossover design with randomized treatment allocation. Twenty-three patients entered the trial, with four dropping out due to either increased seizure frequency following the cross-over from GVG to placebo (n = 1), intolerance to GVG therapy (n = 2), or poor seizure record (n = 1). Of the 19 patients who completed the study, 17 had partial seizures, eight of whom had secondary generalization and two who had primary generalized seizures. Compared with placebo, GVG was associated with a significant reduction in seizure frequency (p less than 0.01), with 11 of 19 patients experiencing greater than 50% reduction in weekly seizure occurrence, two showing a 25-50% reduction, four unchanged, and two showing an increase in seizures. Global efficacy ratings were greater in the GVG period for 15 patients (p less than 0.05) compared with one in whom there was no period difference and two in whom ratings were higher in the placebo period. Fourteen of the 19 patients indicated a preference for the GVG period. Adverse effects observed during GVG treatment were generally mild and consisted of drowsiness, confusion, nausea, irritability, and constipation. No clinically significant alterations in laboratory test results were observed. No treatment-related changes in plasma concentrations of concomitant antiepileptic drugs were noted. These results confirm the antiepileptic efficacy of oral GVG in refractory epileptics.