Analysis of post-market adverse events of istradefylline: a real-world study base on FAERS database.

Analyze the adverse event (AE) signals of istradefylline based on the FAERS database. By extracting large-scale data from the FAERS database, this study used various signal quantification techniques such as ROR, PRR, BCPNN, and MGPS to calculate and evaluate the ratio and association between istradefylline and specific AEs. In the FAERS database, this study extracted data from the third quarter of 2019 to the first quarter of 2023, totaling 6,749,750 AE reports. After data cleansing and drug screening, a total of 3633 AE reports related to istradefylline were included for analysis. Based on four calculation methods, this study unearthed 25 System Organ Class (SOC) AE signals and 82 potential preferred terms (PTs) related to istradefylline. The analysis revealed new AEs during istradefylline treatment, including reports of Parkinsonism hyperpyrexia syndrome (n = 3, ROR 178.70, PRR 178.63, IC 1.97, EBGM 165.63), Compulsions (n = 5, ROR 130.12, PRR 130.04, IC 2.53, EBGM 123.02), Deep brain stimulation (n = 10, ROR 114.42, PRR 114.27, IC 3.33, EBGM 108.83), and Freezing phenomenon (n = 60, ROR 97.52, PRR 96.76, IC 5.21, EBGM 92.83). This study provides new risk signals and important insights into the use of istradefylline, but further research and validation are needed, especially for those AE that may occur in actual usage scenarios but are not yet explicitly described in the instructions.

Eficacia y seguridad de obinutuzumab más clorambucil en pacientes adultos mayores de 65 años con leucemia linfocítica crónica sin tratamiento sistémico previo que no son tributarios a fludarabina / Efficacy and safety of obinutuzumab plus chlorambucil in adult patients older than 65 years with chronic lymphocytic leukemia without prior systemic treatment who are not candidates for fludarabine

