ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.

Antimicrobial effect of para-alkoxyphenylcarbamic acid esters containing substituted N-phenylpiperazine moiety

In current research, nine basic esters of para-alkoxyphenylcarbamic acid with incorporated 4-(4fluoro-/3-trifluoromethylphenyl)piperazin-1-yl fragment, 6i-6m and 8f-8i, were screened for their in vitro antimicrobial activity against Candida albicans, Staphylococcus aureus and Escherichia coli, respectively. Taking into account the minimum inhibitory concentration assay (MIC), as the most active against given yeast was evaluated 8i (MIC = 0.20 mg/mL), the most lipophilic structure containing para-butoxy and trifluoromethyl substituents. Investigating the efficiency of the compounds bearing only a single atom of fluorine and appropriate para-alkoxy side chain against Candida albicans, the cut-off effect was observed. From evaluated homological series, the maximum of the effectiveness was noticed for the stucture 6 k (MIC = 0.39 mg/mL), containing para-propoxy group attached to phenylcarbamoyloxy fragment, beyond which the compounds ceased to be active. On the contrary, all the tested molecules were against Staphylococcus aureus and Escherichia coli (MICs > 1.00 mg/mL) practically inactive.

Simultaneous determination of cetirizine and pseudoephedrine combined in tablet dosage form by high performance liquid chromatography

This study develops and validates an efficient, sensitive and simple method for the simultaneous determination of cetirizine dihydrochloride and pseudoephedrine combined in tablet dosage form by high performance liquid chromatography [HPLC] with an ultraviolet [UV] detector.The validation of this method was carried out according to ICH and USP guidelines. In this study, the mobile phase used was acetonitrile: water [530:470 [v/v]] with 200mg sodium heptane sulfonic acid and the pH value was adjusted to 2.5 with sulfuric acid. The limit of detection and quantification for cetirizinedihydrochloride were 0.805 and 2.685 microg/mL, respectively, and the limit of detection and quantification for pseudoephedrine were 17.976 and 59.921 microg/mL, respectively. The linearity was studied in the concentration range of 12.2 and 36.5 microg/mL forcetirizinedihydrochloride and 295.91 and 861.73 microg/mL for pseudoephedrine. The recovered amounts of cetirizinedihydrochloride and pseudoephedrine were 98.2% -102.9% and 99.5%- 102.4%, respectively.

Analysis of binding energy activity of imatinib and Abl tyrosine kinase domain based on simple consideration for conformational change: An explanation for variation in imatinib effect in mutated type.

Imatinib is a clinically well-tolerated small molecule inhibitor that exerts selective, dual inhibition on the transforming growth factor beta and platelet-derived growth factor pathways. The recognition of an inactive conformation of Abl, in which a catalytically important Asp-Phe-Gly motif is flipped by approximately 180 degrees with respect to the active conformation, underlies the specificity of the cancer drug imatinib, which is used to treat chronic myelogenous leukemia. However, conformational analysis shows that the effect of the drug depends on the potential energy, which varies due to the alpha rotatable angles of the Abl tyrosine kinase domain. In this study, the author determines the change of binding energy between the Abl tyrosine kinase domain, due to the variation in rotatable angles, and bond lengthening. According to this study, the ratio between the required binding energy between the wild and mutated types is equal to 1: 1.16.

Study of the interaction surface for the c-Src-imatinib complex by a molecular dicing technique.

With the beginning of the new millennium, a new and exciting era for cancer therapy has begun with the appearance of molecular targeted drugs. Imatinib is a clinically well-tolerated small molecule that exerts selective, dual inhibition of the transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) pathways. Imatinib is also suggested as a chemopreventive for recurrent and metastatic malignancies. An interesting point to be clarified regarding the mechanism of imatinib is its interaction with c-Src. Fortunately, complexing of c-Src and imatinib has recently reported, which provides a basis for further study of the interactions between the two molecules. In the present study, the author used the technique named molecular dicing to study the interaction surface between the two molecules. Accordingly, the interaction surface in c-Scr and imatinib could be identified.

Synthesis of N, N'-bis [N-4-N-methylcarbamyl-oxymethylthioxanthen-9-on-1-yI aminoethyI] piperazine of possible antitumor activity

N,N'-bis [N-[4-hydroxymethylthioxanthen-9-on-1-yl] piperazine and its N-methylcarbamate derivative have been synthesized. The compounds are considered a combination of two molecules of the antischistosomal drug, hycanthone. The two compounds are possibly active as antitumor as well as antischistosomal

Zopiclona: hipnótico da terceira geraçäo / Zopiclone: third generation hypnotic

A zopiclona é a primeira das ciclospirinas, nova classe de agentes psicoterápicos. Possui perfil farmacológico de alta eficácia de baixa toxicidade. Liga-se a receptores específicos do Gaba (canal de cloreto e sítios alostéricos benzodiazepínicos). Embora a zopiclona manifeste atividade anticonvulsionante, miorrelaxante e ansiolítica, o principal uso é hipnótico, devido ao efeito sedativo