To compare the efficacy and incidence of severe hematological adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia / 中华血液学杂志

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.

Cholesteryl ester transfer protein inhibitory oxoacetamido-benzamide derivatives: Glide docking, pharmacophore mapping, and synthesis

Abstract Dyslipidemia is an abnormal lipid profile associated with many common diseases, including coronary heart disease and atherosclerosis. Cholesteryl ester transfer protein (CETP) is a hydrophobic plasma glycoprotein that is responsible for the transfer of cholesteryl ester from high-density lipoprotein athero-protective particles to pro-atherogenic very low-density lipoprotein and low-density lipoprotein particles. The requirement for new CETP inhibitors, which block this process has driven our current work. Here, the synthesis as well as the ligand-based and structure-based design of seven oxoacetamido-benzamides 9a-g with CETP inhibitory activity is described. An in vitro study demonstrated that most of these compounds have appreciable CETP inhibitory activity. Compound 9g showed the highest inhibitory activity against CETP with an IC50 of 0.96 µM. Glide docking data for compounds 9a-g and torcetrapib provide evidence that they are accommodated in the CETP active site where hydrophobic interactions drive ligand/CETP complex formation. Furthermore, compounds 9a-g match the features of known CETP active inhibitors, providing a rationale for their high docking scores against the CETP binding domain. Therefore, these oxoacetamido-benzamides show potential for use as novel CETP inhibitors

Fluid Retention Associated with Imatinib Treatment in Patients with Gastrointestinal Stromal Tumor: Quantitative Radiologic Assessment and Implications for Management

OBJECTIVE: We aimed to describe radiologic signs and time-course of imatinib-associated fluid retention (FR) in patients with gastrointestinal stromal tumor (GIST), and its implications for management. MATERIALS AND METHODS: In this Institutional Review Board-approved, retrospective study of 403 patients with GIST treated with imatinib, 15 patients with imaging findings of FR were identified by screening radiology reports, followed by manual confirmation. Subcutaneous edema, ascites, pleural effusion, and pericardial effusion were graded on a four-point scale on CT scans; total score was the sum of these four scores. RESULTS: The most common radiologic sign of FR was subcutaneous edema (15/15, 100%), followed by ascites (12/15, 80%), pleural effusion (11/15, 73%), and pericardial effusion (6/15, 40%) at the time of maximum FR. Two distinct types of FR were observed: 1) acute/progressive FR, characterized by acute aggravation of FR and rapid improvement after management, 2) intermittent/steady FR, characterized by occasional or persistent mild FR. Acute/progressive FR always occurred early after drug initiation/dose escalation (median 1.9 month, range 0.3-4.0 months), while intermittent/steady FR occurred at any time. Compared to intermittent/steady FR, acute/progressive FR was severe (median score, 5 vs. 2.5, p = 0.002), and often required drug-cessation/dose-reduction. CONCLUSION: Two distinct types (acute/progressive and intermittent/steady FR) of imatinib-associated FR are observed and each type requires different management.

Evaluation of new gastro-intestinal prokinetic (ENGIP-I) study.

The ENGIP-I study was conducted to investigate the efficacy, and safety of itopride in patients of gastro-oesophageal reflux disease. There were significant reductions in heartburn frequency, heartburn severity, gastro-oesophageal regurgitation frequency at day 3 only. ENGIP-I study concluded that itopride was well tolerated by patients and appears to be the drug of choice in patients with gastro-oesophageal reflux disease.

Efficacy and tolerability of itopride hydrochloride in patients with non-ulcer dyspepsia.

To document the clinical efficacy and tolerability of itopride hydrochloride in patients with non-ulcer dyspepsia an open-label, non-comparative study, was undertaken at the Medical College, Thiruvananthapuram, among patients with endoscopically confirmed diagnosis of non-ulcer dyspepsia or chronic gastritis. Itopride hydrochloride 50 mg (1 tablet) thrice a day for 2 weeks was administered among them. Relief of symptoms at the end of two weeks treatment, assessed as marked/complete, moderate, slight, none or worse; QT interval on ECG; adverse events; haemogram; serum chemistry for hepatic and renal functions. None had QT prolongation on ECG. At the end of 2 weeks' treatment, moderate to complete relief of symptoms was reported by 22 patients (73%), whereas 5 (17%) reproted slight improvement, and 3 (10%) reported no improvement. Clinical tolerability was excellent in 28 patients (93%) and good in 2 (7%). None of the patients had any prolongation of QT on ECG, nor did any patient show any abnormality in haemogram or serum chemistry during the treatment.