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de obinutuzumab más clorambucil (O + C) en comparación con rituximab más clorambucil (R + C) en pacientes adultos mayores de 65 años con leucemia linfocítica crónica (LLC) sin tratamiento sistémico previo que no son tributarios a fludarabina. La leucemia linfocítica crónica (LLC) es una neoplasia caracterizada por una acumulación progresiva de linfocitos B monoclonales en sangre periférica. Constituye la leucemia más común en adultos en los países occidentales (edad media para el diagnóstico de 70 años), y representa el 25 % al 30 % de todas las leucemias. Aproximadamente, la mediana de sobrevida global (SG) es de 10 años y la tasa de SG del 80 %. El inicio del tratamiento del paciente con LLC depende de la progresión y del estado general de salud del individuo, iniciándose terapia bajo criterios específicos. El Petitorio Farmacológico de EsSalud dispone de fludarabina, clorambucil y rituximab para el tratamiento sistémico de primera línea de los pacientes mayores de 65 años con LLC que cuentan con indicación de inicio de tratamiento sistémico. No obstante, fludarabina cuenta con contraindicaciones de uso en su inserto, entre los que se listan: la hipersensibilidad al principio activo o excipientes, enfermedad renal crónica avanzada, anemia hemolítica descompensada, y la lactancia. En ese sentido, en los pacientes que no son tributarios al tratamiento con fludarabina, en EsSalud se opta por el uso de rituximab (R) asociado a clorambucil (C) (R + C). No obstante, los especialistas han sugerido la evaluación de uso de obinutuzumab (O) asociado a clorambucil (O + C), bajo la hipótesis de que éste tendría un mejor perfil de eficacia y seguridad que (R + C), como tratamiento sistémico de primera línea en la población de pacientes mayores de 65 años con LLC que no son tributarios de fludarabina. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia científica sobre la eficacia y seguridad de (O + C), en comparación con (R + C), en pacientes adultos mayores de 65 años con LLC sin tratamiento sistémico previo que no son tributarios a fludarabina. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como FDA, EMA, y DIGEMID en el Perú. Se realizó tanto una búsqueda sistemática en las principales bases de datos, tales como MEDLINE vía PubMed y en Cochrane Library. Asimismo, se realizó una búsqueda manual en las páginas web de grupos dedicados a la investigación y educación en salud que elaboran GPC y ETS: National Institute for Health and CareExcellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Haute Authorité de Santé (HAS), Institute for Quality and Efficiency in HealthCare (IQWiG), Institute for Clinical and EconomicReview (ICER), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la Organización Mundial de la Salud (OMS), el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de las GPC de las principales sociedades o instituciones especializadas en cáncer, tales como el Instituto Nacional de Enfermedades Neoplásicas (INEN) del Perú, National Comprehensive Cancer Network (NCCN), la American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO), American Society of Hematology (ASH), y The European Hematology Association (EHA). Adicionalmente, se buscaron ensayos clínicos en desarrollo o que no hayan sido publicados aún en la página web www.clinicaltrials.gov que contengan estudios acerca de la tecnología evaluada y así disminuir el sesgo de publicación. Finalmente, se consideró extraer información con una estrategia de "bola de nieve" mediante la revisión de las listas de referencias de las revisiones sistemáticas, estudios primarios y revisiones narrativas seleccionadas que sean relevantes para responder a la pregunta PICO del presente dictamen preliminar. RESULTADOS: En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: En el presente documento, se evaluó la evidencia científica disponible hasta la actualidad sobre la eficacia y seguridad de (O + C), en comparación con (R + C), en pacientes adultos mayores de 65 años con LLC sin tratamiento sistémico previo que no son tributarios a fludarabina. La evidencia científica identificada para la presente evaluación corresponde a dos GPC (NCCN y ESMO), dos ETS (NICE y pCODR) y un ECA de fase 3 denominado CLL11. Los panelistas de las GPC de NCCN y ESMO recomiendan, en general, el uso de (O + C) y (R + C) como alternativas terapéuticas para los pacientes adultos mayores de 65 años con LLC sin tratamiento sistémico previo, sin las mutaciones del(17p) o TP53, con una alta calidad de evidencia. El panel de la GPC de NCCN establece como tratamiento de preferencia el uso de (O + C). Ambos paneles basaron sus recomendaciones en los beneficios que a su criterio se habría evidenciado con (O + C) y (R + C) en el desenlace de SLP en el ECA CLL11. Los comités que elaboraron las ETS de NICE y pCODR recomendaron el empleo de (O + C) para pacientes con LLC sin tratamiento sistémico previo que no pueden recibir terapias basadas en fludarabina. Ambas ETS basaron sus recomendaciones en los beneficios que a su criterio se observó en el desenlace de SLP en el ECA CLL11. Además, NICE señaló que los análisis económicos mostraron que (O + C) era un tratamiento costo-efectivo en comparación con (R + C) para el sistema de salud inglés. Por otro lado, el comité de pCODR argumentó que el esquema (O + C), comparado con (R + C), no ofrecía beneficio adicional en la SG y calidad de vida; pero sí observó diferencias favorables al compararse con (C) en monoterapia. Estos escenarios deben ser interpretados tomando en cuenta las diferencias entre los sistemas de salud inglés y canadiense con el sistema de salud peruano al cual pertenece EsSalud, por tratarse de diferentes contextos económicos y sanitarios. Las recomendaciones de las GPC y ETS incluidas en este dictamen se apoyan en los resultados del ECA CLL11; el cual es un ensayo clínico fase 3, multicéntrico, de etiqueta abierta cuyo objetivo fue comparar la eficacia y seguridad de (O + C) con los esquemas de (R + C) y (C) en monoterapia en pacientes adultos con LLC sin tratamiento sistémico previo. La población de interés de este ECA es más amplia que la planteada en la pregunta PICO del presente dictamen preliminar; por lo tanto, sus resultados deben tomarse como evidencia indirecta. Se desconoce qué proporción de pacientes del ECA CLL11 corresponde a la población de interés del presente dictamen. Los resultados disponibles a la fecha muestran que, luego de una mediana de seguimiento de 59.4 meses, la SG26 y la calidad de vida de los esquemas (R + C) y (O + C) eran similares. Sin embargo, el análisis de los EA mostró que (O + C) tiene un perfil de seguridad desfavorable en comparación con (R + C), dado que presentó una mayor proporción de EA totales, EA de grado 3 a 5, y EA serios. El diseño de etiqueta abierta del ECA CLL11 introduce riesgo de sesgo de realización y de detección en los desenlaces de eficacia y seguridad. Además, la alta proporción de uso de terapias subsecuentes en los grupos (O + C) y (R + C) -las cuales quedaron a criterio del investigador- aumenta la incertidumbre sobre la existencia de verdaderas diferencias entre los grupos de tratamiento en evaluación. Por último, cabe incidir en el hecho del alto riesgo de error del tipo I en los análisis del ECA CLL11, al evidenciarse múltiples comparaciones estadísticas para el desenlace de interés del presente dictamen (SG), para el cual no se llevaron a cabo procedimientos de ajuste por multiplicidad. De este modo, la evidencia disponible a la fecha, sugiere que el balance riesgo-beneficio sería desfavorable con (O + C), en comparación con (R + C), en la población de interés del presente dictamen preliminar. Esto porque los resultados del ECA CLL11 no han mostrado que (O + C) ofrezca un beneficio adicional, en comparación con (R + C), respecto a los desenlaces de eficacia de SG y calidad de vida, en la población total del estudio. Mientras que, los análisis de los EA mostraron que (O + C) tendría un peor perfil de seguridad que (R + C), en la población total del estudio. En se sentido, no es posible sustentar técnicamente una recomendación favorable para (O + C) en la población de interés del presente dictamen preliminar. Además, se debe tener en cuenta que las GPC también recomiendan el uso de esquemas basados en (R + C) como alternativas terapéuticas para una población similar a la población de interés del presente dictamen, estando estos medicamentos actualmente disponibles en la institución. Por lo expuesto, el IETSI no aprueba el uso de (O + C) en pacientes adultos mayores de 65 años con LCC sin tratamiento sistémico previo que no son tributarios a fludarabina.

