Two cases of neural tube defects with dolutegravir use at conception in south Brazil

ABSTRACT Dolutegravir (DTG) is amongst the most prescribed antiretrovirals worldwide and is recommended as first line regimen in most HIV treatment guidelines. Its use, although infrequently, had been associated to an increased chance of neural tube defects (NTD) in Botswana, Africa. Herein we describe two cases of NTD in women who conceived while taking DTG as part of their antiretroviral treatment in the city of Porto Alegre, Brazil.

Renal tuberculosis in an imatinib-treated chronic myeloid leukemia / Tuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe

ABSTRACT Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.

RESUMO O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.

Nicotinamide activates latent HIV-1 ex vivo in ART suppressed individuals, revealing higher potency than the association of two methyltransferase inhibitors, chaetocin and BIX01294

ABSTRACT Background: Latent HIV-1 is a major hurdle in obtaining HIV-1 sustained virological remission (SVR). Here we explored histone deacetylation inhibition property of nicotinamide (NAM; n = 17) for the first time in comparison to a combination of methyltransferase inhibitors (MTIs; Chaetocin and BIX01294; n = 25) to reactivate latent HIV ex vivo in CD8-depleted PBMCs from antiretroviral treated aviremic individuals. Results: NAM reactivated HIV-1 from 13/17 (76.4%) samples compared to 20/25 (80.0%) using MTIs with mean viral load (VLs) of 4.32 and 3.22 log10 RNA copies/mL, respectively (p = 0.004). Mean purging time after NAM and MTIs stimulation was 5.1 and 6.75 days, respectively (p = 0.73). Viral purging in autologous cultures exhibited blunted HIV recovery with fluctuating VLs followed by a complete viral extinction when expanded in allogenic system. Electron microscopy from five supernatants revealed anomalous viral particles, with lack of complete viral genomes when characterized by ultradeep sequencing through metagenomics approach (n = 4). Conclusion: NAM alone was more potent HIV-1 activator than combination of MTIs, with potential of clinical use.

Which antiretroviral regimen is associated with higher adherence in Brazil? A comparison of single, multi, and dolutegravir-based regimens / Qual esquema antirretroviral está associado à maior adesão no Brasil? Uma comparação dos esquemas de comprimido único, múltiplos comprimidos e com dolutegravir / ¿Qué tratamiento antirretroviral está asociado con adherencia más alta en Brasil? Una comparación de tratamientos únicos, múltiples y basados en el dolutegravir

Abstract: We evaluated adherence to highly active antiretroviral therapy (HAART) and its associated factors according to the type of regimen in patients initiating treatment in Belo Horizonte, Minas Gerais State, Brazil. We measured adherence using the eight items Morisky Therapeutic Adhesion Scale (MMAS-8) and compared the use of "backbone" tenofovir/lamivudine plus efavirenz one tablet once-daily (STR) or dolutegravir in multi-tablet once-daily (MTR-DTG), or other multi-tablet regimens (MTR-other). We conducted a multivariate logistic regression analysis to address factors associated with adherence. A total of 393 patients were included, 254 used STR, 106 MTR-DTG, and 33 MTR-other. The overall adhesion rate was 44.8% (95%CI: 39.4; 50.1), 50% for MTR-DTG, 43.3% for STR and 39.4% for MTR-other. Multivariate analysis showed a higher chance of adherence among patients using MTR-DTG, those who received and understood counseling about their treatment and with a higher quality of life. Prior use of illicit drugs in the lifetime was associated with poorer adherence. Overall adherence was low, highlighting the need for strategies focusing on counseling about medicines and substance use. Pill burden was not an issue for patients using MTR-DTG once-daily, who achieved better results.

