Pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats / 中国中药杂志

This work aimed to investigate the differences of pharmacokinetics and tissue distribution of four alkaloids in Ermiao Pills and Sanmiao Pills in normal and arthritic model rats. The rat model of arthritis was established by injecting Freund's complete adjuvant, and ultra-high performance liquid chromatography-tandem mass spectrometry(UPLC-MS/MS) in the positive ion multiple reaction monitoring(MRM) mode was used for the determination of four alkaloids in plasma and tissues of normal and arthritic rats after administration of Ermiao Pills and Sanmiao Pills, respectively. The differences in pharmacokinetics and tissue distribution of the four active components were compared, and the effect of Achyranthis Bidentatae Radix on the major components of Sanmiao Pills was explored. This study established an UPLC-MS/MS for simultaneous determination of four alkaloids, and the specificity, linearity, accuracy, precision, and stability of this method all met the requirements. Pharmacokinetics study found that as compared with normal rats, the AUC and C_(max) of phellodendrine, magnoflorine, berberine and palmatine in model rats were significantly decreased after administration of Ermiao Pills, the clearance rate CL/F was significantly increased, and the distribution and tissue/plasma concentration ratio of the four alkaloids in the liver, kidney, and joint were significantly reduced. Achyranthis Bidentatae Radix increased the AUC of phellodendrine, berberine, and palmatine, reduced the clearance rate, and significantly increased the distribution of the four alkaloids in the liver, kidney, and joints in arthritic rats. However, it had no significant effect on the pharmacokinetics and tissue distribution of the four alkaloids in normal rats. These results suggest that Achyranthis Bidentatae Radix may play a guiding role in meridian through increasing the tissue distribution of effective components in Sanmiao Pills under arthritis states.

Effects of gut microbiota on five absorbed components of Berberis kansuensis in rat serum by HPLC-QqQ-MS / 中国中药杂志

To elucidate the absorption and metabolism of alkaloids in Berberis kansuensis in vivo, a high performance liquid chromatography-triple quadrupole mass spectrometry(HPLC-QqQ-MS) method was developed to qualitatively and quantitatively analyze the absorption components in rat serum in multiple-reaction monitoring mode. The mobile phase consisted of 0.1% formic acid and acetonitrile with a gradient elution mode. In addition, to investigate the effects of gut microbiota on five absorbed components of B. kansuensis in rat serum, diabetic rat and pseudo germ-free diabetic rat models were established, and partial least squares discriminant analysis and One-way ANOVA were used to study the content differences of five components among different groups. In this study, a HPLC-QqQ-MS method for quantitative analysis of five components in rat serum after oral administration of B. kansuensis was established for the first time. It was found that there were differences in the five constituents in rat serum between different groups. By comparing the normal group with the diabetic model group, we found that the absorption and metabolism capacities of berberine and magnoflorine were different under the health and pathological conditions. It was also found that the serum levels of berberine, magnoflorine and jatrorrhizine in pseudo germ-free diabetic rats were significantly lower than those in diabetic rats, indicating that gut microbiota plays an important role in the metabolism of alkaloids of B. kansuensis in vivo. These results provide a good reference for clarifying the active ingredients of B. kansuensis in the treatment of diabetes.

Síntese, avaliação biológica e modelagem molecular de potenciais antitumorais análogos da sanguinarina planejados por simplificação molecular / Synthesis, biological evaluation and molecular modeling of potential antitumors analogues from sanguinarine designed by molecular simplification

A sanguinarina é um alcaloide capaz de inibir Bcl-xL, uma proteína antiapoptótica que se encontra superexpressa em linhagens tumorais e que está frequentemente relacionada à resistência destas frente a quimioterápicos antineoplásicos. No intuito de identificar potenciais agentes antitumorais, o objetivo deste trabalho foi sintetizar três séries de análogos da sanguinarina planejados por simplificação molecular e avaliar sua atividade biológica. Dez N-benzil-naftil-aminas (3a-e; 4a-e) e dez arilisoquinolinas (6a-e; 7a-e) foram sintetizadas em duas a três etapas reacionais, utilizando-se métodos de aminação redutiva e acoplamento de Suzuki. Insucesso na etapa de reação de Heck impossibilitou a síntese da terceira série, benzofenantridínica, apesar de testadas diversas condições reacionais. Avaliação da citotoxicidade em linhagens de glioblastoma U87MG revelou que a série N-benzilnaftil-amina apresenta melhor atividade quando comparada às aril-isoquinolinas, sendo para ambas, observada atividade superior à temozolamida, principal fármaco para o tratamento de glioblastoma. Estudos em linhagem não tumorigênica MRC-5 demonstraram que os análogos foram significativamente superiores à sanguinarina em relação à seletividade. Os compostos mais mais promissores, 4a e 6e, induziram morte celular por apoptose e causaram despolarização da membrana mitocondrial, indicando morte apoptótica pela via extrínseca. Ademais, 4a interrompeu o ciclo interrompeu o ciclo celular na fase G2/M, indicando que o mesmo seria um agente ciclo celular específico. Simulações de dinâmica molecular sugerem que os compostos interagem com a proteína Bcl-xL principalmente por interações hidrofóbicas, e que o composto 4a apresentaria afinidade com o alvo semelhante à sanguinarina, embora esta tenha apresentado atividade superior em células U87. Perspectivas incluem estudos das vias de indução de morte celular, além da expansão do painel de células. Conclui-se, portanto, que os análogos da sanguinarina representam um arcabouço a ser explorado pelos químicos medicinais no desenvolvimento de potenciais antineoplásico