Duvelisib for the treatment of chronic lymphocytic leukemia.

INTRODUCTION: Duvelisib, a first in class, oral, dual PI3 k-delta/gamma inhibitor recently received FDA approval for previously treated CLL (chronic lymphocytic leukemia)/SLL (small lymphocytic lymphoma) and follicular lymphoma. Data coming from the phase III 'DUO' trial, in fact, showed a superior progression-free survival (PFS) in CLL patients treated with duvelisib compared to ofatumumab. AREAS COVERED: This review provides analysis of the mechanism of action of duvelisib and includes the rationale for the use of double inhibition. The authors also give their clinical experience with duvelisib. Overall, despite the high efficacy of the drug, some concern remains on duvelisib-related adverse events leading to treatment interruption in a significant proportion of patients. EXPERT OPINION: Considering the unmet need of salvage therapies in patients failing BTK and/or Bcl2 inhibitors, treatment with duvelisib represents a new valid option in the CLL therapeutic armamentarium. Therefore, the correct management of adverse events with early treatment suspension, dose reductions and prompt supportive treatment could help to manage treatment, thus improving patient outcome. Finally, the association of duvelisib with other targeted therapies, such as ibrutinib or venetoclax, could allow clinicians to capitalize on the synergistic activity of these agents.

Safety of Short-Term Supplementation with Methylliberine (Dynamine®) Alone and in Combination with TeaCrine® in Young Adults.

Methylliberine (Dynamine®; DYM) and theacrine (Teacrine®; TCR) are purine alkaloids purported to have similar neuro-energetic effects as caffeine. There are no published human safety data on DYM, and research on TCR is limited. The purpose of this study was to examine the effect of four weeks of DYM supplementation with and without TCR on cardiovascular function and blood biomarkers. One-hundred twenty-five men and women (mean age 23.0 yrs, height 169.7 cm, body mass 72.1 kg; n = 25/group) were randomly assigned to one of five groups: low-dose DYM (100 mg), high-dose DYM (150 mg), low-dose DYM with TCR (100 mg + 50 mg), high-dose DYM with TCR (150 mg + 25 mg) , and placebo. Regardless of group and sex, significant main effects for time were noted for heart rate, systolic blood pressure, and QTc (p < 0.001), high-density lipoproteins (p = 0.002), mean corpuscular hemoglobin (p = 0.018), basophils (p = 0.006), absolute eosinophils (p = 0.010), creatinine (p = 0.004), estimated glomerular filtration rate (p = 0.037), chloride (p = 0.030), carbon dioxide (p = 0.023), bilirubin (p = 0.027), and alanine aminotransferase (p = 0.043), among others. While small changes were found in some cardiovascular and blood biomarkers, no clinically significant changes occurred. This suggests that DYM alone or in combination with TCR consumed at the dosages used in this study does not appear to negatively affect markers of health over four weeks of continuous use.

Dietary factors and risk of gout and hyperuricemia: a meta-analysis and systematic review.

