Assignment of the absolute configuration at the sulfur atom of thioridazine metabolites by the analysis of their chiroptical properties: The case of thioridazine 2-sulfoxide

Thioridazine (THD) is a commonly prescribed phenotiazine neuroleptic drug, which is extensively biotransformed in the organism producing as main metabolites sulfoxides and a sulfone by sulfur oxidation Significant differences have been observed in the activity of the THD enantiomers as well as for its main metabolites, and enantioselectivity phenomena have been proved in the metabolic pathway. Here the assignment of the absolute configuration at the sulfur atom of enantiomeric THD-2-sulfoxide (THD-2-SO) has been carried out by circular dichroism (CD) spectroscopy The stereoisomers were separated by HPLC on Chiralpak AS column, recording the CD spectra for the two collected enantiomeric fractions The theoretical electronic CD spectrum has been obtained by the TDDFT/B3LYP/6-31G*. as Boltzmann averaging of the contributions calculated for the most stable conformations of the drug The comparison of the simulated and experimental spectra allowed the absolute configuration at the sulfur atom of the four THD-2-SO stereoisomers to be assigned The developed method should be useful for a reliable correlation between stereochemistry and activity and/or toxicity

Investigation of the in vivo activity of CYP3A in Brazilian volunteers: comparison of midazolam and omeprazole as drug markers

Objective This study compares midazolam with omeprazole as marker drugs for the evaluation of CYP3A activity in nine healthy self-reported white Brazilian volunteers. Methods Omeprazole was also used to evaluate the CYP2C19 phenotype. The volunteers received p.o. 20 mg omeprazole, and blood samples were collected 3.5 h after drug administration. After a washout period of 10 days, the volunteers received p.o. 15 mg midazolam maleate, and serial blood samples were collected up to 6 h after administration of the drug. CYP2C19 was genotyped for the allelic variants CYP2C19*1, CYP2C19*2, CYP2C19*3, and CYP2C19*17. Analysis of omeprazole, hydroxyomeprazole, omeprazole sulfone, and midazolam in plasma was carried out by LC-MS/MS. Results The volunteers genotyped as CYP2C19*1*17, CYP2C19*17*17, CYP2C19*1*1 (n=8), or CYP2C19*17*2 (n=1) presented a median hydroxylation index (omeprazole/hydroxyomeprazole) of 1.35, indicating that all of them were extensive metabolizers of CYP2C19. The volunteers (n=9) presented a 0.12 log of the omeprazole/sulfone ratio and a median oral clearance of midazolam of 17.89 ml min(-1) kg(-1), suggesting normal CYP3A activity. Conclusions Orthogonal regression analysis between midazolam clearance and log of the plasma concentrations of the omeprazole/omeprazole sulfone ratio (R=-0.7544, P < 0.05) suggests that both midazolam and omeprazole can be used as markers of CYP3A activity in the population investigated.

Albendazole-praziquantel interaction in healthy volunteers: kinetic disposition, metabolism and enantioselectivity

center dot Pharmacokinetic interactions between albendazole and praziquantel are based on plasma concentrations of the enantiomeric mixture of both drugs with contradictory data, although the antiparasitic activity arises from (-)-(R)-praziquantel and (+)-albendazole sulfoxide. WHAT THIS STUDY ADDS center dot The pharmacokinetic interaction between albendazole and praziquantel is enantioselective. Praziquantel increased the plasma concentrations of (+)-albendazole sulfoxide more than those of (-)-albendazole sulfoxide and the administration of albendazole did not change the kinetic disposition of (+)-(S)-praziquantel, but increased the plasma concentration of (-)-(R)-praziquantel. AIM This study investigated the kinetic disposition, metabolism and enantioselectivity of albendazole (ABZ) and praziquantel (PZQ) administered alone and in combination to healthy volunteers. METHODS A randomized crossover study was carried out in three phases (n = 9), in which some volunteers started in phase 1 (400 mg ABZ), others in phase 2 (1500 mg PZQ), and the remaining volunteers in phase 3 (400 mg ABZ + 1500 mg PZQ). Serial blood samples were collected from 0-48 h after drug administration. Pharmacokinetic parameters were calculated using a monocompartmental model with lag time and were analyzed using the Wilcoxon test; P < 0.05. RESULTS The administration of PZQ increased the plasma concentrations of (+)-ASOX (albendazole sulphoxide) by 264% (AUC 0.99 vs. 2.59 mu g ml-1 h), (-)-ASOX by 358% (0.14 vs. 0.50 mu g ml-1 h) and albendazole sulfone (ASON) by 187% (0.17 vs. 0.32 mu g ml-1 h). The administration of ABZ did not change the kinetic disposition of (+)-(S)-PZQ (-)-(R)-4-OHPZQ or (+)-(S)-4-OHPZQ, but increased the plasma concentration of (-)-(R)-PZQ by 64.77% (AUC 0.52 vs. 0.86 mu g ml-1 h). CONCLUSIONS The pharmacokinetic interaction between ABZ and PZQ in healthy volunteers was demonstrated by the observation of increased plasma concentrations of ASON, both ASOX enantiomers and (-)-(R)-PZQ. Clinically, the combination of ABZ and PZQ may improve the therapeutic efficacy as a consequence of higher concentration of both active drugs. On the other hand, the magnitude of this elevation may represent an increased risk of side effects, requiring, certainly, reduction of the dosage. However, further studies are necessary to evaluate the efficacy and safety of this combination.

