Pharmacokinetics and microsomal oxidation of praziquantel and its effects on the P450 system in three-month-old lambs infested by Fasciola hepatica.

Praziquantel (PZQ) is a broadly effective trematocide and cestocide, widely employed in veterinary and human medicine. In view of several differences in both its pharmacokinetic profile in different animal species and in the cytochrome P450-dependent system between ruminant and nonruminant species, the present study was undertaken to determine the pharmacokinetics of this drug, its effects on the P450 system and the involvement of cytochrome P450 in its metabolism in 3-month-old lambs infested by Fasciola hepatica. Following both oral and i.m. administration, PZQ disposition was best described by a linear one-compartment open model with a rapid absorption and elimination. Although the PZQ dose used by the i.m. route was only half of that used by the oral route, the mean PZQ plasma concentration was higher after i.m. than after oral treatment. Oral treatment with 30 mg/kg/day of PZQ did not modify the mono-oxygenase activities tested, whilst the administration of PZQ at a dose of 60 mg/kg/day for 2 days caused a significant decrease in the P450 3A-dependent erythromycin N-demethylase and 6beta testosterone hydroxylase activities. From the incubation of microsomes from lambs not treated with PZQ, a single metabolite (PZQ 11b-OH or PZQ 1-OH) was identified by GC/MS analysis. By selective inhibition of the 3A subfamily performed with triacetyloleandromycin, the production of this metabolite declined by about 90% suggesting a prominent role of P450 3A isoforms in this oxidation. These features indicate that agents or drugs which are able to modulate P450 3A-dependent catalysis may interfere with the metabolism, bioavailability and therapeutic effects of PZQ.

Hb Lepore Washington-Boston in two Mexican mestizo families.

Two Mexican mestizo families with Hb Lepore Washington-Boston are described. One family is from Cordova, in the State of Veracruz, in the East coast of Mexico: the proband is a 44-year old asymptomatic male with italian ancestors; the other family is from the city of Durango, State of Durango, in the northwestern part of the country: the propositus is a 32-year old pregnant female with French ancestors. In both cases the Hb Lepore was identified by alkaline electrophoresis and characterized by high performance liquid chromatography and PCR with specific probes flanking the deletion frame. The beta-haplotype in both families was +(-)-(-)-(++), the commonest beta-haplotype reported with this mutation. This paper describes the first cases of this entity in Mexico.

Synthesis and antimicrobial evaluation of 2 beta-chloromethyl-6 beta-carbamoylmethyl-penam-1,1-dioxide-3-carboxylic acid.

A new 2 beta-Chloromethyl-6 beta-carbamoylmethyl-penam-1,1-dioxide-3-carboxylic acid was synthesised and evaluated for its antimicrobial and beta-lactamase inhibitory activity. The compound was found to be inactive.

In vitro evaluation of the potential antitumor activity of an N-acridyl-pentanoyloxypyridine-2-thione derivative.

The synthesis and in vitro evaluation of the antitumor activity of an N-acridyl-pentanoyloxypridine-2-thione derivative (APPT), hypothesized to act as a DNA-intercalating compound, are described. The compound showed dose-dependent antiproliferative activity against all of the tested murine and human tumor cell lines, as evaluated by using the tetrazolium-based colorimetric assay. In addition, a comparative evaluation of the cytotoxic property was performed also against primary cultures of normal bone marrow cells. The results demonstrated that APPT possesses preferential antitumor activity and is endowed with an in vitro therapeutic index very similar to those of well known DNA-binding anti-neoplastic compounds, such as daunorubicin (DNR) and amsacrine (mAMSA). Therefore, APPT can be considered to be a potential selective cytoreductive drug.

Effects of substituent size upon adenosine receptor A1/A2 affinity of some newly synthesised 8-cycloalkyl xanthines.

The activity of a series of 1,3-dipropyl-xanthines bearing C8-cycloalkyl substituents as antagonists at A1 and A2 adenosine receptors is examined. Pharmacological results showed that the size of the 8-substituent is an important feature for response in activity of such class of antagonists. Among compounds 3-8, the 2-norbornyl analog 6 showed the best A1/A2 selectivity. A new route for the synthesis of 8-alkyl-substituted xanthines is presented. This method, consisting of a direct alkylation of the imidazole moiety through a radical mechanism reaction, was shown to be a more convenient strategy in comparison with the commonly employed synthetic schemes.

