Assessment of anti-diabetic activity of a novel hydrazine-thiazole derivative: in vitro and in vivo method

Diabetes mellitus is a chronic disease resulting in oxidative stress that promotes tissue damage. The appearance of this disease is highly related to lifestyle and food of the population, being of great interest to search for a dietary supplement that can also act by reducing oxidative alterations. Based on the broad range of biological activity of thiazole derivatives, this work aimed to evaluate the in vitro antioxidant activity of a novel hydrazine-thiazole derivative and studies in vivo. In in vivo experiments, the liver extracts of healthy and diabetic Wistar rats were used, with analysis to determine the enzymatic activity of SOD, CAT, GPx, and GR, and determination of lipid peroxidation. Finally, in the blood of these animals, biochemical parameters were evaluated. Statistical evidence of changes caused in liver enzymes and liquid peroxidation was not detected; however, these parameters were also not changed between control groups with and without diabetes. On the other hand, concerning biochemical parameters, significant differences were detected in uric acid, alkaline phosphatase, ALT, and urea, indicating a possible antioxidant protective role of such substances in the liver and kidney of diabetic animals that could be acting by means other than that commonly reported in the literature.

Trombocitopenia hereditaria relacionada a gen MYH-9: primera familia reportada en Chile con diagnóstico molecular: caso clínico / Hereditary thrombocytopenia associated with a mutation in the MYH-9 gene: report of one case

We report a 51-year-old female who had a first episode of thrombocytopenia at 23 years of age during a pregnancy. At the age of fifty, a hysterectomy was indicated due to a metrorrhagia: a platelet count of 21,000/ul was detected. She was treated with eltrombopag with a good response. The family history of the patient revealed the presence of thrombocytopenia in several family members. Suspecting a hereditary thrombocytopenia, a genetic study revealed a mutation in the MYH-9 gene. This mutation can be suspected when there is a family history of thrombocytopenia with autosomal dominant inheritance, macrothrombocytopenia and in this particular case, due to the response to thrombopoietin receptor agonist, eltrombopag.

Impairment of locomotor activity induced by the novel N-acylhydrazone derivatives LASSBio-785 and LASSBio-786 in mice

The N-acylhydrazone (NAH) analogues N-methyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-785) and N-benzyl 2-thienylidene 3,4-benzoylhydrazine (LASSBio-786) were prepared from 2-thienylidene 3,4-methylenedioxybenzoylhydrazine (LASSBio-294). The ability of LASSBio-785 and LASSBio-786 to decrease central nervous system activity was investigated in male Swiss mice. LASSBio-785 or LASSBio-786 (30 mg/kg, ip) reduced locomotor activity from 209 ± 26 (control) to 140 ± 18 (P < 0.05) or 146 ± 15 crossings/min (P < 0.05), respectively. LASSBio-785 (15 or 30 mg/kg, iv) also reduced locomotor activity from 200 ± 15 to 116 ± 29 (P < 0.05) or 60 ± 16 crossings/min (P < 0.01), respectively. Likewise, LASSBio-786 (15 or 30 mg/kg, iv) reduced locomotor activity from 200 ± 15 to 127 ± 10 (P < 0.01) or 96 ± 14 crossings/min (P < 0.01), respectively. Pretreatment with flumazenil (20 mg/kg, ip) prevented the locomotor impairment induced by NAH analogues (15 mg/kg, iv), providing evidence that the benzodiazepine (BDZ) receptor is involved. This finding was supported by the structural similarity of NAH analogues to midazolam. However, LASSBio-785 showed weak binding to the BDZ receptor. LASSBio-785 or LASSBio-786 (30 mg/kg, ip, n = 10) increased pentobarbital-induced sleeping time from 42 ± 5 (DMSO) to 66 ± 6 (P < 0.05) or 75 ± 4 min (P < 0.05), respectively. The dose required to achieve 50% hypnosis (HD50) following iv injection of LASSBio-785 or LASSBio-786 was 15.8 or 9.5 mg/kg, respectively. These data suggest that both NAH analogues might be useful for the development of new neuroactive drugs for the treatment of insomnia or for use in conjunction with general anesthesia.