Resumo: Avaliamos a adesão à terapia antirretroviral (TARV) e fatores associados de acordo com o tipo de esquema em pacientes no início do tratamento em Belo Horizonte, Minas Gerais, Brasil. Mensuramos a adesão com a Escala de Adesão Terapêutica de Morisky, de oito itens (MMAS-8), e comparamos o uso de tenofovir/lamivudina com efavirenz, um comprimido uma vez ao dia (STR), ou dolutegravir em múltiplos comprimidos uma vez ao dia (MTR-DTG), com outros esquemas com múltiplos comprimidos ao dia (MTR-outros). Conduzimos uma análise de regressão logística multivariada para avaliar os fatores associados à adesão. Foram incluídos 393 pacientes: 254 em uso de STR, 106 MTR-DTG e 33 MTR-outros. A taxa global de adesão foi 44,8% (IC95%: 39,4; 50,1), sendo 50% para MTR-DTG, 43,3% para STR e 39,4% para MTR-outros. A análise multivariada mostrou chances maiores de adesão em pacientes em uso de MTR-DTG, pacientes que haviam recebido e compreendido o aconselhamento sobre o tratamento e pacientes com melhor qualidade de vida. Uso anterior de drogas ilícitas em qualquer período da vida está associada à pior adesão. A adesão global foi baixa, enfatizando a necessidade de estratégias focadas no aconselhamento sobre medicamentos e uso de drogas. A quantidade de comprimidos não foi um problema para pacientes em uso de MTR-DTG uma vez ao dia, os quais alcançaram melhores taxas de adesão.

Resumen: Evaluamos la adherencia a la terapia antirretroviral altamente activa (TARAA) y sus factores asociados, según el tipo de tratamiento en pacientes que comenzaron su tratamiento en Belo Horizonte, Minas Gerais, Brasil. La adherencia se mensuró por la Escala de Adhesión Terapéutica de Morisky, de ocho ítems (MMAS-8), y se comparó el uso del "eje" tenofovir/lamivudina, además de un comprimido de efavirenz una vez al día (STR) o dolutegravir con varios comprimidos una vez al día (MTR-DTG), u otros tratamientos con múltiples comprimidos (MTR-otros). Se realizó un análisis multivariado de regresión logística para evaluar los factores asociados a la adherencia. Se incluyeron un total de 393 pacientes, 254 usaron STR, 106 MTR-DTG, y 33 MTR-Otros. La tasa de adherencia general fue de un 44,8% (95%CI: 39,4; 50,1), 50% en el MTR-DTG, 43,3% en el STR y 39,4% en el MTR-otros. El análisis multivariado mostró una probabilidad más alta de adherencia entre pacientes usando MTR-DTG, quienes recibieron y comprendieron las orientaciones acerca de sus tratamientos y los que disfrutaban de una calidad mejor de vida. El consumo previo de drogas ilícitas a lo largo de la vida estuvo asociado con una adherencia más escasa. La adherencia general fue baja y resalta la necesidad de estrategias que se enfoquen en brindar orientación sobre el uso de la medicación y de sustancias. El número de comprimidos no fue un problema para los pacientes que tomaban MTR-DTG una vez al día, que obtuvieron mejores resultados.

Synthesis and in silico study of 2-furyl(4-{4-[(substituted)sulfonyl]benzyl}-1-piperazinyl)methanone derivatives as suitable therapeutic agents

Abstract In the study presented here, a new series of 2-furyl(4-{4-[(substituted)sulfonyl]benzyl}-1-piperazinyl)methanone derivatives was targeted. The synthesis was initiated by the treatment of different secondary amines (1a-h) with 4-bromomethylbenzenesulfonyl chloride (2) to obtain various 1-{[4-(bromomethyl)phenyl]sulfonyl}amines (3a-h). 2-Furyl(1-piperazinyl)methanone (2-furoyl-1-piperazine; 4) was then dissolved in acetonitrile, with the addition of K2CO3, and the mixture was refluxed for activation. This activated molecule was further treated with equi-molar amounts of 3a-h to form targeted 2-furyl(4-{4-[(substituted)sulfonyl]benzyl}-1-piperazinyl)methanone derivatives (5a-h) in the same reaction set up. The structure confirmation of all the synthesized compounds was carried out by EI-MS, IR and 1H-NMR spectral analysis. The compounds showed good enzyme inhibitory activity. Compound 5h showed excellent inhibitory effect against acetyl- and butyrylcholinesterase with respective IC50 values of 2.91±0.001 and 4.35±0.004 µM, compared to eserine, a reference standard with IC50 values of 0.04±0.0001 and 0.85±0.001 µM, respectively, against these enzymes. All synthesized molecules were active against almost all Gram-positive and Gram-negative bacterial strains tested. The cytotoxicity of the molecules was also checked to determine their utility as possible therapeutic agents.