2-Substituted 5-methoxy-N-acyltryptamines: synthesis, binding affinity for the melatonin receptor, and evaluation of the biological activity.

A series of 2-substituted 5-methoxy-N-acyltryptamines was synthesized and their affinity for the melatonin receptor, isolated from whole quail brains, was tested in a succession of in vitro ligand-receptor binding experiments, using 2-[125I]iodomelatonin as a labeled ligand. Optimization of the C2 substituent and the N-acyl group resulted in compounds having picomolar affinity for the receptor (vs nanomolar affinity for melatonin). In two tests for evaluation of the biological activity (effects on the spontaneous firing activity of single neurons in the rabbit parietal cortex in situ, and the Syrian hamster gonadal regression model in vivo) most of the analogs behaved as agonists. Isopropyl substitution at C2 alone, or concomitantly with cyclopropyl substitution at the N-acyl position, resulted in much lower affinity and weaker biological effect, or lack of activity in the latter case. Of interest are the compounds 4d (R = phenyl, R1 = CH3) and 4g (R = phenyl, R1 = cyclopropyl), which expressed high affinity for the receptor and apparent antagonistic activity under the conditions of the experimental models employed, though the analog 4g (R = phenyl, (R1 = cyclopropyl) seemingly was a weak antagonist and in situ expressed mixed activity in the higher concentration range. Cyclopropyl substitution at the N-acyl position inevitably resulted in lower affinity for the receptor and weaker biological activity. These data demonstrate that the N-acetyl group is important for both affinity and agonist biological activity. The substituents at C2 are crucial for the affinity of the compound for the receptor and can be utilized to create putative high-affinity agonists or antagonists.

Methyl N-(diphenylmethyl)-D,L-tryptophanates: synthesis and benzodiazepine receptor affinity.

Several Methyl N-(diphenylmethyl)-D,L-tryptophanates were synthetized and the affinity for the central benzodiazepine receptor was measured. Disappointingly, none of the tested compounds showed to be active, even at the high concentration examined.

7-Substituted theophyllines. Part VI--N-[2-(4-chlorophenoxy)-1-phenyl-alkyl]-alkylamido derivatives.

The new amides are inhibitors of cholesterol biosynthesis in vitro as well as in vivo. These compounds are also inhibitors in vivo of triglyceride biosynthesis and of platelet aggregation. All tests showed activity (values expressed as percentage variation) much greater than clofibrate. Besides, all compounds have no effect on coagulation or diuresis and showed low acute toxicity.

[Use of plasmapheresis in the treatment of hemolytic-uremic syndrome in children]. / Sull'impiego della plasmaferesi nel trattamento della sindrome uremico-emolitica nel bambino.

The plasma-exchange has been recently adopted in the therapy of the hemolytic-uremic syndrome. We experimented this therapy, without any complication with traditional treatment (anti platelet-aggregation, frozen fresh plasma), on a child of 6 years and 8 months old. A rapid normalization of the clinical syntomatology was obtained without sequences also after a long period. The PE therapy has to be carefully valued on the solution of the SUE in order to establish the cases to be treated, missing proved results from controlled experiments.

[Aryloxy- and arylthioalkylamine hypolipidemic agents]. / Arilossi e ariltioalchilamine ipolipidemizzanti.

Aryloxy and arylthioalkylamines related respectively to clofibrate and 2-(3,5-di-t-butyl-4-hydroxyphenylthio)hexanoic acid, a derivative of an active probucol metabolite, were prepared and pharmacologically screened as hypolipidemic substances. Some of them showed interesting antilipemic activity but also, unfortunately, high acute toxicity.

[Synthesis of O-(beta-diethylaminoethyl)cinchoninaldoxime with local anesthetic activity]. / Sintesi di O-(beta-dietilaminoetil)cinconinaldossime dotate di attività anestetica locale.

The synthesis and the pharmacological evaluation of a new series of O-(beta-diethylaminoethyl)aldoxines derived from cinchonine-aldehydes substituted at position 2 by alkyl and alkoxyl groups are described.