A systematic study of the microwave and thermal cure kinetics of the TGDDM/DDS and TGDDM/DDM epoxy-amine resin systems

The microwave and thermal cure processes for the epoxy-amine systems N,N,N',N'-tetraglycidyl-4,4'-diaminodiphenyl methane (TGDDM) with diaminodiphenyl sulfone (DDS) and diaminodiphenyl methane (DDM) have been investigated. The DDS system was studied at a single cure temperature of 433 K and a single stoichiometry of 27 wt% and the DDM system was studied at two stoichiometries, 19 and 32 wt%, and a range temperatures between 373 and 413 K. The best values the kinetic rate parameters for the consumption of amines have been determined by a least squares curve Ft to a model for epoxy-amine cure. The activation energies for the rate parameters for the MY721/DDM system were determined as was the overall activation energy for the cure reaction which was found to be 62 kJ mol(-1). No evidence was found for any specific effect of the microwave radiation on the rate parameters, and the systems were both found to be characterized by a negative substitution effect. Copyright (C) 2001 John Wiley & Sons, Ltd.

Retreatment in leprosy: a case-control study

OBJECTIVE: To assess risk factors for retreatment of leprosy patients. METHODS: A case-control study with patients from two reference care units in Recife, northeastern Brazil, in 2003. The case group included retreated patients (N=155) and the control group comprised those patients who were not retreated (N=155) matched by year of diagnosis and health care unit. Univariate and multivariate analyses were conducted to test the associations and odds ratios and related 95% confidence intervals were estimated. RESULTS: The following factors were found to be significantly associated (p<0.05) with retreatment: occurrence of adverse immunological reactions after treatment completion (OR=2.3; 95% CI=1.18;4.83), final bacterial index > 1 (OR=6.43; 95% CI=1.67;24.74), therapeutic regimen consisting of sulfone monotherapy (OR=10; 95% CI=0.01;0.78) and reports of household contacts (OR=2.2; 95% CI=0.24;0.85). CONCLUSIONS: The study findings reinforce that the use of dapsone monotherapy should be discontinued, and highlight the need for epidemiological monitoring of specific groups of leprosy patients after treatment completion through periodical clinical and laboratory evaluation. Further studies to explore the association between final bacterial index and retreatment are strongly recommended.

Dapsone hypersensitivity syndrome in an adolescent during treatment during of leprosy

A 12 y old girl was admitted 24 days after start a WHO multidrug therapy scheme for multibacillary leprosy (dapsone, clofazimine and rifampicin) with intense jaundice, generalized lymphadenopathy, hepatoesplenomegaly, oral erosions, conjunctivitis, morbiliform rash and edema of face, ankles and hands. The main laboratory data on admission included: hemoglobin, 8.4 g/dL; WBC, 15,710 cells/mm³; platelet count, 100,000 cells/mm³; INR = 1.49; increased serum levels of aspartate and alanine aminotransferases, gamma-glutamyl transpeptidase, alkaline phosphatase, direct and indirect bilirubin. Following, the clinical conditions had deteriorated, developing exfoliative dermatitis, shock, generalized edema, acute renal and hepatic failure, pancytopenia, intestinal bleeding, pneumonia, urinary tract infection and bacteremia, needing adrenergic drugs, replacement of fluids and blood product components, and antibiotics. Ten days after admission she started to improve, and was discharged to home at day 39th, after start new supervised treatment for leprosy with clofazimine and rifampicin, without adverse effects. This presentation fulfils the criteria for the diagnosis of dapsone hypersensitivity syndrome (fever, generalized lymphadenopathy, exfoliative rash, anemia and liver involvement with mixed hepatocellular and cholestatic features). Physicians, mainly in geographical areas with high prevalence rates of leprosy, should be aware to this severe, and probably not so rare, hypersensitivity reaction to dapsone.