Propolis protective role against morphological, hormonal biochemical and histological alterations induced by sildenafil overdoses / Rol protector del propóleo contra las alteraciones morfológicas, hormonales, bioquímicas e histológicas inducidas por sobredosis de sildenafil

Sildenafil is widely used for the treatment of erectile dysfunction with few studies are available on the protective role of propolis against its reproductive toxicity. The present study aims to investigate the hormonal biochemical and histomorphometric alterations induced in the testicular tissues by sildenafil overdoses. Four groups of rabbits were exposed to sildenafil with or without propolis as follows: Group I received the formulated vehicle, Group II received sildenafil (3 mg/kg), Group III received propolis (50 mg/kg), Group IV received sildenafil plus propolis. Sildenafil lowered body weight gain, testosterone and follicular stimulating hormone concentration but increased testis index while luteinizing hormone was almost not affected. Moreover, sildenafil treated rabbits showed degenerative seminiferous tubules and disturbance of spermatogenesis together with spermatocytes sloughing and nuclear alterations. Exposure to sildenafil plus propolis ameliorated tubular alterations, spermatogenesis disturbances, hormonal levels changes and partially protected spermatocytes from morphological nuclear alterations but could not ameliorate the effect on the body weight gain and testis index. The findings of the present work may indicate that propolis can ameliorate partially the reproductive toxicity induced by sildenafil overdoses with more need for further studies on the adverse effect of these doses on the other vital organs.

El sildenafil es un medicamento ampliamente utilizado para el tratamiento de la disfunción eréctil y existen pocos estudios disponibles referente a la función protectora del propóleo contra su toxicidad reproductiva. El objetivo fue investigar las alteraciones hormonales, bioquímicas e histomorfométricas, inducidas en los tejidos testiculares por sobredosis de sildenafil. Cuatro grupos de conejos fueron expuestos a sildenafil con o sin propóleo de la siguiente manera: grupo I recibió el sildenafil formulado, grupo II recibió sildenafil (3 mg/kg), grupo III recibió propóleo (50 mg/kg) y el grupo IV recibió sildenafil más propóleo. El sildenafil redujo el peso corporal, la testosterona y la concentración de la hormona foliculoestimulante, sin embargo, se observó un aumento del índice testicular mientras que la hormona luteinizante casi no se vio afectada. Por otra parte, los conejos tratados con sildenafil mostraron degeneración de los túbulos seminíferos, trastornos de la espermatogénesis y alteraciones nucleares de los espermatocitos. Con el uso de sildenafil más propóleo fue posible disminuir las alteraciones de los túbulos seminíferos, los trastornos de la espermatogénesis y los niveles de cambios hormonales; los espermatocitos fueron protegidos parcialmente de alteraciones nucleares morfológicas, pero no pudo mejorar el efecto de aumento de peso corporal e índice testicular. Los resultados indican que el propóleo puede aliviar, en parte, la toxicidad en la reproducción inducida por sobredosis de sildenafil. No obstante, existe la necesidad de realizar más estudios sobre los efectos adversos de estas dosis en otros órganos vitales.

Effects of sildenafil on dental pulp: immunohistochemical and ultrastructural evaluation / Efectos de sildenafil en la pulpa dental: evaluación inmunohistoquímica y ultraestructural

Sildenafil is a strong peripheral vasodilator and is used to treat cardiovascular and neurosurgery. The purpose of this study was to investigate the immunohistochemical and ultrastructural effects of sildenafil on dental pulp of rats. The study was performed with adult female Wistar-Albino rats. Control group (n= 7) were fed on standard laboratory diet until surgery. The study group (n= 7) were administered sildenafil orally with orogastric tube 10 mg·kg-1 once a day for 30 days. Each rat was anesthetized and incisor teeth were removed. This study examined the immunohistochemical and ultrastructural effects of sildenafil on the dental pulp in rats. The relaxation from the vessel, endothelial cell hyperplasia, moderate degeneration of collagen fibers were observed to cause degenerative changes in odontoblast with sildenafil. In the pulp tissue long-term use sildenafil is thought to cause degeneration and new vessel formation.

