Clinical utility of dabigatran in United Arab Emirates: A pharmacovigilance study

Objectives:

To provide early data regarding clinical utility of dabigatran in Al-Ain, United Arab Emirates (UAE).

Methods:

This was an ethics approved retrospective cross sectional study. We retrieved a total of 76 patients who were using dabigatran from September to December 2014 in the Cardiology Clinic at Al-Ain Hospital, Al-Ain, UAE. The primary analysis was designed to test the frequency of bleeding events (rate) with dabigatran 75, 110, and 150 mg.

Results:

The mean age ± standard deviation of cohort was 67.9 ± 1.5 years (range; 29-98 years), composed of males (52.6%) with mean age of 66.3 ± 1.7 years, and females (47.4%) with mean age of 69.6 ± 1.1 years. The highest age group was those between 61-80 years (60.5%). Most comprised the age strata of ≤75 years (73.7%). The main indication for dabigatran use was atrial fibrillation. The rate of bleeding with dabigatran was 18/76 (23.7%), and melena was the leading cause of bleeding 8/76 (10.7%). The hospitalization rate was 67.1%, dabigatran withdrawal rate was 0.01%, and mortality rate was 6.5%. The cohort had exhibited incidences of minor bleeding with one fatal major bleeding, high co-morbidities, admission, and readmission, which was not directly linked to dabigatran. We did not identify any relation of death due to dabigatran.

Conclusion:

Dabigatran is a suitable alternative to warfarin obviating the need for repetitive international normalized ratio monitoring, however, it may need plasma drug monitoring.Atrial fibrillation (AF) is the most common cardiac arrhythmia that affects 1-1.5% of population worldwide.1 Atrial fibrillation prevalence increases with age, and rises from 0.7% in those between 55-59 years to 17.8% in those ≥85 years. Nearly 85% of patients with AF are aged >65 years old.2 The lifetime risk for the development of AF as demonstrated in the Framingham study was one in 4 for men and women aged ≥40 years,3 which pose certain concerns in countries with aging populations.4,5 In addition to this, hospitalization related to AF is alarmingly increasing.6 The risk of stroke in patients with AF is 5 folds, and systemic thromboembolism is 3 folds.7,8 Banerjee, et al9 has deployed stroke prevention score in patients with AF, however, the predictive value is of less magnitude. The European Society of Cardiology set estimation of stroke risk in patients with AF as per CHA₂DS₂-VASc score to determine the recommendation for initiating an oral anticoagulant,10 whereas in patients with CHA₂DS₂-VASc ≥2, HAS-BLED score can be used to assess the risk of bleeding, and commencement of anticoagulant.11Warfarin (vitamin K antagonist [VKA]) has proven efficacy in reducing the risk of stroke in patients with AF, however, it poses high bleeding incidences, emergency hospitalizations, unpredictable therapeutic effect, and multiple international normalized ratio (INR) tests leading to many limitations in its clinical utility.12 Novel oral anticoagulants (NOACs) are proved as effective anticoagulants in prevention of stroke in patients with AF. Novel oral anticoagulants were preferred in non-valvular AF, and do not require coagulation monitoring, however, strict adherence to approved indication is highly warranted.13 Dabigatran (Pradaxa^®), a competitive inhibitor of thrombin was approved in October 2010 by the United States of America Food and Drug Administration to reduce the risk of stroke, and systemic embolism in patients with non-valvular AF.14 A systematic review incorporated 6 economic reviews from diverse healthcare systems (USA, Canada, and United Kingdom) utilizing different economic models. It has suggested the benefit of dabigatran in patients with high-risk of stroke, high-risk of intra-cerebral hemorrhage, or suboptimal use of warfarin. The review outlined concerns on tolerability of dabigatran, adherence issues, and adverse consequences.15In comparison with warfarin, dabigatran 150 mg has shown low rates of stroke, and systemic embolism (dabigatran p<0.001 for superiority). However, both drugs exhibited comparable rates of major hemorrhage.16-18 Greater fatal, and non fatal bleeding events were reported with dabigatran than warfarin.19,20 A recent (2015) retrospective Medicare data analysis study20 on dabigatran’s safety highlighted that the incidence of bleeding was higher than with warfarin (33% versus 27%), major bleeding (9% versus 6%), and gastrointestinal bleeding (17% versus 10%). Intracranial hemorrhage occurred more often with warfarin than dabigatran (1.8% versus 0.6%).20 It has been documented that risks of major bleeding from dabigatran is high for patients with chronic kidney disease, and in African Americans.20 The Randomized Evaluation of Long-term Anticoagulant Therapy: Dabigatran versus warfarin-RE-LY studies18 have showed similar risk of bleeding with warfarin versus dabigatran in patients with non-valvular AF. This dictated the importance of age sub-group analysis in studies. In real clinical practice, patients from different countries may have more co-morbid conditions than those in the RE-LY study.21 The current available data around bleeding incidences from dabigatran is relevant to populations with diverse characteristics. Revealing the clinical utility of dabigatran in our Emirati population may demonstrate different perspectives. Therefore, we intend to provide early data around the clinical utility of dabigatran in United Arab Emirates (UAE) Emirati population.     

