1-Aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives. A new series of potential antidepressants.

A series of 1-aryl-2-(aminomethyl)cyclopropanecarboxylic acid derivatives were synthesized and evaluated as potential antidepressants. Compounds with the Z configuration were synthesized from 1-aryl-2-oxo-3-oxabicyclo[3.1.0]hexane and those with the E configuration from (E)-1-phenyl-2-(hydroxymethyl)cyclopropanecarboxylic acid. The compounds were evaluated in animal tests designed to reveal potential antidepressant activity and the existence of undesirable side effects. Several derivatives were more active than imipramine and desipramine. On the basis of its activity in pharmacological animal tests of antidepressant activity and its potential lack of side effects, 1-phenyl-1-[(diethylamino)carbonyl]-2- (aminomethyl)cyclopropane hydrochloride, midalcipran (INN), was selected for further development. This compound is currently in phase III clinical evaluation.

Intestinal calcium absorption in the rat after oral Tween 80 administration.

Calcium absorption into rat intestine was investigated in vitro and in vivo after oral administration of Tween 80 (Polyoxyethylene (20) sorbitan monooleate). The in vivo study showed a significant decrease in serum calcium and in the quantity of calcium excreted by the intestine. In vitro, measurement of calcium influx into slices of intestine taken from Tween 80 treated animals showed that passive calcium diffusion was unchanged and that a decrease in the active transport alone is responsible for reduction in total calcium influx. Lineweaver-Burk analysis of the saturable component of calcium flux showed that the main variation was not due to a change of affinity of the system for the calcium but a decrease of the maximal calcium influx. Thus there are some arguments in favor of non-specific modifications of intestinal medium affecting calcium bioavailability rather than a specific action on the carrier.

In vitro and in vivo alpha-blocking activity of thymoxamine and its two metabolites.

The alpha-adrenoceptor potency of thymoxamine and its two metabolites deacetylthymoxamine and demethyldeacetylthymoxamine were determined on the contraction of rat vas deferens induced by noradrenaline, the blood pressure increase induced by noradrenaline given i.v. to dogs and the contraction of the nictitating membrane induced by electrical stimulation in cats. In vivo the three drugs were administered at 6.35 x 10(-6) mol kg-1 intravenously. Deacetylthymoxamine presented nearly the same alpha-blocking activity as the parent drug. This was ascribed in vivo to the rapid deacetylation of thymoxamine. Demethyldeacetylthymoxamine was less active. In vitro its pA2 was 6.20 +/- 0.09 compared with 6.75 +/- 0.20 for thymoxamine and 6.57 +/- 0.13 for deacetylthymoxamine. In vivo, it was inactive in dog and less active than the other two drugs soon after its administration in the cat. The oral LD 50 values in the mouse for the three drugs were respectively 0.81, 0.71 and 1.14 mmol kg-1 for thymoxamine, deacetylthymoxamine and demethyldeacetylthymoxamine.

Metabolism of thymoxamine: identification of metabolites in rat.

Thymoxamine hydrochloride administered by mouth to rats at 25 or 100 mg kg-1 was excreted in the urine as the deacetyl and N-demethyl-deacetyl metabolites. These were completely sulpho- and glucuronoconjugated at 25 mg kg-1 but only partially so at the higher dose. Thymoxamine deacetylation in vitro is catalysed by plasma and hepatic cytosol esterases and the deacetyl metabolite undergoes N-demethylation catalysed by the cytochrome P 450 hepatic microsome mixed function monooxygenase system. Because of the rapidity of the deacetylation it is concluded that thymoxamine is a prodrug leading in vivo to the active deacetyl thymoxamine.

Serum kinetics of doxycycline polyphosphate in dogs.

Serum kinetics of Doxycycline polyphosphate (DPP) have been studied in dogs after oral administration of 10 mg.kg-1 by measurement of total serum concentration (Ct) of tetracycline derivatives by a chemical assay and active concentration (Ca) by a microbiological method. Kinetics have been studied using a one compartment open model with absorption by oral route. DPP is rapidly absorbed, the peak serum level is reached three hours after absorption and slowly eliminated (elimination half-life = 12 hours). The main differences observed between Ct and Ca kinetics are in the values of the areas under the curves (AUC) and the peak serum level. The values obtained for these parameters for Ca kinetics were found to be 50% of those obtained for Ct, the volumes of distribution being in inverse proportion. These results are in a good agreement with the correlation and linear regression observed between Ca and Ct showing that 55% of total serum Doxycycline possesses immediate antibacterial activity. It is postulated that this difference between Ct and Ca kinetics is essentially a reflection of the ratios of bound and free drug. Similar results were obtained with the finished pharmaceutical form except for a 15% increase of AUC indicating improvement of the bioavailability of the drug.

[Toxicologic analysis of chloralose. Application to 3 cases of acute intoxication]. / Toxicologie analytique du chloralose. Application dans 3 cas d'intoxication aiguë

The authors describe the study of three human intoxication case by chloralose. The detection and dosage of the toxic in the urine of patients have been carried out by the mean of a technic perfected by the same authors. In two case, it has been possible to trace the elimination of the toxic in the urine, the data relative to the third case were not sufficiently precised but they enable to show the existence of criminal etiology of chloralose.

