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.

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.

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.

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. .

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. .

Neoadyuvancia cnn imatinib en el manejo de gist gigante del tabique rectovaginal / Neo-adjuvant treatment with imatinib for a rectal gastrointestinal stromal tumor

Introducción: Los tumores estromales gastrointestinales (GIST) del recto son muy raros. En la última década se ha planteado la neoadyuvancia con imatinib en los casos de tumores localmente avanzados o inicialmente irresecables. Caso clínico: Se presenta una paciente portadora de un GIST maligno del tabique rectovaginal inicialmente considerado irresecable que fue sometido a neoadyuvancia con Imatinib como terapia de inducción durante 3 meses, logrando una respuesta clínica notable que permitió realizar una resección local exitosa por vía endoanal. La presencia de factores pronósticos deletéreos (tamaño tumoral mayor de 5 cm y 13 mitosis por 50 campos de aumento mayor) determinó la mantención del tratamiento con Imatinib por 15 meses luego de la cirugía con el fin de reducir el riesgo de recidiva local. Luego de 20 meses de seguimiento la paciente está libre de enfermedad, con continencia fecal plena, ha recuperado la actividad sexual, aunque persisten algunos efectos residuales de la droga que están en franca disminución. Conclusión: La neoadyuvancia con imatinib se considera actualmente la terapia estándar en el manejo de los GIST localmente avanzados y/o irresecables.

Background: Rectal gastrointestinal stromal tumors (GIST) are rare. Neo-adjuvant therapy with imatinib is recommended for locally advanced or non-resectable tumors. Case report: We report a 63 years old woman with a malignant GIST located in the recto-vaginal septum which was initially considered non-resectable. The patient was treated with imatinib as induction therapy for three months. After this lapse the tumor was successfully excised using an endo-anal approach. Due to a tumor size over 5 cm and the presence of 13 mitoses per 50 high power fields, two bad prognostic factors, treatment with imatinib was maintained for 15 months after surgery. After 20 months of follow up, the patient is free of disease with complete fecal continence and with an adequate sexual life. Secondary effects of imatinib are gradually subsiding.

Leucemia eosinofílica crónica con respuesta hematológica sostenida tras tratamiento con bajas dosis de imatinib / Sustained hematologic response in chronic eosinophilic leukemia with low dose imatinib. Report of one case

We report a 58 year-old-man without comorbid conditions, with a history of two months of weight loss, malaise and headache. His initial laboratory analysis showed leukocytosis of 16,100/mL with 65% eosinophils and an absolute eosinophil count of 10,465/mL. Both bone marrow biopsy and aspirate showed infiltration by mature appearing eosinophils. Treatment was started with hydroxyurea, associated with prednisone without satisfactory decrease in the eosinophil count. Polymerase chain reaction showed the presence of the gene fusion product FIP1L1/PDGFRA. Imatinib therapy was initiated, resulting in a rapid and progressive reduction in the absolute eosinophil count, with normalization at the second week of treatment. The incidence of the myeloproliferative variant causing hypereosinophilic syndrome is rare. However, the dramatic response to imatinib emphasizes the need to study the presence of the fusion product FIP1L1/PDGFRA in all patients with eosinophilia of unknown etiology.

Chronic myeloid leukemia in case of Klinefelter syndrome.

Klinefelter syndrome (KS) is a sex chromosome disorder and has been reported to be associated with increased risk for malignancies. We report a 22‑year‑old male patient who was diagnosed to have chronic myeloid leukemia in chronic phase. Bone marrow cytogenetic examination revealed karyotype 47, XXY, t (9; 22)(q34, q11) suggestive of KS with presence of Philadelphia chromosome. The patient was treated with oral imatinib mesylate (400 mg/day). Complete hematological response was achieved after 2 months of therapy. The bcr‑abl/abl transcript percentage measured from peripheral blood at baseline, 1 and 2 years after imatinib were 97%, 1.99%, 0.007%, respectively. He remains in complete hematological and major molecular remission after 2 years of continued imatinib therapy.

Imatinib mesylate as first‑line therapy in patients with chronic myeloid leukemia in accelerated phase and blast phase: A retrospective analysis.

INTRODUCTION: Imatinib is a bcr‑abl tyrosine kinase inhibitor which has revolutionized the treatment for chronic myeloid leukemia (CML). Even though there is much data on CML chronic phase, there is limited data on imatinib‑naïve advanced phase CML. MATERIALS AND METHODS: We retrospectively analysed 90 patients with advanced phase CML (accelerated phase [AP]: 51 and blast crisis [BC]: 39), patients who received imatinib as frontline therapy. RESULTS: The median age of presentation in CML‑AP and CML‑BC were 32 years (12‑61) and 39 years (8‑59), respectively. Imatinib at 600 mg/day was initiated within 2 weeks of diagnosis. Median time to complete hematological response in both CML‑AP and CML‑BC was 3 months (CML‑AP: 1‑9 months and CML‑BC: 1‑14 months). At 6 months 30 (59%) CML‑AP and 15 (38%) CML‑BC patients achieved major cytogenetic response (MCyR), of them 24 (47%) and 10 (25.6%) being the complete cytogenetic response, respectively. At a median follow‑up of 41 months, the median overall survival in CML‑AP was 61 months, but in CML‑BC it was 14 months. The median progression‑free survival and event‑free survival were 30 months and 23 months in CML‑AP and 14 and 12 months in CML‑BC, respectively. On univariate analysis, performance status (PS), spleen size, and MCyR predicted survival in AP, whereas in BC, platelet count, PS, and early MCyR were predictive. Non‑hematologic and hematologic adverse events were observed in 80% and 60% of patients, respectively. Dose was reduced in 10% of patients for grade IV toxicity and interrupted in 30% for grade III toxicity. CONCLUSION: Front‑line imatinib is an option in advanced phases of CML especially in CML‑AP in low‑resource countries, where stem cell transplantation and alternate TKIs are not available.