HOMO-raising strategies in aminocatalysis, from Enamine to Tetraenamine

Dissertação para obtenção do Grau de Mestre em Bioorgânica

Incommensuración conformacional en cristales moleculares

Existen sólidos orgánicos en los cuales las interacciones intermoleculares tienen un efecto determinante sobre la conformación de equilibrio y la dinámica molecular. Tal es el caso de los compuestos de la familia de los bifenilos, que presentan en general valores bajos para la energía de torsión fenil-fenil, en algunos casos comparables a los de las interacciones intermoleculares. Esta competencia de interacciones inter. e intramoleculares, al variar con la temperatura, ocasiona transiciones de fase que pueden involucrar la pérdida de la periodicidad del cristal, como ocurre con el bifenilo y el bis(4-clorofenil)sulfone ((ClC6H4)2SO2), abreviado como BCPS). En estos compuestos se producen transiciones a fases inconmensuradas (IC), en las cuales los ángulos interfenilos están modulados espacialmente con una periodicidad irracional respecto de la red cristalina subyacente. Por otra parte, estos mismos factores estéricos y dinámicos internos juegan un rol crucial en el nivel de actividad biológica de una sustancia, a nivel molecular. En los bifenilos clorados se ha demostrado, que la conformación interna de la molécula y la libertad reorientacional de ciertos grupos moleculares (como por ejemplo anillos bencénicos, C-Cl3, etc.) son determinantes en la interacción con las membranas celulares durante el proceso de absorción. La toxicidad de los pesticidas derivados del DDT esta basada en este hecho. Así, el problema de cómo se modifica la conformación interna de la molécula y su dinámica debido a interacciones con su entorno (vecinos próximos en el sólido, membrana celular, etc.) guarda interés tanto desde el punto de vista de la física del sólido (estudio de fases aperiódicas, dinámica molecular) como de la física aplicada (grado de bioactividad). El objetivo general del proyecto es realizar la caracterización, el análisis y la descripción de los mecanismos que originan, en compuestos bifenilos colorados, transiciones a fases conformacionalmente inconmensuradas. Como objetivo específico, se plantea un estudio de compuestos estructuralmente semejantes al BCPS y soluciones sólidas de estos compuestos de BCPS. Se efectuarán de esta forma, perturbaciones del balance entre las interacciones intra e intermoleculares, observándose el efecto sobre los diagramas de fases, con referencia al correspondiente al BCPS.