Efeitos da moclobemida sobre os processos mnemônicos e de aprendizagem em ratos, em modelo de condicionamento operante / Effects of moclobemide on mnemonics and learning processes in an operative behavior of rats

A moclobemida, um antidepressivo inibidor reversível da MAO-A, foi utilizada num experimento em ratos no intuito de verificar se a droga provoca alguma alteração no comportamento discriminatório. Não foi encontrado na literatura nenhum experimento similar onde foram usados animais. No experimento foi utilizada a caixa de Skinner como meio de avaliação e observação do comportamento do animal. Os ratos foram treinados a associar o estímulo luminoso ao ato de beber água. No grupo controle, o índice discriminativo manteve-se praticamente constante (97 por cento), e no grupo tratado com moclobemida observou-se uma queda significativa de 97 por cento para 72 por cento ao final do experimento. Com resultados obtidos no experimento, concluímos que a moclobemida tem efeitos deletérios na memória dos animais de experimentação

Efectos indeseables de las benzamidas / Undesirables effects of the benzamides

La benzamidas constituyen un grupo farmacológico, conocido también por ortopramidas, que se caracterizan por bloquear de forma diferenciada y específica grupos selectivos de receptores dopaminérgicos a nivel del sistema nervioso central. Fundamentalmente, estos fármacos tienen su principal aplicación, no sólo a nivel del SNC, sino también a nivel del aparato digestivo, bien por su efecto antipsicótico o antidepresivo, bien como antieméticos o reguladores del peristaltismo gastrointestinal. De este modo podríamos dividir a las benzamidas en un primer grupo de fármacos con caracteres neurolépticos, y un segundo con característica antieméticas; y aunque cualquier fármaco de esta familia sea capaz de ejercer ambas funciones, la acción principal que pueda producir sin causar efectos tóxicos le incluirá en alguno de los dos grupos mencionados. Dentro del primer subgrupo farmacológico, aquel con caracter neurolépticos, cabría incluir, principalmente, a la sulpirida, tiaprida y remoxiprida

Eficácia e tolerabilidade da moclobemida em dois regimes terapêuticos no tratamento de episódios depressivos maiores / Efficacy and tolerability of moclobemide in two therapeutic regimens for treatment of major depressive episodes

O antidepressivo moclobemida, da classe das benzamidas, exerce seus efeitos farmacológicos e químicos por inibiçäo predominante da monoaminoxidase A. Seu espectro de atividade antidepressiva é mais amplo e a interaçäo com a tiramina é muito menor que a dos IMAOs clássicos. Dados preliminares sugeriam que a droga apresentava eficácia comparável em regime de administraçäo três ou duas vezes ao dia, sendo a melhor tolerabilidade nesse último regime terapêutico. Em estudo aberto prospectivo e randomizado, compararam-se esses regimes terapêuticos em paciente adultos, dos sexos masculino e feminino, com episódios depressivos maiores de acordo com definiçäo dos DSM-III-R. O protocolo, aprovado pelo Comitê de Ética em Pesquisa das intituiçöes, obedeceu as normas da Declaraçäo de Helsinque-Tóquio-Veneza-Hong-Kong com consentimento escrito, após informaçäo, de todos os pacientes participantes. As doses utilizadas foram 300-450mg/dia e a duraçäo do tratamento foi de oito semanas. Os regimes terapêuticos foram: Regime BID: 300 a 450mg/dia em doses individuais, administradas pela manhä e à noite; Regime TID: 450mg em doses divididas, três vezes ao dia. A Escala de Depressäo de Hamilton e a Impressäo Clínica Global para eficácia e tolerabilidade, bem como um questionário para análise do sono foram avaliados pré-tratamento e cinco vezes durante o tratamento de 56 dias. Anamnese e exame físico, eletrocardiograma e exames de laboratório foram feitos antes e depois do tratamento. Os efeitos colaterais adversos foram avaliados em cada visita de evoluçäo (5 visitas) e os pacientes foram instruídos para procurar o serviço em qualquer ocasiäo, caso tivessem qualquer intercorrência. Näo houve qualquer restriçäo da dieta alimentar. Foram incluídos 64 pacientes, ambulatoriais, com idades entre 18 e 63 anos, com média de 38,6. Trinta e quatro pacientes foram incluídos no Regime BID e 30 no Regime TID, sendo que näo houve qualquer diferença demográfica expressiva entre os grupos. A média da soma de escores da Escala de Hamilton antes do tratamento foi de 34,3 ñ 3,6 BID e 34,1 ñ 4,0 no regime TID. A eficácia da moclobemida näo diferiu significativamente no tratamento BID e TID