El sildenafil es un vasodilatador periférico importante y se utiliza para tratar enfermedades cardiovasculares y en neurocirugía. El propósito de este estudio fue investigar los efectos inmunohistoquímicos y ultraestructurales del sildenafil sobre la pulpa dental de ratas. El estudio se realizó con ratas Wistar albinas, hembras adultas. El grupo de control (n= 7) fue alimentado con una dieta estándar de laboratorio hasta que se realizó la cirugía. El grupo de estudio (n= 7) fue tratado con sildenafil por vía oral y sonda orogástrica 10 mg·kg-1 una vez al día durante 30 días. Cada rata fue anestesiada y se extrajeron los dientes incisivos. Se examinaron los efectos inmunohistoquímicos y ultraestructurales del sildenafil sobre la pulpa dentaria. Con la administración de sildenafil se observó la relajación de los vasos, la hiperplasia de las células endoteliales y una degeneración moderada de fibras colágenas causando cambios degenerativos en los odontoblastos. En el tejido pulpar, el uso de sildenafil a largo plazo puede causar la degeneración y neoformación de vasos.

Selective 5-HT7 receptor agonists LP 44 and LP 211 elicit an analgesic effect on formalin-induced orofacial pain in mice

ABSTRACT The most recently identified serotonin (5-HT) receptor is the 5-HT7 receptor. The antinociceptive effects of a 5-HT7 receptor agonist have been shown in neuropathic and inflammatory animal models of pain. A recent study demonstrated the functional expression of 5-HT7 receptors in the substantia gelatinosa (SG) of the trigeminal subnucleus caudalis, which receives and processes orofacial nociceptive inputs. Objective To investigate the antinociceptive effects of pharmacological activation of 5-HT7 receptors on orofacial pain in mice. Material and Methods Nociception was evaluated by using an orofacial formalin test in male Balb-C mice. Selective 5-HT7 receptor agonists, LP 44 and LP 211 (1, 5, and 10 mg/kg), were given intraperitoneally 30 min prior to a formalin injection. A bolus of 10 µl of 4% subcutaneous formalin was injected into the upper lip of mice and facial grooming behaviors were monitored. The behavioral responses consisted of two distinct periods, the early phase corresponding to acute pain (Phase I: 0–12 min) and the late phase (Phase II: 12–30 min). Results LP 44 and LP 211 (1, 5, and 10 mg/kg) produced an analgesic effect with reductions in face rubbing time in both Phase I and Phase II of the formalin test. Conclusion Our results suggest that 5-HT7 receptor agonists may be promising analgesic drugs in the treatment of orofacial pain.

Eszopiclone versus zopiclone in the treatment of insomnia

OBJECTIVE: To determine the therapeutic effects of two selective GABA-A agonists, zopiclone and eszopiclone, in the treatment of insomnia. METHODS: This study comprised a phase III, single-center, randomized, double-blind, double-dummy, parallel-group, non-inferiority trial. Patients were randomized to receive zopiclone 7.5 mg or eszopiclone 3 mg, both orally, for four weeks. In total, 199 patients were evaluated during two visits and then followed for at least six weeks. The primary endpoint was the Insomnia Severity Index after four weeks of treatment. Secondary endpoints were obtained through polysomnography data, including total sleep time, sleep latency and sleep efficiency. The frequency of adverse events was also analyzed. ClinicalTrials.gov: NCT01100164. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of eszopiclone over zopiclone. Analysis of objective parameters assessed by polysomnography showed that eszopiclone increased total sleep time and also improved sleep efficiency. The safety profile of both study treatments was similar and the most common events reported in both groups were dysgeusia, headache, dizziness, irritability and nausea. Adverse events were observed in 223 patients, 109 (85.2%) in the eszopiclone group and 114 (87.7%) in the zopiclone group. CONCLUSION: Based on the Insomnia Severity Index at the end of four weeks of treatment, eszopiclone demonstrated efficacy comparable to that of zopiclone in the treatment of insomnia, increasing total sleep time as well as sleep efficiency according to polysomnography.

ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia

This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and hepatocytes (half-life of 11 min). LDT5 is highly permeable across the MDCK-MDR1 monolayer (Papp ∼32×10-6 cm/s), indicating good intestinal absorption and putative brain penetration. LDT5 is not extensively protein-bound and is a substrate of human CYP2D6 and CYP2C19 but not of CYP3A4 (half-life >60 min), and did not significantly influence the activities of any of the human cytochrome P450 isoforms screened. LDT5 was considered safe albeit new studies are necessary to rule out putative central adverse effects through D2, 5-HT1A and 5-HT2B receptors, after chronic use. This work highlights the drug-likeness properties of LDT5 and supports its further preclinical development.

Effects of vardenafil on the kidney of Wistar rats submitted to acute ischemia and reperfusion

PURPOSE: To investigate the effect of vardenafil in kidney of rats submitted to acute ischemia and reperfusion. METHODS: Twenty-eight rats were randomly distributed into two groups. Right nephrectomy was performed and the vardenafil group received vardenafil solution (at a concentration of 1 mg/ml in 10 mg/kg) while the control group received 0.9% saline solution (SS) one hour prior to the ligature of the left renal pedicle. After one hour of ischemia, animals were submitted to twenty-four hours of reperfusion, followed by left nephrectomy. The kidney's histological parameters evaluated on the study included vacuolar degeneration and tubular necrosis. Apoptosis was assessed by immunohistochemistry for cleaved caspase-3 using the point-counting and digital methods (Cytophotometry). Also, a biochemical analysis for creatinine was conducted. RESULTS: There were statistically significant differences between groups only with regards to the vacuolar degeneration parameter and to the cleaved caspase-3 digital method. CONCLUSION: Vardenafil showed a protective effect on the kidney of rats subjected to acute ischemia and reperfusion in this model .

Effects of PDE type 5 inhibitors on Left Ventricular Diastolic Dysfunction in Resistant Hypertension / Efeitos dos Inibidores da PDE do Tipo 5 sobre a Disfunção Diastólica Ventricular Esquerda na Hipertensão Arterial Resistente

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.

A Hipertensão arterial resistente (HAR) é uma doença multifatorial caracterizada por níveis pressóricos acima das metas (140/90 mmHg), a despeito de tratamento farmacológico otimizado de 3 ou mais fármacos anti-hipertensivos de diferentes classes. Pacientes diagnosticados como hipertensos resistentes apresentam alta prevalência de disfunção diastólica do ventrículo esquerdo (DDVE) que proporciona risco aumentado para insuficiência cardíaca. Esta revisão reúne dados de estudos prévios avaliando os efeitos dos inibidores de fosfodiesterase-5 (PDE-5) (administração aguda de sildenafil e de curto prazo de tadalafil) na função diastólica e nos parâmetros bioquímicos e hemodinâmicos em pacientes com HAR. O estudo agudo com sildenafil demonstrou que a inibição da PDE-5 melhorou os parâmetros hemodinâmicos e de relaxamento diastólico. Além disso, o estudo curto prazo com o uso de tadalafil revelou melhora da DDVE e dos níveis de GMPc e BNP-32, independente de redução de pressão arterial. A função endotelial não apresentou alteração com ambos os tratamentos. Os resultados dos estudos agudo e de curto prazo sugerem efeitos terapêuticos potenciais dos fármacos inibidores da PDE-5 na disfunção diastólica em pacientes com HAR.