BACKGROUND AND OBJECTIVES: To evaluate the associations of dietary factors and the risk of gout and hyperuricemia. METHODS AND STUDY DESIGN: PubMed and Embase databases were searched from inception to June 2017 for eligible studies. Nineteen prospective cohort or cross-sectional studies with adequate sample sizes are included, all involving red meat, seafoods, alcohol, fructose, dairy products, soy foods, high-purine vegetables and coffee. RESULTS: Meta-analysis revealed several dietary associations with gout risk: red meat: OR 1.29 (95% CI 1.16-1.44); seafoods: OR 1.31 (95% CI 1.01-1.68); alcohol: OR 2.58 (95% CI 1.81-3.66); fructose: OR 2.14 (95% CI 1.65- 2.78); dairy products: OR 0.56 (95% CI 0.44-0.70); soy foods: OR 0.85 (95% CI 0.76-0.96); high-purine vegetables: OR 0.86 (95% CI 0.75-0.98); coffee: OR 0.47 (95% CI 0.37-0.59).Dietary association with hyperuricemia risk (red meat: OR 1.24 (95% CI 1.04-1.48); seafoods: OR 1.47 (95% CI 1.16-1.86); alcohol: OR 2.06 (95% CI 1.60-2.67); fructose: OR 1.85 (95% CI 1.66-2.07); dairy products: OR 0.50 (95% CI 0.37-0.66); soy foods: OR 0.70 (95% CI 0.56-0.88); high-purine vegetables ingestion: OR 1.10 (95% CI 0.88-1.39), P=0.39; coffee:OR0.76 in men (95% CI 0.55-1.06), OR 1.58 in women (95% CI 1.16-2.16). CONCLUSION: The risk of hyperuricemia and gout is positively correlated with the intake of red meat, seafoods, alcohol or fructose, and negatively with dairy products or soy foods. High-purine vegetables showed no association with hyperuricemia, but negative association with gout. Coffee intake is negatively associated with gout risk, whereas it may be associated with increased hyperuricemia risk in women but decreased risk in men.

Discovery and characterization of GSK256073, a non-flushing hydroxy-carboxylic acid receptor 2 (HCA2) agonist.

Niacin has been used for many years in the treatment of dyslipidemia due to its ability to decrease serum levels of triglycerides and low-density lipoprotein cholesterol and to increase levels of high density lipoprotein cholesterol. However, niacin causes severe flushing resulting in poor patient compliance. The discovery of hydroxy-carboxylic acid receptor 2 (HCA2) as a high affinity receptor for niacin has opened avenues to investigate the mechanism of action of niacin, and to potentially discover agonists which maintain the antilipolytic effects of niacin accessed by a decrease in circulating non-esterified fatty acids (NEFA) and thereby perhaps the lipid/lipoprotein effects, but avoid the flushing effects. Here we describe the strategy we implemented to identify such compounds. This approach resulted in the discovery of GSK256073, a highly potent HCA2 agonist, which produced similar NEFA lowering effects to niacin in preclinical models (rat and guinea pig). A guinea pig model was used to predict flushing, via an increase in ear temperature, and GSK256073 was found to have a minimal effect in this model. These preclinical models appeared to be predictive of human response, since in a first-time-in-human study, GSK256073 displayed long lasting NEFA and triglyceride lowering effects in healthy male subjects, which were not associated with flushing. GSK256073 can be used as a pharmacological tool to better understand the role of HCA2 in lipid metabolism.

Effects of chicory inulin on serum metabolites of uric acid, lipids, glucose, and abdominal fat deposition in quails induced by purine-rich diets.

Inulin, a group of dietary fibers, is reported to improve the metabolic disorders. In the present study, we investigated the effects of chicory inulin on serum metabolites of uric acid (UA), lipids, glucose, and abdominal fat deposition in quail model induced by a purine-rich diet. In this study, 60 male French quails were randomly allocated to five groups: CON (control group), MOD (model group), BEN (benzbromarone-treated group), CHI-H (high-dosage chicory inulin-treated group), and CHI-L (low-dosage chicory inulin-treated group). The serum UA level was significantly increased in the model group from days 7 to 28, as well as triglyceride (TG) and free fatty acid (FFA) increased later in the experimental period. The abdominal fat ratio was increased on day 28. Benzbromarone can decrease UA levels on days 14 and 28. The high and low dosage of chicory inulin also decreased serum UA levels on days 7, 14, and 28. The abdominal fat ratio, activity, and protein of acetyl-CoA carboxylase (ACC) were decreased in chicory inulin-treated groups. The activities of xanthine oxidase (XOD) and fatty acid synthase (FAS) were increased in the model group and decreased in the benzbromarone and chicory inulin groups. This study evaluated a quail model of induced hyperuricemia with other metabolic disorders caused by a high-purine diet. The results indicated that a purine-rich diet might contribute to the development of hyperuricemia, hypertriglyceridemia, and abdominal obesity. Chicory inulin decreased serum UA, TG, and abdominal fat deposition in a quail model of hyperuricemia by altering the ACC protein expression and FAS and XOD activities.

