ABSTRACT
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.
Subject(s)
Anthelmintics/pharmacokinetics , Cytochrome P-450 Enzyme System/metabolism , Fascioliasis/veterinary , Microsomes, Liver/metabolism , Praziquantel/pharmacokinetics , Sheep Diseases/drug therapy , Administration, Oral , Animals , Animals, Newborn , Anthelmintics/administration & dosage , Anthelmintics/chemistry , Anthelmintics/therapeutic use , Area Under Curve , Chromatography, High Pressure Liquid , Fasciola hepatica , Fascioliasis/drug therapy , Female , Gas Chromatography-Mass Spectrometry , Injections, Intramuscular/veterinary , Male , Oxidation-Reduction , Praziquantel/administration & dosage , Praziquantel/chemistry , Praziquantel/therapeutic use , SheepABSTRACT
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.
Subject(s)
Globins/genetics , Hemoglobins, Abnormal/analysis , beta-Thalassemia/genetics , Adult , Blood Protein Electrophoresis , Child , Female , France/ethnology , Gene Frequency , Haplotypes/genetics , Hemoglobins, Abnormal/genetics , Heterozygote , Humans , Indians, North American/genetics , Italy/ethnology , Male , Mexico/epidemiology , Middle Aged , Pregnancy , Pregnancy Complications, Hematologic , Sequence Deletion , White People/genetics , beta-Thalassemia/blood , beta-Thalassemia/ethnologyABSTRACT
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.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Lactams , beta-Lactamase Inhibitors , beta-Lactams/chemical synthesis , Amoxicillin/pharmacology , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Clavulanic Acid , Clavulanic Acids/pharmacology , Enzyme Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Penicillins/pharmacology , Staphylococcus aureus/drug effects , beta-Lactams/pharmacologyABSTRACT
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.
Subject(s)
Acridines/chemical synthesis , Antineoplastic Agents/chemical synthesis , Acridines/pharmacology , Animals , Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor , Humans , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Magnetic Resonance Spectroscopy , Mice , Tetrazolium Salts , Thiazoles , Tumor Cells, CulturedABSTRACT
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.
Subject(s)
Purinergic P1 Receptor Antagonists , Xanthines/chemical synthesis , Xanthines/metabolism , Animals , Cerebral Cortex/metabolism , Ligands , Magnetic Resonance Spectroscopy , Neostriatum/metabolism , Rats , Receptors, Purinergic P1/metabolism , Sheep , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Receptors, Cell Surface/metabolism , Tryptamines/chemical synthesis , Tryptamines/metabolism , Animals , Binding Sites , Cricetinae , Male , Mesocricetus , Quail , Rabbits , Receptors, Melatonin , Structure-Activity Relationship , Tryptamines/chemistryABSTRACT
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.
Subject(s)
Receptors, GABA-A/metabolism , Animals , Benzodiazepines/metabolism , Binding, Competitive/drug effects , Brain/drug effects , Brain/metabolism , Diazepam/metabolism , In Vitro Techniques , Male , Radioligand Assay , Rats , Rats, Inbred Strains , Receptors, GABA-A/drug effectsABSTRACT
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.
Subject(s)
Anticholesteremic Agents/chemical synthesis , Platelet Aggregation Inhibitors/chemical synthesis , Theophylline/analogs & derivatives , Triglycerides/biosynthesis , Animals , Blood Coagulation/drug effects , Chemical Phenomena , Chemistry , Clofibrate/pharmacology , Diuresis/drug effects , In Vitro Techniques , Male , Rats , Rats, Inbred StrainsABSTRACT
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.
Subject(s)
Hemolytic-Uremic Syndrome/therapy , Plasmapheresis , Aspirin/therapeutic use , Blood Transfusion , Child , Combined Modality Therapy , Dipyridamole/therapeutic use , Hemolytic-Uremic Syndrome/drug therapy , Humans , MaleABSTRACT
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.
Subject(s)
Amines/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Amines/pharmacology , Animals , Chemical Phenomena , Chemistry , Male , Rats , Rats, Inbred StrainsABSTRACT
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.