ABSTRACT Melochia villosa (Mill.) Fawc. & Rendle is one of the species belonging to the Sterculiaceae family that has been little studied phytochemically. The objective of the research was to perform phytochemical analysis and characterization of the alcoholic and ethereal extracts of the stem of this species, in order to identify secondary metabolites present in this botanical part with properties of application as possible drugs, as well as contributing to the chemotaxonomy of the species. For structural elucidation, techniques such as infrared spectroscopy, nuclear magnetic resonance, and gas chromatography coupled to mass spectrometry were used. In the chromatographic fractionation of the alcoholic extract, nine fractions were obtained, of which only fractions 3, 5, 8 and 9 could be tested, with antifungal activity against Fusarium vercillioides, and F. poae for fractions 3 and 9 respectively. Fractions 5 and 8 produced lethality on nauplios of Artemia salina. Eight fractions were obtained from the fractionation of the ethereal extract, mostly with the presence of unsaturated sterols, where fractions II, VII and VIII lethal activity. The presence of the carbonyl group and the ester bond was evidenced, as well as the diisoctylic ester of 1,2-benzenedicarboxylic acid. The presence of hexadecanoic acid, mono-(2-ethylhexyl) ester of 1,2-benzenedicarboxylic acid, undecyl ester of undecanoic acid, as well as cholestan-3-one and spinasterone, both compounds derived from unsaturated sterols, were also observed.

RESUMEN Melochia villosa (Mill.) Fawc. & Rendle es una de las especies pertenecientes a la familia Sterculiaceae que fitoquímicamente ha sido muy poco estudiada. El objetivo de la investigación fue identificar metabolitos secundarios presentes en el tallo de M. villosa con propiedades de aplicación como posibles fármacos y contribuir con la quimiotaxonomía de la especie. Para la elucidación estructural se utilizaron técnicas como la espectroscopia infrarroja, resonancia magnética nuclear, y cromatografía de gases acoplada a espectrometría de masas. En el fraccionamiento cromatográfico del extracto alcohólico se obtuvieron nueve fracciones, de las cuales se realizaron ensayos con las fracciones 3, 5, 8 y 9. Las fracciones 3 y 9 mostraron actividad antifúngica contra Fusarium vercillioides y F. poae. Las fracciones 5 y 8 produjeron letalidad en nauplios de Artemia salina. Del fraccionamiento del extracto etéreo se obtuvieron ocho fracciones, en su mayoría con presencia de esteroles insaturados, donde las fracciones II, VII y VIII con actividad letal. Se evidenció la presencia del grupo carbonilo y el enlace éster, así como el éster diisoctilico del ácido 1,2-bencenodicarboxílico. También se observó la presencia del ácido hexadecanoico, éster mono (2-etilhexílico) del ácido 1,2-bencenodicarboxílico, éster undecílico del ácido undecanoico, así como colestan-3-ona y la spinasterona, ambos compuestos derivados de esteroles insaturados.

Clofazimina e laritromicina são utilizadas no tratamento da hanseníase e em infecções causadas pelo complexo Mycobacterium avium. Devido à escassez de dados sobre a toxicidade de esquemas terapêuticos que associam estes fármacos, este estudo teve por objetivo avaliar os efeitos adversos desta terapia, em ratos machos Wistar, por meio da determinação da contagem global e específica de leucócitos e ensaios de fagocitose e burst oxidativo de neutrófilos por citometria de fluxo. Houve aumento do número de leucócitos (dose múltipla) e de células polimorfonucleares (doses única e múltipla) nos grupos tratados com claritromicina em monoterapia ou associada à clofazimina e redução das células mononucleares, em doses única e múltipla, nos mesmos grupos. Os fármacos parecem inverter a proporção entre células mono e polimorfonucleares. Observou-se aumento do burst oxidativo nos animais tratados com os fármacos isolados ou associados. Concluindo, clofazimina e claritromicina provocam alterações leucocitárias e os resultados podem contribuir para melhor entendimento dos mecanismos relacionados aos efeitos da administração dos fármacos em associação.