Lethal and Sublethal Effects of Methoxyfenozide on the Development, Survival and Reproduction of the Fall Armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae)

The lethal and sublethal effects of the ecdysone agonist methoxyfenozide on the fall armyworm, Spodoptera frugiperda (J. E. Smith), were investigated by feeding a methoxyfenozide-treated diet to fifth instars until pupation in doses corresponding to the LC10 and LC25 for the compound. Larval mortality reached 8 percent and 26 percent in the low and high concentration groups, respectively, on the seventh day of the experiment. A progressive larval mortality of 12 percent for the LC10 and 60 percent for the LC25 was observed before pupation. Treated larvae exhibited lower pupal weights, higher pupal mortality, presence of deformed pupae, and more deformed adults than untreated larvae. The incorporation of methoxyfenozide into the diet had a significant effect on the timing of larval development. The development period for males and females was about seven days longer than the controls for both concentrations tested. In contrast, the compound affected neither pupae nor adult longevity. Finally, S. frugiperda adults that resulted from fifth instars treated with methoxyfenozide were not affected in their mean cumulative number of eggs laid per female (fecundity), nor percentages of eggs hatched (fertility), or the sex ratio. Our results suggest that the combination of lethal and sublethal effects of methoxyfenozide may have important implications for the population dynamics of the fall armyworm.

Bioassay screening of Amazonian plants

OBJECTIVE: The purpose of this study was to evaluate several biological activities of thirty plant extracts collected in the North West Amazon (Ecuador). Some of these plants are being used for their reputed medicinal properties by the natives of this region. METHODS: Five in vitro bioassays were used to screen the plant material. 1. The brine shrimp lethality examination (BSLT) in microplate is a general test that seems capable of detecting a broad spectrum of bioactivity present in crude plant extracts. 2. Free radical scavenging properties were studied in a colorimetric assay using 2,2-diphenyl-1-picrylhydrazyl (DPPH). 3. The beta-glucosidase inhibition test is thought to be a method for the evaluation of anti-AIDS, anti-diabetic or anti-obesity compounds. 4. The xanthine oxidase inhibition assay is used to identify potential anti-gout agents. 5. The antibacterial activity that is being used to isolate and identify antibiotic drugs. RESULTS: In the BSLT, we found that Piscidia carthagenensis demonstrated very good activity with a LC50: 21.81 micrograms/mL. It is considered that plant extracts with low LC50 values may contain metabolites with cytotoxic, antifungal, insecticidal or pesticide activities. In the antioxidant activity bioassay, several plant extracts were confirmed to have excellent free radical scavenging properties. Rhus juglandifolia and Clusia venusta leaves exhibited an ED50: 3.12 micrograms/mL and 3.61 micrograms/mL, respectively. Piper reticulatum (84 per cent), Inga heteroptera (77 per cent), Clusia venusta (70.9 per cent), and Rhus juglandifolia (70.5 per cent) showed fairly good inhibition activity for beta-glucosidase. On the other hand, none of the plant extracts was capable of inhibiting xanthine oxidase. Finally, the Gram-positive microorganisms Staphylococcus aureus and Corynebacterium diphteriae were found to be sensitive to the majority of the plant extracts, whereas the Gram-negative bacteria Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, and Salmonella typhi were proved to be resistant toward the plant extracts. CONCLUSIONS: It is important to continue investigating our plant kingdom, especially the world tropical reserves as an alternative for finding new or better drugs. It should be essential to follow-up this type of investigation to isolate and elucidate the active principles of the bio-positive plants.

Nitric oxide regulates angiotensin-I converting enzyme under static conditions but not under shear stress

Mechanical forces including pressure and shear stress play an important role in vascular homeostasis via the control of the production and release of a variety of vasoactive factors. An increase in vascular shear stress is accompanied by nitric oxide (NO) release and NO synthase activation. Previously, we have demonstrated that shear stress induces angiotensin-I converting enzyme (ACE) down-regulation in vivo and in vitro. In the present study, we determined whether NO participates in the shear stress-induced ACE suppression response. Rabbit aortic endothelial cells were evaluated using the NO synthase inhibitor L-NAME, and two NO donors, diethylamine NONOate (DEA/NO) and sodium nitroprusside (SNP). Under static conditions, incubation of endothelial cells with 1 mM L-NAME for 18 h increased ACE activity by 27 percent (from 1.000 ± 0.090 to 1.272 ± 0.182) while DEA/NO and SNP (0.1, 0.5 and 1 mM) caused no change in ACE activity. Interestingly, ACE activity was down-regulated similarly in the presence or absence of L-NAME (delta(0 mM) = 0.26 ± 0.055, delta(0.1 mM) = 0.21 ± 0.22, delta(1 mM) = 0.36 ± 0.13) upon 18 h shear stress activation (from static to 15 dyn/cm²). Taken together, these results indicate that NO can participate in the maintenance of basal ACE levels in the static condition but NO is not associated with the shear stress-induced inactivation of ACE