Tratamento eclético da lepra: 20 anos de experiência

The author gives the clinical records of 20 patients, 14 of which were treated during 17 months, and the rest much less. The method used for treatment was the ecclectical — preferred by the A. since many years —, in which he associates electricity with minor surgery, chaulmestrol (pure or with 0.5 p. c. iodine or 4 p. c. creosote) and other auxilliary curative agents. The chaulmoogra derivatives were used daily as nostrils tamponage (2 p.c. mentholated or thymolated ester), periodically by injections inside the enlarged lymph nodes and nerve abscesses, and twice weekly by subcutaneous infiltrations (MUIR method) 5 c.c. each, and chaulmoogra soap tablets per os. The galvanocauterisation session was once per week, on active leprotic lesions, followed by painting with 30 p. c. trichloracetic acid solution. All 20 patients were bacilliferous before treatment, and became stronger positive after some months treatment. At the end 14 negativated and 6 remained positive and sometimes bacilli being very scanty. 16 out of 20 gave interesting serological reactions, viz.: Wassermann, Stern, Kahn. Rubino, Witebsky and Gaté (Formol-gel) positive in 5; Stern, Rubino. Witebsky and Gaté positive and Wassermann and Kahn negative in 2; Stern. Kahn, Witebsky and Gaté positive and Wassermann anticomplementary in 1; Wassermann. Stern, Kahn, Rubino and Gaté negative in 1. in the beginning, and a few months later Stern. Witebsky and Gaté becoming positive; Stern. Rubino. Witebsky and Gaté positive and anticomplementary W. in 1; Stern, Witebsky and Gaté positive and Wassermann. Kahn and Rubino negative in 1; Witebsky and Gaté positive and Wassermann, Stern, Kahn and Rubino negative in 1; Witebsky 3 times anticomplemantary and strongly positive Gaté in 1; Wassermann and Gaté positive in 1; Stern and Rubino positive in 1 and Stern test negative in one. In 7 cases high Formol-gel were associated with a high sedimentation index. Many cases had very high S.I. being a false measure of the severity of the disease; others remained very high notwithstanding the great improvement of the disease. All patients with more than 12 months treatment became practically symptom free. Lepra reaction amongst them was rare and always started by embolic rash, being controlled by destruction of such skin lesions by galvanocauterisation. In a few cases the lepromata infiltrated with "Subintrol" (a 3 p. c. special chaulmoogra soap prepared by Dr. ASTROGILDO MACHADO) were completely destroyd and never relapsed. In October 1946 Dr. ERNEST MUIR saw here a few cases treated by the author's method and suggested the combination of Diasone with galvanocauterisation which is being done now with satifactory results. The second part of this paper, reporting many leprosy cases treated by the so-called ecclectical method, which are symptom free and negativated since five to ten years, will be published as soon as the sulfone-therapy be summarised in some reliable scientific report to be compared with.

Two approaches to discovering and developing new drugs for Chagas disease

This review will focus on two general approaches carried out at the Sandler Center, University of California, San Francisco, to address the challenge of developing new drugs for the treatment of Chagas disease. The first approach is target-based drug discovery, and two specific targets, cytochrome P450 CYP51 and cruzain (aka cruzipain), are discussed. A "proof of concept" molecule, the vinyl sulfone inhibitor K777, is now a clinical candidate. The preclinical assessment compliance for filing as an Investigational New Drug with the United States Food and Drug Administration (FDA) is presented, and an outline of potential clinical trials is given. The second approach to identifying new drug leads is parasite phenotypic screens in culture. The development of an assay allowing high throughput screening of Trypanosoma cruzi amastigotes in skeletal muscle cells is presented. This screen has the advantage of not requiring specific strains of parasites, so it could be used with field isolates, drug resistant strains or laboratory strains. It is optimized for robotic liquid handling and has been validated through a screen of a library of FDA-approved drugs identifying 65 hits.

Interhuman transmission as a potential key parameter for geographical variation in the prevalence of Pneumocystis jirovecii dihydropteroate synthase mutations.

BACKGROUND: Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations are associated with failure of prophylaxis with sulfa drugs. This retrospective study sought to better understand the geographical variation in the prevalence of these mutations. METHODS: DHPS polymorphisms in 394 clinical specimens from immunosuppressed patients who received a diagnosis of P. jirovecii pneumonia and who were hospitalized in 3 European cities were examined using polymerase chain reaction (PCR) single-strand conformation polymorphism. Demographic and clinical characteristics were obtained from patients' medical charts. RESULTS: Of the 394 patients, 79 (20%) were infected with a P. jirovecii strain harboring one or both of the previously reported DHPS mutations. The prevalence of DHPS mutations was significantly higher in Lyon than in Switzerland (33.0% vs 7.5%; P < .001). The proportion of patients with no evidence of sulfa exposure who harbored a mutant P. jirovecii DHPS genotype was significantly higher in Lyon than in Switzerland (29.7% vs 3.0%; P < .001). During the study period in Lyon, in contrast to the Swiss hospitals, measures to prevent dissemination of P. jirovecii from patients with P. jirovecii pneumonia were generally not implemented, and most patients received suboptimal prophylaxis, the failure of which was strictly associated with mutated P. jirovecii. Thus, nosocomial interhuman transmission of mutated strains directly or indirectly from other individuals in whom selection of mutants occurred may explain the high proportion of mutations without sulfa exposure in Lyon. CONCLUSIONS: Interhuman transmission of P. jirovecii, rather than selection pressure by sulfa prophylaxis, may play a predominant role in the geographical variation in the prevalence in the P. jirovecii DHPS mutations.