Failure of recombinant human interleukin-3 therapy to induce erythropoiesis in patients with refractory Diamond-Blackfan anemia [see comments]

In two previous studies, we observed that recombinant human interleukin- 3 (IL-3) induced an increase in marrow burst-forming unit-erythroid- derived colonies in vitro in some patients with Diamond-Blackfan anemia (DBA). To determine whether a similar erythropoietic response could be induced in vivo, we treated 13 patients with DBA (aged 4 to 19 years) with two preparations of IL-3. All patients had absent absolute reticulocyte counts and markedly reduced to absent recognizable bone marrow erythroid elements; patients with circulating reticulocytes in the previous 12 months were excluded from study. All patients except 1 had failed steroid therapy and had been transfusion-dependent since infancy; 1 patient was maintained on high-dose prednisone at the time of enrollment. On the first arm of the study, IL-3 (Immunex Corp, Seattle, WA) was administered subcutaneously using a dose escalation regimen of 125 to 500 micrograms/m2/day in divided dosage at 12-hour intervals, coadministered with 1.5 mg/kg/d of oral ferrous sulphate. Of the 13 patients that entered the trial, 4 stopped prematurely because of adverse side effects. In the other 9 evaluable cases, reticulocytes increased transiently in 1 patient from 0 to 65 x 10(9)/L after 35 days of IL-3 therapy at 250 micrograms/m2, but transfusion dependency persisted. One transient peak in absolute reticulocyte count was noted in 6 other patients, but no erythroid response was observed after completion of a full course of IL-3. Oral prednisone at 0.5 mg/kg/d was then coadministered with IL-3 at 500 micrograms/m2 to 5 of the patients without effect, and treatment was stopped. In 2 patients, a second preparation of IL-3 (Sandoz Canada Inc, Dorval, Quebec, Canada) was initiated in a dose escalation regimen of 2.5 to 10 micrograms/kg and was coadministered with ferrous sulphate. No erythroid response was observed in either patient, and in one of the two, alternate-day subcutaneous recombinant erythropoietin at 300 U/kg was administered for 3 weeks in combination with daily IL-3 at 10 micrograms/kg, but no increased erythropoiesis was seen. Significant increases in white blood cell and eosinophil counts during administration of both preparations of IL-3 were observed in all patients. These data show that the response of DBA patients to IL-3 in vivo is heterogeneous and cannot be predicted from in vitro studies. The absence of a corrective effect of IL-3 in these patients with DBA indicates that a deficiency of the cytokine is not central in the pathogenesis of the disorder.     

白花蛇舌草-半枝莲药对组分对结肠腺癌Lovo细胞生物学行为的影响

摘要:目的　探讨白花蛇舌草-半枝莲药对组分对结肠腺癌Lovo细胞增殖、侵袭、迁移和凋亡的影响及作用机制。方法　将白花蛇舌草、半枝莲按质量1∶1进行3次煎煮,获得水提物,后取适量浸膏用石油醚回流脱脂,再以乙酸乙酯进行多次萃取,获得白花蛇舌草-半枝莲药对组分,并计算得率。实验分为对照组（正常培养Lovo细胞）、白花蛇舌草-半枝莲药对组分低剂量组（10 mg/L）、中剂量组（30 mg/L）及高剂量组（50 mg/L）。通过噻唑蓝比色法（MTT）检测各组细胞培养24、48、72 h后的增殖抑制率。各组细胞培养48 h后,流式细胞仪检测细胞周期分布;Transwell实验检测细胞侵袭能力;划痕实验检测细胞迁移能力;TUNEL法检测细胞凋亡情况;Western blot法检测Grb2相关结合蛋白1（Gab1）、血管内皮生长因子受体2（VEGFR-2）、磷脂酰肌醇3-激酶（PI3K）、苏氨酸激酶（Akt）、基质金属蛋白酶-9（MMP-9）、B淋巴细胞瘤-2基因（Bcl-2）、Bcl-2相关X蛋白（Bax）蛋白表达情况。结果　化学萃取后的白花蛇舌草-半枝莲药对中主要含有对羟基苯乙酮、野黄芩苷、木犀草素和芹菜素4种化合物,组分得率为0.61%。与对照组相比,低、中、高剂量组细胞增殖抑制率升高,G1期肿瘤细胞比例增加,细胞凋亡指数增高,侵袭细胞数和划痕闭合率明显减小（均P＜0.05）,细胞中Gab1、VEGFR-2、PI3K、Akt、MMP-9、Bcl-2蛋白表达降低,Bax表达升高（均P＜0.05）,且存在剂量依赖性。结论　白花蛇舌草-半枝莲药对组分可抑制结肠腺癌Lovo细胞的增殖,降低其迁移和侵袭能力,诱导细胞凋亡,其机制可能与抑制Gab1/VEGFR-2/PI3K/Akt信号通路活化有关。     

Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation

The effects of granulocyte-macrophage colony-stimulating factor (GM- CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T- cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM- CSF responsive cell type, thymic AC and T cells were examined for GM- CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single- cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.