Sanguinarine is an alkaloid able to inhibit Bcl-xL, an antiapoptotic protein which is overexpressed in tumor cells and related to their resistance against antineoplastic chemotherapy. Regarding to develop potential antitumor agents, the aim of this work was the synthesis of three series of sanguinarine analogues designed by molecular simplification and their biological evaluation. Ten N-benzyl-naphtyl-amines (3a-e; 4ae) and ten aryl-isoquinolines (6a-e; 7a-e) were synthesized in two or three reaction steps through reductive amination and Suzuki coupling. Failure about Heck-type reaction had impaired the synthesis of the thirth series, benzophenanthridine, although several conditions were tested. Cytotoxicity evaluation against U87MG glioblastoma cell line showed that N-benzyl-naphtyl-amines are more active than aryl-isoquinolines and both series were superior to temozolamide, the main drug for glioblastoma treatment. Tests against non-tumorigenic cell MRC-5 indicated that the analogues were significantly superior to sanguinarine regarding selectivity. The most promising compounds, 4a e 6e, induced cell death by apoptosis and mitochondrial membrane depolarization, indicating apoptotic death by extrinsic pathway. 4a provide cell cycle arrest at G2/M phase, suggesting that it is a specific cell cycle agent. Molecular dynamics suggested that compounds interact with Bcl-xL mainly by hydrophobic interactions and 4a has affinity to the protein like sanguinarine, although the last showed superior activity against U87 cells. Perspectives include mechanistics studies about cell death pathway and expanding cell panel. In conclusion, sanguinarine anlogues represent a scaffold to be explored by medicinal chemists to the development of potential antitumor agent

Tissue distribution & elimination of capsaicin, piperine & curcumin following oral intake in rats.

Background & objectives: Curcumin, capsaicin and piperine - the bioactive compounds present in spices-turmeric (Curcuma longa), red pepper (Capsicum annuum) and black pepper (Piper nigrum) respectively, have a considerable portion of structural homology. Tissue distribution and elimination of these three structurally similar bioactive compounds was examined following their oral intake in rats. Methods: Separate sets of animals (150 - 160 g) were orally administered the three spice principles at dosages of 30 mg (capsaicin), 170 mg (piperine) and 500 mg (curcumin) / kg body weight. The tissue concentrations of administered spice compounds were determined by HPLC. Results: Maximum distribution of 24.4 per cent of administered capsaicin was seen at 1 h, while no intact capsaicin was detectable after 4 days. Absorption of capsaicin was about 94 per cent and very rapid relative to other two compounds. A maximum of 10.8 per cent of administered piperine was seen in tissues at 6 h. Absorption of the administered piperine was about 96 per cent. Curcumin concentration was maximum in the intestine at 1 h; maximum in blood at 6 h and remained at significantly higher level even at 24 h. About 63.5 per cent of the curcumin dose was absorbed. Only a small portion of the administered dose of capsaicin (< 0.1%) and curcumin (0.173 %) was excreted in urine, whereas piperine was not detectable in urine. Enhanced bioavailability of curcumin was evidenced when the same was orally administered concomitant with piperine. Intestinal absorption of curcumin was relatively higher when administered concomitantly with piperine, and it stayed significantly longer in the body tissues. Intact curcumin was detected in brain at 24, 48 and 96 h with a maximum at 48 h. Conclusions: Considerable difference exists in the bioavailability of the three test compounds. Curcumin could be traced in the brain following its administration. Bioavailability of curcumin can be improved by co-administration with piperine.

Cuantificación de los alcaloides de brugnansia arborea (floripondio) y estudio de su efecto farmacológico sobre la función memoria del SNC / Brugnansia arborea (floripondio) alkaloids cuantification and pharmacologic effect study over memory function of Central Nervous System

Este trabajo consiste en la cuantificación de los alcaloides presentes en hojas de brugmansia arborea "floripondio" habiéndose preparado un extracto total alcoholico, y a partir de este un extracto clorofórmico alcaloidico. Su aisló escopolamina de la atropinattiosciamina mediante TLC y se cuantificó espectrofotometicamente a 650nm, encontrándose 0.9 por ciento de alcaloides. Con ambos extractos una vez eliminados los solventes. Se estudió los efectos farmacológicos de dichos alcaloides sobre la memoria. Se utilizó 20 ratones de 3 meses y más de 18 g de peso, que fueron adiestrados en un laberinto durante 7 semanas, lográndose rapidez y que no cometieran errores. A 10 ratones se les administró el extracto total y a 10 el extracto alcaloidico, en cantidad equivalente a 300 mg/k peso de alcaloides, 5 de cada grupo recorrieron el laberinto en fase exitatoria y 5 en fase depresora, observándose que en todos los casos cometieron errores e incrementaron su tiempo de recorrido, lo cual estaba acentuado en los ratones con extracto alcaloidico y en aquellos que se encontraban en fase depresora. Se concluye que los alcaloides presentes afectan la función memoria del SNC, siendo mayor esta alteración con los alcaloides puros, y en la fase depresora.

Efecto producido por la fracción de alcaloides de Mimosa tenuiflora (tepescohuite) sobre el reflejo peristáltico del íleon de cobayo / The effect produced by the alkaloidal fraction of Mimosa tenuiflora (tepescohuite) upon the peristaltic reflex in quinea pig's ilium

De la corteza de tepescohuite, Mimosa tenuiflora (Willd.)Poir. Se obtuvo una fracción de alcaloides compuesta por una indolalquilamina acompañada de otras tres bases monoritarias. Se demuestra que esta fracción es la responsable del efecto inhibidor del reflejo peristáltico descrito en un trabajo anterior