Papel de radicais alquila gerados no metabolismo de derivados de hidrazina na citotoxicidade e transformaçäo de fibroblastos de camundongo transfectados com o proto-oncogene c-myc / Alkyl radicals paper generated in the hidrazine derivatives metabolism in the cytotoxicity and transformation of transfected mouse fibroblasts with c-myc proto-oncogene

Existem diversos derivados de hidrazina com atividade farmacológica, todos apresentando propriedades carcinogênicas em animais experimentais. Muitos derivados mono e dissubstituídos produzem radicais alquila quando da oxidaçäo por sistemas biológicos. Nossos resultados demonstraram que neutrófilos ativados säo capazes de metabolizar derivados de hidrazina mono e dissubstituídos a radicais alquila, detectados por ressonância paramagnética electrônica/captaçäo de spin, sendo caracterizado o papel de mieloperoxidase e de espécies reativas de oxigênio. Na investigaçäo dos mecanismos de toxicidade dos DH, nossos resultados estabeleceram uma correlaçäo entre a citotoxicidade sobre os fibroblastos de camundongo (medida pela inibiçäo da incorporaçäo de [nH]-dT) e a formaçäo de radicais alquila...

Malignant transformation by hydrazine derivatives: a role for carbon-centered radicals?

There are several hydrazine derivatives with pharmacological activity, all of which have carcinogenic properties in experimental animals. Several mono- and disubstituted derivatives have been shown to produce carbon-centered radicals upon oxidation by enzymatic systems such as HbO2' Cytochrome P-450, monoamine oxidases, horseradish peroxidase and myeloperoxidase. Proposed mechanisms of hydrazine metabolism leading to alkylating species are discussed. The in vitro induction of DNA alterations by carbon-centered radicals generated in hydrazine metabolism ascertains the possibility of its occurrence in vivo. Our results, discussed herein, established the induction of cytotoxicity, proliferation and transformation of cultured mouse fibroblasts by systems in which hydrazine-derived alkyl radicals are formed. These studies represent another step towards distinguishing the possible involvement of metabolism-generated carbon-centered radicals in the onset of carcinogenic processes, which reinforces the importance of additional experimental approaches in order to consolidate this hypothesis.

Participaçäo de radicais livres centrados em átomos de carbono na toxicidade de hidrazina / Centered participation free radicals in carbon atoms in the hidrazone toxicity

A produçäo de radicais de carbono "in vivo" durante a biotransformaçäo da hidrazina foi demonstrada por ressonância paramagnética eletrônica, utilizando o método do captador de spin. Eritrócitos de rato também oxidaram a hidrazina, formando radicais de carbono e nitrogênio, além de espécies reativas de oxigênio. Todas estas espécies, possivelmente formadas "in vivo", säo potencialmente causadoras de dano a macromoléculas. Podem, por exemplo, iniciar reaçöes secundárias formando radicais de componentes celulares, como ocorreu com a hemoglobina que foi oxidada a radicais tiil-hemoglobina em eritrócitos tratados com hidrazina. Radicais de carbono formados durante a biotransformaçäo da hidrazina em animais expostos provêm necessariamente de substâncias endógenas e podem ser direta ou indiretamente responsáveis pela modificaçäo (alquilaçäo) de bases no DNA "in vivo"...

DNA alkylation by carbon-centered radicals

1. Over the last two decades, the prevalent view in chemical carcinogenesis has been that most free radicals do not bind to DNA. Recent studies, however, are demonstrating formation of adducts between DNA and free radicals such as hydroxyl radicals and aromatic cation radicals. 2. Within this context, we discuss the recent work from our group demonstrating DNA alkylation by carbon-centered radicals formed during biotransformation of genotoxic hydrazine derivatives both in vitro and in vivo. 3. The mutagenic potential of the identified methyl radical adduct, C8-methylguanine, is discussed, and other possible biological sources of carbon-centered radicals are presented