Estudo da influência do diluente reativo PGE na cinética de cura de resina epóxi utilizada em compósitos estruturais

Phenil glycidyl ether (PGE), a monofunctional diluent, has been used in epoxy resins formulations in order to increase the toughness of the epoxy molded composite. In a systematic study concerning its influence in the cure kinetics of the epoxy resin, it was used in concentrations of 2,5; 5,0; 10 and 20% in relation to a diglycidyl ether bisphenol-A (DGEBA)/diamino diphenil-sulfone (DDS) base matrix. Dynamic and isothermal scanning analysis were carried out using a differential scanning calorimety (DSC) equipment. For all the concentrations of PGE, a n order kinetics was observed, with n varing between 0,35 -- 0,91 as a function of the increase in the PGE concentration.

Interação de compostos organossulfurados derivados do alho com o citocromo-c: um estudo eletroquímico

Organosulfur compounds present in garlic and onion have been evaluated as inhibitors of chemical carcinogenesis. Among them diallylsulfide was mainly investigated and studies demonstrated its metabolization to the corresponding sulfoxide and sulfone. In this work, we report the investigation of the interaction between the diallylsulfide and its oxidized derivatives, through cyclic voltammetry, with horse heart cytocrome-c (on a modified electrode with 4-mercaptopyridine). Our results suggest that there is a reversible interaction between cytocrome-c and diallylsulfide and diallylsulfone and an irreversible interaction with the diallylsulfoxide.

In situ synthesis of nanoclay filled polyethylene using polymer supported metallocene catalyst system

In situ ethylene polymerizations were performed using bis(cyclopentadiene)titanium dichloride supported on polyethersulfone as catalyst. The bis(cyclopentadiene)titanium dichloride supported on polyethersulfone catalyst activity estimated by ethylene polymerization was 360 kgPE/molTi/h. During polymerization the fillers used were montmorillionite nanoclays having surface modifications with 35-45 wt% dimethyl dialkyl(14-18)amine (FA) and 25-30 wt% trimethyl stearyl ammonium (FB). These fillers were pretreated with methylaluminoxine (MAO; cocatalyst) for better dispersion onto the polymer matrix. The formation of polyethylene within the whole matrix was confirmed by FTIR studies. It was found that the nature of nanofiller did not have any remarkable effect on the melting characteristics of the polymer. TGA study indicates that nanoclay FB filled polyethylene has higher thermal stability than nanoclay FA filled polyethylene. The melting temperature of the obtained polyethylenes was 142 ºC, which corresponds to that synthesized by the polyether sulfone supported catalyst.

Albendazole metabolism in patients with neurocysticercosis: antipyrine as a multifunctional marker drug of cytochrome P450

The present study investigates the isoform(s) of cytochrome P450 (CYP) involved in the metabolism of albendazole sulfoxide (ASOX) to albendazole sulfone (ASON) in patients with neurocysticercosis using antipyrine as a multifunctional marker drug. The study was conducted on 11 patients with neurocysticercosis treated with a multiple dose regimen of albendazole for 8 days (5 mg/kg every 8 h). On the 5th day of albendazole treatment, 500 mg antipyrine was administered po. Blood and urine samples were collected up to 72 h after antipyrine administration. Plasma concentrations of (+)-ASOX, (-)-ASOX and ASON were determined by HPLC using a chiral phase column and detection by fluorescence. The apparent clearance (CL/f) of ASON and of the (+) and (-)-ASOX enantiomers were calculated and compared to total antipyrine clearance (CL T) and the clearance for the production of the three major antipyrine metabolites (CLm). A correlation (P<=0.05) was obtained only between the CL T of antipyrine and the CL/f of ASON (r = 0.67). The existence of a correlation suggests the involvement of CYP isoforms common to the metabolism of antipyrine and of ASOX to ASON. Since the CL T of antipyrine is a general measure of CYP enzymes but with a slight to moderate weight toward CYP1A2, we suggest the involvement of this enzyme in ASOX to ASON metabolism in man. The study supports the establishment of a specific marker drug of CYP1A2 in the study of the in vivo metabolism of ASOX to ASON.