Clofazimine and clarithromycin are used to treat leprosy and infections caused by Mycobacterium avium complex. Little data on the toxicity of co-administration of these two drugs are available. Here we evaluated the potential adverse effects of polytherapy with these two drugs in male Wistar rats by determining WBCs counts and other blood cell counts, neutrophilic phagocytosis, and burst oxidative, by flow cytometry. We observed an increase in WBCs, in multiple-dose regimens, and in polymorphonuclear cells, in both single- clarithromycin only and multiple dose regimens. We also observed a reduction in mononuclear cell counts in single and multiple doses. The drugs seem to reverse the mononuclear and polymorphonuclear cell ratio. An increase in oxidative burst was observed in animals treated with the drugs administered either individually or combined. In conclusion, clofazimine and clarithromycin change WBCs counts. Our results may contribute for a better understanding of the mechanisms related to the effects of co-administrating the two drugs.

Claritromicina e clofazimina têm sido utilizadas no tratamento da hanseníase, tuberculose e infecções causadas pelo complexo Mycobacterium avium. Como os dados sobre a toxicidade de esquemas terapêuticos que incluem estes fármacos são escassos, este estudo teve como objetivo determinar os efeitos adversos destas terapias, por meio da avaliação dos parâmetros hematológicos, hemostáticos e bioquímicos. Os fármacos foram administrados em ratos machos Wistar, em monoterapia, em regime de doses única e múltipla. Claritromicina provocou aumento de leucócitos mono e polimorfonucleares. Ambos os fármacos inverteram a proporção entre células mono e polimorfonucleares e provocaram aumento do número de células polimorfonucleares e células em degeneração. Clofazimina e claritromicina prolongaram o tempo de protrombina e claritromicina também prolongou o tempo de tromboplastina parcial ativa. Claritromicina causou aumento de bilirrubinas total e direta e, ambos os fármacos, elevaram os níveis plasmáticos de gama-glutamiltransferase. Portanto, clofazimina e claritromicina induzem alterações hematológicas, hemostáticas e hepáticas.

Clarithromycin and clofazimine have been used to treat leprosy, tuberculosis and infections caused by the Mycobacterium avium complex. Since there is a scarcity of data on the toxicity of therapeutic regimens that include these drugs, this study had the aim of determining the adverse effects of these therapies, through evaluation of hematological, hemostatic and biochemical parameters. The drugs were administered to male Wistar rats, as monotherapy, in regimens of single and multiple doses. Clarithromycin caused increases in the numbers of mononuclear and polymorphonuclear leukocytes. Both of the drugs inverted the proportions between mononuclear and polymorphonuclear cells and increased the numbers of polymorphonuclear cells and degenerating cells. Clofazimine and clarithromycin prolonged the prothrombin time and clarithromycin also prolonged the activated partial thromboplastin time. Clarithromycin caused increases in total and direct bilirubin. Both of the drugs increased the plasma levels of gamma-glutamyltransferase. Therefore, clofazimine and clarithromycin induce hematological, hemostatic and hepatic changes.

Immunosuppressive therapy aims to protect transplanted organs from host responses. The success achieved during the last two decades in patient and graft survival is mainly related to the development and clinical use of efficacious immunosuppressive drugs. Nevertheless, the challenge of achieving a balance of adequate graft protection while minimizing the adverse consequences of excessive immunosuppression in the long-term continues. Current maintenance immunosuppression for renal transplant recipients generally consists of a calcineurin inhibitor plus an adjunctive antiproliferative agent, and steroids. The addition of induction therapy with a variety of monoclonal or polyclonal antibodies provides a more potent immunosuppression and its use is more relevant in patients with a high immunological risk. More recently, mammalian target of rapamycin inhibitors have been incorporated in different schemes proven its efficacy in a number of protocols. The incidence of acute rejection is now in its lower historical percentage and excellent results are reported from many transplant centers all over the world due mainly to a judicious combination of these drugs evaluated through many clinical studies. However, long-term use of immunosuppressive drugs convey inherent risks which translate in an increase of cancers and infections, among others. Ongoing investigations and clinical protocols involving new immunosuppressive drugs and biological agents are yielding important information on how to obtain tolerance or the nearest to this goal. Furthermore, there should be a continuous improvement in patient and graft survival, as the use of different immunosuppressive agents for induction and maintenance are individualized (adapted to each patient).

