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Reid M.E.,University of the West Indies | El Beshlawy A.,Cairo University | Inati A.,Rafik Hariri University | Kutlar A.,Georgia Regents University | And 8 more authors.
American Journal of Hematology | Year: 2014

This placebo-controlled phase II study evaluated the pharmacodynamics, efficacy and safety of 2,2-dimethylbutyrate (HQK-1001), a fetal globin gene-inducing short-chain fatty acid derivative, administered orally at 15 mg/kg twice daily for 48 weeks in 76 subjects with sickle cell disease (SCD). The median age was 26 years (range: 12-55 years) and 37 subjects (49%) were treated previously with hydroxycarbamide. Sixty subjects (79%) had Hb SS and 16 (21%) had S/β0 thalassemia. The study was terminated after a planned interim analysis showed no significant increase in fetal hemoglobin (Hb F) and a trend for more pain crises in the HQK-1001 group. For 54 subjects with Week 24 data, the mean absolute increase in Hb F was 0.9% (95% confidence interval (CI): 0.1-1.6%) with HQK-1001 and 0.2% (95% CI: -0.7-1.1%) with placebo. Absolute increases in Hb F greater than 3% were noted in 9 of 38 subjects (24%) administered HQK-1001 and 1 of 38 subjects (3%) administered placebo. The mean changes in hemoglobin at Week 24 were comparable between the two groups. The mean annualized rate of pain crises was 3.5 with HQK-1001 and 1.7 with placebo. The most common adverse events in the HQK-1001 group, usually graded as mild or moderate, consisted of nausea, headache, vomiting, abdominal pain, and fatigue. Additional studies of HQK-1001 at this dose and schedule are not recommended in SCD. Intermittent HQK-1001 administration, rather than a daily regimen, may be better tolerated and more effective, as shown previously with arginine butyrate, and warrants further evaluation. Am. J. Hematol. 89:709-713, 2014. © 2014 Wiley Periodicals, Inc.

Musallam K.M.,University of Milan | Musallam K.M.,American University of Beirut | Cappellini M.D.,University of Milan | Taher A.T.,American University of Beirut | Taher A.T.,Chronic Care Center
Blood Cells, Molecules, and Diseases | Year: 2013

Iron overload may still occur in transfusion-independent patients with β-thalassemia intermedia due to increased intestinal iron absorption. In this study, we evaluated the association between iron overload, using a liver iron concentration threshold of therapeutic significance (≥. 5. mg/g), and morbidity in 168 chelation naive patients with β-thalassemia intermedia. We demonstrated that patients with a liver iron concentration ≥. 5. mg/g have a significantly higher prevalence of several serious vascular and endocrine/bone morbidities than do patients with <. 5. mg/g, and we established absolute morbidity risk values differentiating both groups. We also demonstrated that the association between iron overload and morbidity in such patients is independent of the effects of advancing age and disease severity. These findings suggest that treating iron burden in β-thalassemia intermedia may be associated with reduction in serious morbidity risk. © 2013 Elsevier Inc.

Musallam K.M.,American University of Beirut | Beydoun A.,American University of Beirut | Hourani R.,American University of Beirut | Nasreddine W.,Rafik Hariri University | And 3 more authors.
European Journal of Haematology | Year: 2011

Background: Hypercoagulability and venous thromboembolism are common in patients with β-thalassemia intermedia (TI), especially in the splenectomized adult. Although arterial involvement is not commonly reported, we have recently observed a high prevalence (60%) of silent brain infarction on brain MRI in 30 splenectomized adults with TI. The pathophysiology of these white matter lesions remains unknown. Methods:In this prospective work, we evaluated magnetic resonance angiography (MRA) scans of the same cohort of 30 patients. Data collected were the presence or absence of vascular lesions, their locations, and severity. Correlations between MRA abnormality and patients/disease characteristics were evaluated. Comparisons between MRA and previous MRI findings were made. Results: Of 29 evaluable patients, 8 (27.6%) had evidence of arterial stenosis on MRA. The majority of lesions had mild narrowing and mostly involved the internal carotid artery. Five patients (17.2%) had evidence of aneurysms. Low total hemoglobin and high non-transferrin-bound iron levels independently characterized patients with evidence of stenosis on MRA. Among the 18 patients with silent brain infarction on MRI, three had evidence of stenosis on MRA with only one patient having lesions that could explain the silent infarcts. Conclusions:Cerebral vasculopathy is common in splenectomized adults with TI. However, large-vessel disease does not explain the occurrence of silent brain infarction. The combined use of MRA and MRI better identifies splenectomized TI adults with neuroimaging abnormalities. © 2011 John Wiley & Sons A/S.