A Case of Isolated Lymphoblastic Relapse of the Central Nervous System in a Patient with Chronic Myelogenous Leukemia Treated with Imatinib

No abstract available.

Rapid Sequential Gain of ABL1 Kinase Domain Mutations with a Complex Karyotype in the Progression of Chronic Myelogenous Leukemia

No abstract available.

Chronic myeloid leukemia as a secondary malignancy after diffuse large B-cell lymphoma

No abstract available.

Inibidores da fosfodiesterase do tipo 5 e perda auditiva neurossensorial subita / Phosphodiesterase Type 5 Inhibitors and sudden sensorineural hearing loss

O uso de inibidores da fosfodiesterase do tipo 5 como sildenafil, vardenafil e tadalafil tem aumentado atualmente e alguns destes pacientes vêm apresentando perda auditiva neurossensorial súbita. OBJETIVO: Apresentar dois casos de pacientes que apresentaram surdez súbita em uso eventual do medicamento e revisar estudos sobre o uso de inibidores da fosfodiesterase do tipo 5 e surdez súbita. MÉTODO: Estudo analítico de dois casos e revisão sobre o tema no banco de dados da Pubmed/ MedLine e Bireme utilizando as palavras-chave inibidores da fosfodiesterase e surdez súbita e seus correlatos na língua inglesa. RESULTADOS: Os pacientes analisados são jovens, sem comorbidades, em uso de inibidores da fosfodiesterase do tipo 5 e após terapia combinada para o tratamento da surdez súbita, apenas um deles obteve melhora auditiva. Nove estudos científicos foram encontrados. Estudos pré-clínicos e clínicos, transversais e prospectivos foram revisados. CONCLUSÃO: O aumento da ocorrência na prática clínica e relatos científicos na literatura sugerem que o uso de inibidores da fosfodiesterase do tipo 5 seja encarado como fator de risco para surdez súbita. Novos estudos com amostras maiores e grupo controle são necessários para investigar esta associação. .

Phosphodiesterase type 5 Inhibitors, such as sildenafil, vardenafil and tadalafil have been increasingly used today and some of the users have developed sudden sensorineural hearing loss. OBJECTIVE: To present two patients with sudden deafness developed after an occasional use of the drug and review studies on the use of phosphodiesterase type 5 inhibitors and sudden hearing loss. METHOD: Analytical study of two cases and review of the subject matter in the Pubmed/Medline and Bireme databases using the keywords: phosphodiesterase type 5 inhibitors and sudden deafness and its correlates in the English language. RESULTS: The patients analyzed are young without additional disorders, using phosphodiesterase type 5 inhibitors, and after combination treatment for sudden hearing loss only one had hearing improvement. We found nine scientific studies and reviewed preclinical studies, clinical trials, prospective and cross-sectional investigations. CONCLUSION: Increased occurrence in clinical practice and scientific reports in the literature suggest that the phosphodiesterase type 5 inhibitors are considered a risk factor for sudden deafness. Further studies with larger samples and control groups are needed for better assessing this association. .

Adherence to treatment with imatinib in chronic myeloid leukemia: a study of the first decade of responses obtained at a Brazilian hospital

Objetive: The aim of this study was to identify the reasons for failure in adherence to imatinib mesylate treatment in chronic myeloid leukemia. Methods: A retrospective review was performed of 100 non-electronic records of patients with Ph+ chronic myeloid leukemia treated with imatinib mesylate. The study period was from January 2001 to January2011. Data were analyzed by Chi-Square and Correspondence analysis using the Statistical Analysis System software package. Results: At the beginning of treatment 41% of patients were in advanced stages of the disease. The unavailability of the drug (44.8%) and myelotoxicity (25.7%) were the most frequent reasons for interruption. The adherence rate was < 90% in 47% of the cases. The low adherence influenced the cytogenetic response (p-value = 0.020) and molecular response (p-value = 0.001). Very high adherence (> 95%) induced complete cytogenetic response, major cytogenetic response and major molecular response. Conclusion: The population of this study obtained lower-than-expected therapeutic responses compared to other studies. .

P2Y12 inhibitors in acute coronary syndromes: Which and when.

Acute coronary syndromes (ACS) are the commonest acute manifestation of coronary artery disease and a major cause of hospitalization and death. Plaque rupture and subsequent platelet activation are the key factors in its pathogenesis. Platelet inhibitors are crucial in the management of ACS. Aspirin remains the standard antiplatelet but use of dual antiplatelet drugs is beneficial in ACS. Platelet P2Y12 receptor inhibitors are an important group of antiplatelet compounds that can be combined with aspirin in the management of ACS. P2Y12 inhibitors may belong to the thienopyridine or nonthienopyridine group of compounds. The former (clopidogrel, prasugrel) combine irreversibly with the receptor and therefore have a prolonged duration of action. On the other hand, the non-thienopyridine compounds (ticagrelor, elinogrel) have a reversible action and hence a shorter duration of action. Several new compounds in this group have become or are likely to become available. The newer agents have a more uniform and complete antiplatelet effect and are much less likely to be affected by genetic variability of CYP2C19 enzyme activity compared with that of clopidogrel. Large phase 3 trials have shown that ticagrelor and prasugrel reduce major cardiovascular events in ACS compared to clopidogrel when given in addition to aspirin. This is accompanied by some increase in bleeding. This review discusses the properties, clinical profile and possible place of P2Y12 receptor inhibitors in clinical practice.