A combination of STI571 and BCR-ABL1 siRNA with overexpressed p15INK4B induced enhanced proliferation inhibition and apoptosis in chronic myeloid leukemia

p15INK4B, a cyclin-dependent kinase inhibitor, has been recognized as a tumor suppressor. Loss of or methylation of the p15INK4B gene in chronic myeloid leukemia (CML) cells enhances myeloid progenitor formation from common myeloid progenitors. Therefore, we examined the effects of overexpressed p15INK4B on proliferation and apoptosis of CML cells. Overexpression of p15INK4B inhibited the growth of K562 cells by downregulation of cyclin-dependent kinase 4 (CDK4) and cyclin D1 expression. Overexpression of p15INK4B also induced apoptosis of K562 cells by upregulating Bax expression and downregulating Bcl-2 expression. Overexpression of p15INK4B together with STI571 (imatinib) or BCR-ABL1 small interfering RNA (siRNA) also enhanced growth inhibition and apoptosis induction of K562 cells. The enhanced effect was also mediated by reduction of cyclin D1 and CDK4 and regulation of Bax and Bcl-2. In conclusion, our study may provide new insights into the role of p15INK4B in CML and a potential therapeutic target for overcoming tyrosine kinase inhibitor resistance in CML.

Preoperative imatinib for patients with primary unresectable or metastatic/recurrent gastrointestinal stromal tumor

OBJECTIVES: Despite its rising popularity, reports on the use of preoperative imatinib mesylate (IM) in patients with advanced gastrointestinal stromal tumor (GIST) are limited. This study aims to explore the clinical efficacy of preoperative IM in patients with primarily unresectable or metastatic/recurrent GIST. METHODS: Between September 2009 and February 2014, patients with primarily unresectable or metastatic/recurrent GIST treated by a single medical team were recruited and considered for preoperative IM therapy. Re-examination was conducted regularly and abdominal enhanced CT data, blood biochemistry and responses to IM were recorded. RESULTS: A total of 18 patients were enrolled, including 13 with a primary tumor (7 stomach, 3 small bowel, 2 rectal and 1 pelvic tumor) and 5 with recurrent or metastatic GIST (2 with liver metastasis, 2 with anastomotic recurrence and 1 with pelvic GIST). The median follow-up time was 9.5 months (range of 3-63). The median tumor sizes before and after initiation of IM treatment were 9.1 cm and 6.0 cm (p = 0.003) based on the CT findings, respectively. All patients showed a decrease in tumor burden and the median tumor size reduction was 35%. Sixteen of the 18 patients showed a partial response to IM and two possessed stable disease. Nine of the 18 patients (50%) underwent surgical resection of primary or metastatic/recurrent tumors, with a median of 7 months of IM therapy. One case each of multivisceral resection and tumor recurrence were noted. CONCLUSIONS: IM as a preoperative therapy is feasible and safe for unresectable or metastatic/recurrent GIST that can effectively decrease tumor size, facilitating resection. .

The effects of vardenafil and pentoxifylline administration in an animal model of ischemic colitis

OBJECTIVES: Vardenafil enhances dilatation of vascular smooth muscle and inhibits platelet aggregation. The purpose of this study was to evaluate the clinical effects of vardenafil and pentoxifylline administration in an experimental model of ischemic colitis. METHODS: Forty female Wistar albino rats weighing 250-300 g were randomized into five experimental groups (each with n = 8) as follows:1) a sham group subjected to a sham surgical procedure and administered only tap water; 2) a control group subjected to a standardized surgical procedure to induce ischemic colitis and administered only tap water; 3) and 4) treatment groups subjected to surgical induction of ischemic colitis followed by the postoperative administration of 5 mg/kg or 10 mg/kg vardenafil, respectively; and 5) a treatment group subjected to surgical induction of ischemic colitis followed by postoperative administration of pentoxifylline at 50 mg/kg/day per day as a single dose for a 3-day period. All animals were sacrificed at 72 h post-surgery and subjected to relaparotomy. We scored the macroscopically visible damage, measured the ischemic area and scored histopathology to determine the severity of ischemia. Tissue malondialdehyde levels were also quantified. RESULTS: The mean Gomella ischemic areas were 63.3 mm2 in the control group; 3.4 and 9.6 mm2 in the vardenafil 5 and vardenafil 10 groups, respectively; and 3.4 mm2 in the pentoxifylline group (p = 0.0001). The mean malondialdehyde values were 63.7 nmol/g in the control group; 25.3 and 25.6 nmol/g in the vardenafil 5 and vardenafil 10 groups, respectively; and 22.8 nmol/g in the pentoxifylline group (p = 0.0001). CONCLUSION: Our findings indicate that vardenafil and pentoxifylline are effective treatment options in an animal model of ischemic colitis. The positive clinical effects produced by these drugs are likely due to their influence on the hemodynamics associated ...