Anti-allergic properties of ethyl-3-methoxyphenyl-4-thiazolyl-2-oxamate (F 1865).

F 1865 (ethyl-3-methoxyphenyl-4-thiazolyl-2-oxamate) has powerful oral anti-allergic properties in immediate hypersensitivity models in rats. In IgE-dependent passive cutaneous anaphylaxis (PCA) the ED50 was of 0.8 mg/kg. In IgG-dependent PCA the ED50 was of 0.6 mg/kg. This oxamate derivative inhibited the liberation of histamine during passive peritoneal anaphylaxis in rats at concentrations of 1 X 10(-6) M or higher. Doses of F 1865, active in PCA, had only weak anti-histamine and anti-serotonin effects, as measured by the increase of cutaneous capillary permeability. Likewise, its inhibitory effect on the bronchospasm due to histamine or serotonin in guinea-pigs was apparent only at doses of 1 mg/kg on i.v. administration. At doses of 100 mg/kg (X2) p.o., F 1865 was inactive against reverse passive Arthus pleurisy induced in rats by rabbit anti-bovine-albumin serum.

Effects of 1.25 dihydroxyvitamin D3 on calcium uptake, into rat intestine after chronic oral cadmium administration.

Calcium influx into rat intestine was investigated, in vitro, after cadmium chronic oral exposure. In active calcium transport, pretreatment by 1.25 dihydroxyvitamin D3 prevents the effect of cadmium on the maximal influx value Jm and leads to an increase of the half-saturation constant Kt.

Effects of 1.25 dihydroxyvitamin D3 on calcium metabolism in rats exposed to cadmium.

The radioisotopic study of calcium metabolism in the rat after chronic oral administration of cadmium (8 mg/kg) has shown two different effects: a) in the intestine cadmium inhibits the absorption of calcium by active transport; b) in the deep bone compartment, the decrease of the bone calcium used for the crystallization goes together with a reduction of the exchange rates between this compartment and the central compartment (serum extracellular and soft tissues calcium). The simultaneous oral administration of 1.25 dihydroxyvitamin D3 (80 ng/kg) even though it increases significantly the calcium intestinal absorption factor does not allow the various parameters of bone calcium metabolism to stay within normal values. In spite of the arrest of osteolysis and of an strong increase of osteogenesis (superficial bone balances and alkaline phosphatases) the loss of calcium caused by cadmium in the deep bone is not compensated.

[Comparative biochemical and ultrastructural study of the hepatic response induced in the rat by 2 hypolipemic agents: clofibrate and itanoxone]. / Etude comparative biochimique et ultrastructurale de la réponse hépatique induite chez le rat par deux agents hypolipémiants: clofibrate et itanoxone.

A comparative biochemical and ultrastructural investigation o hepatic response induced in rats by clofibrate and itanoxone, a new hypolipemic agent, was performed. Normocholesterolemic Sprague-Dawley male rats were distributed into homogeneous groups and orally treated on 10 successive days either by the vehicle alone (1%--carboxymethylcellulose), or by clofibrate (300 mg/kg/day) or by itanoxone (100 and 300 mg/kg/day). On the eleventh day, a last dose was applied after about 16 hours fasting, one hour before sacrificing the animals. Biochemical parameters (total serum cholesterol, hepatic catalase activity) and morphological ones (liver weight, ultrastructural analysis of the hepatic cell with especially cytochemical evaluation and counting of peroxisomes) were studied. The treatment with clofibrate gave the following results: fall in total serum cholesterol (-25%), increase in liver weight (+89%) and hepatic catalase activity (+69%), high proliferation of hepatic peroxisomes (+246%). These data are in agreement with literature. The following observations were noted with itanoxone: a decrease in total serum cholesterol proportional to the dose applied and of higher intensity as compared to clofibrate (-36,5% at 100 mg/kg; -54% at 300 mg/kg), a moderate increase in liver weight (+25% at 100 mg/kg; +41% at 300 mg/kg) and hepatic peroxisomes (+12% at 100 mg/kg; +85% at 300 mg/kg), no effect on hepatic catalase activity. The moderate feature of the hepatic response induced by itanoxone in spite of a marked hypocholesterolemic activity was discussed: first in connection with the hypothesis about a relation between the proliferation of hepatic peroxisomes induced by many hypolipemic agents and the advent of tumors in rats, then, in connection with the association sometimes assumed between the increased number of hepatic peroxisomes and the effect on lipids of several hypolipemic substances related or not to clofibrate.

Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate.

The benign hyperplasia of the prostate is a manifestation of aging, involving the accumulation, within the gland, of dihydrotestosterone, the probable mediator of the hyperplasia. Binding studies were performed on the cytosolic androgenic receptor of the rat prostate using [3H]methyltrienolone as a ligand. The binding of [3H]methyltrienolone at 5 nM, was inhibited by various drugs, such as methyltrienolone and cyproterone acetate. Permixon, a liposterolic extract of the plant, Serenoa Repens B, inhibits competitively the binding to the cytosolic receptor of the rat prostate. Various vegetable and mineral oils, the plant steroid: beta sitosterol and the antiprostatic drug: Tadenan, were all found to be inactive. The antiprostatic activity of Permixon shown in animal studies and controlled clinical trials, may thus result from a direct action at the cytosolic receptor.