Black tea extract and its thearubigins relieve the sildenafil-induced delayed gut motility in mice: a possible role of nitric oxide.

In this study we hypothesize that a standardized black tea aqueous extract (BTE) and thearubigins, its main polyphenolic pigments, will improve sildenafil-induced delay in gastric emptying (GE) and small intestinal transit (SIT) in mice. Twenty groups of mice (n = 8) were given a phenol red meal, and three sets of experiments were performed. In the first and second sets, effects of different concentrations of BTE, thearubigins (TRs), and sildenafil (SLD), alone and in combinations, on GE and SIT were measured. In the third set, influence of nω -Nitro-l-arginine methyl ester hydrochloride (l-NAME) pretreatment on effects of these treatments was tested. Black tea extract (3% and 4.5%) and thearubigins (50 and 60 mg/kg) dose-dependently increased GE and SIT, whereas BTE 6% and thearubigins 70 mg/kg did not affect them. Sildenafil dose-dependently reduced both GE and SIT. Combination of metoclopramide, BTE 4.5%, thearubigins 60, or l-NAME with sildenafil (5 mg/kg) reversed its motility-delaying effects. Pretreatment with l-NAME followed by BTE 4.5%, thearubigins 60, BTE 4.5% + sildenafil 5, or thearubigins 60 + sildenafil 5 only partially affected the accelerating effects of BTE 4.5% and thearubigins 60. In conclusion, a standardized BTE and its thearubigins improve the sildenafil-induced delayed gut motility in mice. This improvement was partially blocked by l-NAME suggesting a possible role of nitric oxide. Thus, BTE 4.5% or TRs 60 mg/kg solution could be considered a reliever therapy for the sildenafil-induced dyspepsia.

The effects of cyclic guanylate cyclase stimulation on right ventricular hypertrophy and failure alone and in combination with phosphodiesterase-5 inhibition.

BACKGROUND: We investigated if soluble guanylate cyclase stimulation either alone or in combination with phosphodiesterase-5 (PDE5) inhibition could prevent pressure overload-induced right ventricular (RV) hypertrophy and failure. METHODS: The soluble guanylate cyclase stimulator BAY 41-2272 (BAY, 10 mg · kg⁻¹ · d⁻¹) either alone or in combination (BAY + SIL) with a PDE5 inhibitor sildenafil (SIL, 100 mg · kg⁻¹ · d⁻¹) was examined for prevention of RV hypertrophy and failure in Wistar rats (n = 73) operated by pulmonary trunk banding. RESULTS: All treatments failed to inhibit the development of RV hypertrophy and failure. In the BAY and BAY + SIL groups, there was an increased mortality. Mean arterial blood pressure was lowered and cardiac output increased in the BAY + SIL group. Systolic RV pressure was increased in the BAY and BAY + SIL groups possibly because of an inotropic response and/or increased venous return. CONCLUSIONS: Stimulation of soluble guanylate cyclase by BAY 41-2272 alone or in combination with sildenafil failed to prevent the development of RV hypertrophy and failure in rats subjected to pulmonary trunk banding. An increased mortality was observed in animals treated by BAY 41-2272 alone and in combination with sildenafil.

Recent advances in management of gout.

Incidence and prevalence of gout have markedly increased over the last few decades in keeping with the rise in prevalence of obesity and metabolic syndrome. Until recently, management of gout in patients with associated metabolic syndrome and comorbid illnesses such as renal impairment was difficult because of limited treatment options. However, significant progress has been made in the last few years, with introduction of new treatments such as interleukin-1 antagonists for management of acute gout, and febuxostat and pegloticase for chronic gout. The association of gout with alcohol, dietary purines and fructose ingestion has been confirmed in large prospective studies, thus enabling the clinician to now provide evidence-based advice to patients. Recent efficacy and safety data favour lower over higher doses of colchicine, and oral corticosteroids over non-steroidal anti-inflammatory drugs for patients with acute gout. Local ice therapy might help to differentiate gout from other forms of inflammatory arthritis, and supplementation with vitamin C help to reduce risk of gout. Several other drugs with rational mechanisms of action are in the pipeline, and likely to be introduced over the next few years. A new era has thus begun in the field of gout.

CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies.

INTRODUCTION: The management of lymphoid malignancies has greatly evolved in the last decade with the advent of targeted therapies, which have improved response and survival in patients with Hodgkin's lymphoma (HL), non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and plasma cell myeloma (PCM). The PI3K pathway seems to play a seminal role in the development of lymphoid malignancies. CAL-101 is a highly selective PI3K p110δ inhibitor currently undergoing clinical development. AREAS COVERED: The aims of this review are to summarize our understanding of the PI3K pathway, its role in lymphoid malignancies, the preclinical and clinical experience accumulated with CAL-101, a PI3Kδ inhibitor, and potential areas of future development. EXPERT OPINION: CAL-101 is a novel drug that has shown preclinical activity against CLL, NHL, HL and PCM cells. There is early evidence of clinical efficacy in CLL and indolent NHL. Studies using CAL-101 alone or in combination are also ongoing in PCM, HL and aggressive NHL. However, additional studies are needed to prove CAL-101 is effective and safe as the goals of therapy for patients with lymphoid neoplasms are not only directed towards improving response and cure rates but also prolonging survival without affecting quality of life.

The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats.

BACKGROUND: Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling. METHOD: Rats treated with 50 mg/kg AEE788 or solvent every other day orally were subjected to 90%PH. Animals were sacrificed at 1, 2, 7 and 28 days after PH. We measured plasma and liver levels of AEE788 and assessed anti-proliferative side effects, liver regeneration, and liver architecture. RESULT: Liver regeneration and liver architecture were not impaired by AEE788 treatment after 90%PH. 90%PH caused a clinically relevant drug accumulation within 1 week of treatment (AEE788 serum and tissue levels: 90%PH*>70%PH*>normal control, *p < 0.05), suggesting a liver-size-dependent metabolism of the drug. Drug accumulation after 90%PH was associated with severe side effects (delayed body weight recovery, diarrhea, impaired hair growth) within 1 week of treatment. CONCLUSION: Treatment with AEE788 could be a potential strategy for adjuvant treatment after oncological liver resection, as liver regeneration was not impaired. Our results suggest a liver-size-dependent metabolism of AEE788 leading to drug accumulation and subsequently to severe side effects. It calls for therapeutic drug monitoring in the early postoperative phase after extended resection.

An open label, randomized, fixed-dose, crossover study comparing efficacy and safety of sildenafil citrate and saffron (Crocus sativus Linn.) for treating erectile dysfunction in men naïve to treatment.

Saffron (Crocus sativus Linn.) have been perceived by the public as a strong aphrodisiac herbal product. However, studies addressing the potential beneficial effects of saffron on erectile function (EF) in men with ED are lacking. Our aim was to evaluate the efficacy and safety of saffron administration on EF in men with ED. After a 4-week baseline assessment, 346 men with ED (mean age 46.6+/-8.4 years) were randomized to receive on-demand sildenafil for 12 weeks followed by 30 mg saffron twice daily for another 12 weeks or vice versa, separated by a 2-week washout period. To determine the type of ED, penile color duplex Doppler ultrasonography before and after intracavernosal injection with 20 microg prostaglandin E(1), pudendal nerve conduction tests and impaired sensory-evoked potential studies were performed. Subjects were assessed with an International Index of Erectile Function (IIEF) questionnaire, Sexual Encounter Profile (SEP) diary questions, patient and partner versions of the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire and the Global Efficacy Question (GEQ) 'Has the medication you have been taking improved your erections?' No significant improvements were observed with regard to the IIEF sexual function domains, SEP questions and EDITS scores with saffron administration. The mean changes from baseline values in IIEF-EF domain were +87.6% and +9.8% in sildenafil and placebo groups, respectively (P=0.08). We did not observe any improvement in 15 individual IIEF questions in patients while taking saffron. Treatment satisfaction as assessed by partner versions of EDITS was found to be very low in saffron patients (72.4 vs 25.4, P=0.001). Mean per patient 'yes' responses to GEQ was 91.2 and 4.2% for sildenafil and saffron, respectively (P=0.0001). These findings do not support a beneficial effect of saffron administration in men with ED.