Mallat N.S.,American University of Beirut | Mallat S.G.,American University of Beirut | Musallam K.M.,Foundation Medicine | Taher A.T.,American University of Beirut | Taher A.T.,Chronic Care Center
Journal of Nephrology | Year: 2013

Improvement of survival in patients with β-thalassemia has allowed several clinical morbidities to manifest, including renal complications. Patients may experience proximal tubular dysfunctions and abnormalities in glomerular filtration rate. Several risk factors have been proposed. Hypoxia may lead to renal damage with resulting proximal tubular epithelial cell dysfunction and interstitial fibrosis, while anemia induces renal hemodynamic changes. Iron overload secondary to regular transfusion therapy can also result in an increase in oxidative stress and direct cytotoxicity to the kidney. Moreover, the use of certain iron-chelating agents is associated with a transient, nonprogressive increase in serum creatinine levels. However, most available evidence comes from small, cross-sectional studies. Longitudinal follow-up of patients is needed to better understand the mechanisms of renal abnormalities in this patient population. © 2013 Società Italiana di Nefrologia.

Farra C.,American University of Beirut | Awwad J.,American University of Beirut | Fadlallah A.,Hotel Dieu de France Hospital | Sebaly G.,Hotel Dieu de France Hospital | And 6 more authors.
Journal of Community Genetics | Year: 2012

This study aims to investigate the association of human leukocyte antigen (HLA) class II genes and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with autoimmune thyroid diseases in the Lebanese population. A total of 128 patients with autoimmune thyroid disease (55 with Graves' disease (GD) and 73 with Hashimoto's thyroiditis (HT)) were typed for HLA DQA1 (0301 and 0501) and DQB1 (0201, 0302, and 0303) and for 49A/G CTLA-4 using PCR-based sequence-specific priming methods. A total of 186 matched controls were typed for the same alleles and compared to the diseased population. Results showed no significant differences in HLA DQB1*0201 or DQB1 *0301 allelic frequencies or CTLA-4 polymorphisms between patients and controls. For GD, there was a weak association with HLA DQB1 *0302 [34.6% (19 of 55) vs. 21.5% (40 of 186), P00.048, odds ratio (OR)01.926, confidence interval (CI)00.999-3.715] and HLA DQB1 *0302-DQA1*0501 haplotype [56.36% (31 of 55) vs. 40.8% (76 of 186), P00.042, OR01.870, CI01.018-3.433]. For HT, the frequencies of DQB1*0302-DQA1*0501 haplotype [28.8% (21 of 73) vs. 14.5% (27 of 186), P00.008, OR02.378, CI01.241-4.558] and DQB1*0302-DQA1*0301 haplotype [60.2% (44 of 73) vs. 38.7% (72 of 186), P00.002, OR02.402, CI01.381-4.180] were significantly higher in patients. On the other hand, weak association was found between HT and DQA1*0301 allele [32.9% (24 of 73) vs. 20.9% (39 of 186), P00.044, OR01.846, CI01.011-3.373]. Findings show that DQB1 *0302-DQA1*0501 and DQB1 *0302-DQA1*0301 haplotypes may play a role in the pathogenesis of HT in the Lebanese population. For the 49A/G CTLA-4 polymorphism, no significant difference was found between patients and controls. © Springer-Verlag 2012.

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