La terapia inmunosupresora empleada en receptores de trasplante tiene el objetivo de proteger el injerto de la respuesta inmunoloógica generada por parte del huésped. El éxito logrado en el transcurso de las últimas dos décadas en la supervivencia de receptores e injertos, ha dependido en gran medida del desarrollo y uso clínico de fármacos inmunosupresores de probada eficacia. Empero el enorme beneficio que han representado, el reto continúa para mantener un balance adecuado entre la protección inmunológica del injerto y la minimización de las consecuencias adversas derivadas de su indispensable utilización a largo plazo. La terapia inmunosupresora actual de mantenimiento en receptores de trasplante renal consiste habitualmente en la administración de un inhibidor de calcineurina, un agente antiproliferativo, como adyuvante, y esteroides. La adición de terapia de inducción, con modalidades biológicas de anticuerpos mono o policlonales, proveen un mayor grado de inmunosupresión y su empleo adquiere gran relevancia en pacientes con mayor riesgo inmunológico. En una etapa más reciente, los inhibidores del blanco de rapamicina han sido introducidos en varios esquemas después de probar su eficacia en múltiples protocolos. La incidencia de rechazo agudo ha alcanzado sus más bajos índices históricos y los resultados alcanzados en muchos centros de trasplante del mundo son excelentes, derivados en gran medida de la combinación juiciosa de estos fármacos, evaluados en una gran variedad de estudios. El empleo crónico de estos fármacos conlleva riesgos inherentes que se traducen en riesgos incrementados para el desarrollo de infecciones y neoplasias, entre otros. Así, mientras esperamos nuevos avances derivados de una gran profusión de estudios de investigación y protocolos clínicos con nuevas drogas inmunosupresoras y compuestos biológicos, encaminados a obtener tolerancia o lo más cercano a este propósito, deberemos ser capaces de continuar mejorando la vida funcional de la mayoría de los injertos y, desde luego, de sus receptores, "individualizando" (de acuerdo con los riesgos de cada paciente) el empleo de los agentes inmunosupresores disponibles para inducción y mantenimiento.

From a total of 560 different epileptics visited during 16 months, we have practiced 140 plasmatic dosifications of antiepileptic drugs according to EMIT technic. The antiepileptic drugs studied were: PB, DPH, PRM, VPA, CBZ and ESM. In this study only the 70 patients treated with PB in monotherapy or combined with DPH, CBZ, VPA and PRM are considered. From the 70 patients, 45 have been controlled; from them 21 (46,5%) did not reach efficient levels from anyone of the used antiepileptics. From the 70 patiens 25 have been partially or bad controlled, 20 of them (80%) had PB in efficient levels, 13 (52%) had the other antiepileptic in efficient levels, 12 (47%) had both antiepileptics in efficient levels and 4 (16%) had no antiepileptic drug in efficient levels in spite of using the efficient dose in mg/Kg/day. The conclusions of this results are: - we reached a good effect by using PB alone or combined under the considered efficient levels in a 46.5% of the patients; - the bad controlled patients, kept on being bad controlled in spite of having 80% of them PB, the other antiepileptic or both in efficient levels.

De un total de 560 epilépticos diferentes visitados en el transcurso de 16 meses, hemos practicado 140 dosificaciones plasmáticas de fármacos antiepilépticos utilizando la técnica EMIT. Los antiepiléticos que hemos dosificado han sido: PB, DPH, PRM, VPA, CBZ y ESM. En este trabajo hemos revisado unicamente los 70 pacientes que tomaban PB en monoterapia ó asociado a DPH, CBZ, VPA y PRM. De los 70 pacientes 45 estaban bien controlados. De entre ellos 21 (46,5%) no llegaban a niveles eficaces de ninguno de los antiepilépticos utilizados, y sin embargo hemos conseguido un buen efecto terapeutico tanto en mono como biterapia. De estos mismos 70 pacientes, 25 estaban parcialmente ó mal controlados. De entre ellos 20 (80%) tenían el PB en niveles eficaces, 13 (52%) tenían el otro antiepiléptico en niveles eficaces, 12 (47%) tenían ambos antiepilépticos en niveles eficaces y 4 (16%) no tenían ningún antiepiléptico en niveles eficaces a pesar de utilizar en todos, la dósis media considerada como eficaz y expresada en mg/Kg/día.