Design, synthesis and biological study of new antiparasitic spiroarsoranes.

Thirty-eight new spiroarsoranes were synthesized after structure-activity relationship studies from the first series. These compounds were predicted to cross more easily the membrane of protozoae or the cuticle of Nematodes and to reach their biological target with efficiency. The spiroarsoranes were evaluated for their antiparasitic properties, on helminths and protozoa models in regard of their parent arsonic acids. The following parasite models were used: Entamoeba histolytica and Trichomonas vaginalis in vitro; Molinema dessetae infective larvae in vitro, adults and microfilariae in vivo; Nippostrongylus brasiliensis infective larvae in vitro. The results obtained on these models indicated that the "spiranization" of arsonic acids produced new compounds with a biological activity 10-fold superior to those of arsonic acids. Nevertheless, each parasite had its own sensitivity to spiroarsoranes. Moreover, in vivo results showed that the lipophilicity of the molecules should be optimal to avoid high toxicity in host such as arsenical encephalopathy.

Placental transfer of glycosaminoglycans in the human perfused placental cotyledon model.

Placental transfer of unfractionated heparin (UH), of low molecular weight heparin CY 216 (LMWH) and of Dermatan sulphate (DS) was studied using the human perfused placental cotyledon model. Two different techniques were used to assess the transfer: labelled molecules and biological activities as measured by antifactor Xa or antifactor IIa activities. No biological activity was present in the fetal circulation, for any of the drugs used; however, very low fractions of the perfused radioactivity were recorded, 0.76% +/- 0.36%, 1.46% +/- 1.44% and 2.37% +/- 0.89% for DS, UH and LMWH, respectively.

Four compartment mammillary model applied to the pharmacokinetics of a spiroarsorane administered orally to rabbits.

Rekik et al. dealt with the pharmacokinetics of two spiroarsoranes molecules administered intravenously or orally to rabbits. For the intravenous study they used an open two-compartment model. For the oral study they admitted that they were unable to fit the data to a model. In this paper the plasma concentration profile of molecule 2 after oral administration using a four mammillary open compartment model is described. This type of model (which requires a fourth degree equation) has been previously described. Here it is applied to a concrete situation.

Pharmacokinetics of two spiroarsoranes administered intravenously or orally to rabbits.

The pharmacokinetics of two spiroarsorane molecules (1,2) were investigated after both intravenous bolus and an oral administration in rabbits. After iv administration of a 15-mg/kg dose, for the two substances, the plasma concentration-time curves were well described by an open two-compartmental model. The half-lives of the first phase were 0.47 +/- 0.12 and 0.27 +/- 0.02 h for 1 and 2, respectively. The half-lives of the terminal phase were of the same order of magnitude for the two substances: 4.38 +/- 0.24 and 6.03 +/- 1.14 h, respectively. Total plasma clearances were 2.47 +/- 0.44 and 0.81 +/- 0.04 L/h, respectively, and the steady-state volume of distribution of 2 (14.99 +/- 2.57 L) was larger than that of 1 (4.27 +/- 0.28 L). After oral administration, spiroarsorane 2 was not absorbed. The availability of the suspension of 1 was 18%. The rate of the absorption phase of 1 showed a saturation process, probably due to the solubility of the molecule. When increasing oral doses of 1 (15, 30, and 60 mg/kg) were administered, the plasma concentrations did not increase to the same extent.