Meta-analysis on the efficacy and tolerability of the augmentation of antidepressants with atypical antipsychotics in patients with major depressive disorder

We assessed the efficacy and tolerability of the augmentation of antidepressants (ATDs) with atypical antipsychotics (AAPs) to treat patients with major depressive disorder. A retrograde study to identify relevant patient data included databases of PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and Database of Abstracts of Reviews of Effects. Data from 17 trials, involving 3807 participants, were identified. The remission rate (RR) and overall response rate (ORR) of adjunctive treatment with AAPs were significantly higher than placebo treatment: RR=1.90 (95%CI=1.61-2.23, z=7.74, P<0.00001) and ORR=1.68 (95%CI=1.45-1.94, z=7.07, P<0.00001). We found that the short-term (4 weeks) treatment [ORR=1.70 (95%CI=0.98-2.95, Z=1.89, P=0.06)] was significantly different from the long-term (6-12 weeks) treatment [ORR=1.68 (95%CI=1.45-1.94, z=7.07, P<0.00001)]. No significant difference in ORR was observed between groups with or without sedative drugs. The discontinuation rate due to adverse effects was higher for adjunctive treatment with AAPs: ORR=3.32 (95%CI=2.35-4.70, z=6.78, P<0.00001). These results demonstrate that the augmentation of ATDs with AAPs (olanzapine, quetiapine, aripiprazole, and risperidone) was more effective than a placebo in improving response and remission rates, although associated with a higher discontinuation rate due to adverse effects.

PDE5 Inhibitor Treatment Persistence and Adherence in Brazilian Men: Post-hoc Analyses from a 6-Month, Prospective, Observational Study

Purpose Characterize persistence and adherence to phosphodiesterase type - 5 inhibitor (PDE5I) on-demand therapy over 6 months among Brazilian men in an observational, non-interventional study of Latin American men naïve to PDE5Is with erectile dysfunction (ED). Materials and Methods Men were prescribed PDE5Is per routine clinical practice. Persistence was defined as using ≥ 1 dose during the previous 4 - weeks, and adherence as following dosing instructions for the most recent dose, assessed using the Persistence and Adherence Questionnaire. Other measures included the Self - Esteem and Relationship (SEAR) Questionnaire, and International Index of Erectile Function (IIEF). Multivariate logistic regression was used to identify factors associated with persistence/adherence. Results 104 Brazilian men were enrolled; mean age by treatment was 53 to 59 years, and most presented with moderate ED (61.7%). The prescribed PDE5I was sildenafil citrate for 50 (48.1%), tadalafil for 36 (34.6%), vardenafil for 15 (14.4%), and lodenafil for 3 patients (2.9%). Overall treatment persistence was 69.2% and adherence was 70.2%; both were numerically higher with tadalafil (75.0%) versus sildenafil or vardenafil (range 60.0% to 68.0%). Potential associations of persistence and/or adherence were observed with education level, ED etiology, employment status, and coronary artery disease. Improvements in all IIEF domain scores, and both SEAR domain scores were observed for all treatments. Study limitations included the observational design, brief duration, dependence on patient self - reporting, and limited sample size. Conclusion Approximately two-thirds of PDE5I-naive, Brazilian men with ED were treatment persistent and adherent after 6 months. Further study is warranted to improve long-term outcomes of ED treatment. .