9-Arylpurines as a novel class of enterovirus inhibitors.

Here we report on a novel class of enterovirus inhibitors that can be structurally described as 9-arylpurines. These compounds elicit activity against a variety of enteroviruses in the low microM range including Coxsackie virus A16, A21, A24, Coxsackie virus B3, and echovirus 9. Structure-activity relationship (SAR) studies indicate that a chlorine or bromine atom is required at position 6 of the purine ring for antiviral activity. The most selective compounds in this series inhibited Coxsackie virus B3 replication in a dose-dependent manner with EC(50) values around 5-8 microM. No toxicity on different cell lines was observed at concentrations up to 250 microM. Moreover, no cross-resistance to TBZE-029 and TTP-8307 CVB3 resistant strains was detected.

Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

Boehringer Ingelheim Corp is developing the novel, xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor linagliptin for the potential treatment of type 2 diabetes mellitus. In vitro assays suggested that linagliptin was a potent DPP-4 inhibitor, with good selectivity for DPP-4 compared with other DPPs and proteases. The inhibition of DPP-4 by linagliptin was also demonstrated in vivo, resulting in increased glucagon-like peptide 1 levels and improved glucose tolerance in both healthy animals and models of disease. Furthermore, linagliptin exhibited prolonged pharmacodynamic activity, with long-lasting DPP-4 inhibition across different species. The prolonged DPP-4 inhibition observed in preclinical models has translated to humans; linagliptin demonstrated approximately 80% inhibition of DPP-4 activity at daily doses as low as 5 mg in phase II clinical trials. The effects were sustained, and no signs or symptoms of hypoglycemia were observed, even at high doses of up to 600 mg. The low therapeutic dose of linagliptin, the long-lasting inhibition of DPP-4 activity and the good safety/tolerability profile exhibited thus far suggest that linagliptin may be superior to competitors. The results from ongoing phase III clinical trials will provide further information on such aspects; however, from the available data, linagliptin appears to have promise for market success.

Isolation and identification of hydroxythiohomosildenafil in herbal dietary supplements sold as sexual performance enhancement products.

An unknown compound is detected and isolated from two herbal dietary supplements bought on the internet. The structure of the unknown compound is elucidated using ESI-MS/MS, NMR, UV and IR. The compound, named hydroxythiohomosildenafil, is identified as an analogue of sildenafil in which the oxygen atom is substituted with a sulfur atom in the pyrazolopyrimidine moiety, and a hydroxyethyl group instead of a methyl group is attached to the piperazinyl nitrogen. It is the first report of this compound being detected in herbal dietary supplements. The UV, IR and completely assigned NMR data of hydroxythiohomosildenafil is recorded.

You'll "get viagraed:" Mexican men's preference for alternative erectile dysfunction treatment.

The pharmaceutically focused clinical and epidemiological literature on erectile dysfunction (ED) treatment has paid little attention to men's non-medical responses to changing erectile function. This study explores the relationship of erectile function change, resulting use of medical or alternative treatments, and Mexican men's understandings of masculinity and aging, through a mixed method approach utilizing both quantitative survey and ethnographic interview data. A survey of 750 men undertaken at the Instituto Méxicano del Seguro Social hospital in Cuernavaca, Mexico in April to June 2008 showed that only about half of those who experienced erectile function changes sought treatment for these changes; treatment users were far more likely to seek alternative treatment than medical treatment, especially preferring lifestyle change and vitamins. Ethnographic data from interviews with 250 male urology patients undertaken from October 2007 to August 2008 at the same site reveal that treatment users' preferences were linked to fears about the safety and situational inappropriateness of medical ED treatment. These findings suggest that by focusing on patients' use of pharmaceuticals, biomedically oriented research has overlooked the most common responses to changing erectile function. Broadening the focus of ED treatment research to include analysis of men's rejection of pharmaceutical treatment - either in favor of alternative treatment, or because they do not see their erectile function changes as requiring medical intervention - would correct this imbalance in the literature. Further, the knowledge that even men who seek treatment may prefer alternatives to pharmaceutical interventions will help physicians to offer treatments, such as lifestyle change, that their patients might find more acceptable. Such measures would simultaneously help to mitigate the chronic illnesses, like diabetes and hypertension, which frequently co-occur with diminished erectile function.