Acne medicamentosa / Acne medicamentosa

Foram revistos os casos de acne medicamentosa atendidos em um período de 17 anos, sendo encontrados 66/22890 novas consultas (2,9:1.000 novas consultas). O quadro predomina em mulheres, na proporçäo 3,7 para cada homen. As drogas desencadeantes foram principalmente a vitamina B12 (29 casos - 43,9%) e os corticóides(17 - 25,7%); seguem-se iodo, bromo, hidrazida e lítio. Do ponto de vista clínico foram avaliados aspectos relacionados com duraçäo da erupçäo, presença de prurido, morfologia e distribuiçäo das lesöes, relaçäo com acne vulgar. Do ponto de vista histopatológico, foi discutida a possível sede de lesäo inicial, no folículo piloso

Avaliaçäo de cem casos de tuberculose pulmonar / Evaluation of 100 cases of pulmonary tuberculosis

Os autores analisaram a evoluçäo baciloscópica normal dos escarros de cem pacientes portadores de tuberculose pulmonar virgens de tr atamento, com baciloscopia positiva no diagnóstico e que obtiveram alta por cura ao fim dos seis meses de quimioterapia com o esquema rifampicina, hidrazida e pirazinamida. Obtiveram várias informaçöes como os resultados das baciloscopias diagnósticas, que foram positivas uma cruz em 43% dos casos e positivas duas cruzes em 45% dos casos. A maior percentagem de negativaçäo dos escarros, 89% ocorreu nos dois primeiros meses de tratamento. Concluido o tratamento o escarro havia desaparecido em 50% dos pacientes. As repositivaçöes säo infreqüentes e ocorrem principalmente: nos últimos meses, 4§ e 5§ meses, do tratamento. O incentivo à continuidade do tratamento nas reconsultas evita as repositivaçöes dos escarros, e a busca dos faltosos abreviam a duraçäo das repositivaçöes, evitando e diminuindo o contágio as pessoas sadias. Estas informaçöes contribuem para o aperfeiçoamento do combate a tuberculose

Decrescimo da populacao bacteriana eliminada por pacientes com tuberculose pulmonar tratados com esquema de curta duracao. / Decrease of bacterial population in patients with pulmonary tuberculosis treated with short-term chemotherapy

Foram estudados 10 pacientes tuberculosos, com baciloscopia e cultura positivas, tratados com esquema de curta duracao constituido de rifampicina, hidrazida e etambutol ou pirazinamida. A avaliacao da populacao bacteriana, antes e depois da quimioterapia foi feita por dois metodos quantitativos: baciloscopia direta do escarro, apos coloracao pelo descontaminacao pelo metodo de Petroff. A populacao bacteriana inicial variou entre 600.000 e 51.200.000 bacilos por ml e 45.450 e 1.511.250 colonias por ml de escarro. O decrescimo desta populacao nos dois subsequentes ao inicio do tratamento nao esta relacionada com a populacao inicial, seja ela alta ou baixa. Entretanto, pela baciloscopia, observa-se que o primeiro exame negativo e o ultimo positivo ocorreram mais precocemente no grupo de populacao baixa do que na alta. Nos primeiros 10 dias de tratamento verificou-se, em media, uma reducao na populacao bacteriana eliminada igual a 33% da inicial, atingindo 2,2% nos primeiros 30 dias a contagem de colonias, nos mesmos periodos, reduziu-se a 31,4% e 1% respectivamente. O percentual de colonicas sobre o numero total de bacilos, expressao da viabilidade bacilar, era de 3,6% antes da medicacao, caindo para 0,3% apos 30 dias de tratamento

Levodopaterapia no parkinsonismo.Carbidopa versus benserazida. / Levodopa therapy in parkinsonism. Carbidopa versus benserazide

Os autores referem-se a experiencia pessoal no emprego da levodopa associado aos inibidores da descarboxilase periferica em 66 casos de sindrome parkinsoniana, no periodo de nove anos. Entre os inibidores da descarboxilase periferica foram utilizadas a benserazida e a carbidopa nas proporcoes 4:1 e 10:1, respectivamente.Baseando-se em indices na avaliacao quantitativa, analisam e comentam os resultados obtidos, comparando-os entre si e com os colhidos na literatura. Detem-se, em particular, na eficacia dos medicamentos sobre as manifestacoes clinicas, nas repercussoes nos diferentes orgaos e sistemas e, ainda, nos seus multiplos efeitos adversos