Warfarin is extensively metabolized by cytochrome P450 2C9 (CYP2C9). Concomitant use with the potent CYP2C9 inducer, rifampin, requires close monitoring and dosage adjustments. Although, in theory, warfarin dose increase should overcome this interaction, most reported cases over the last 50 years have not responded even to high warfarin doses, but some have responded to modest doses. To investigate the genetic polymorphisms' impact on this unexplained interpatient variability, we performed genotyping of CYP2C9, VKORC1, and CYP4F2 for warfarin and rifampin concomitant receivers from 2016 to 2022 at Hamad Medical Corporation, Doha, Qatar. We identified and included 36 patients: 22 responders and 14 nonresponders. Warfarin‐responders were significantly more likely to have one or more warfarin‐sensitizing CYP2C9/VKORC1 alleles than nonresponders (odds ratio = 23.2, 95% confidence interval = 3.2–195.6; P = 0.0001). The mean genetic‐based pre‐interaction calculated dose was significantly lower for responders than for nonresponders (P < 0.001); and was negatively correlated with warfarin sensitivity index (WSI) (r = −0.58; P = 0.0002). The median percentage time in therapeutic range and mean WSI were significantly higher in the warfarin‐sensitizing CYP2C9/VKORC1 alleles carriers than noncarriers (P = 0.017 and 0.0004, respectively). Whereas the warfarin‐sensitizing CYP2C9/VKORC1 genotypes were associated with modest on‐rifampin warfarin dose requirements, the noncarriers would have required more than double these doses to respond. Warfarin‐sensitizing CYP2C9/VKORC1 genotypes and low genetic‐based warfarin calculated doses were associated with higher warfarin sensitivity and better anticoagulation quality in patients receiving rifampin concomitantly.

Pharmacogenomics (PGx) is a crucial part of precision medicine; however, its integration into clinical practice has been slow, primarily due to knowledge gaps regarding pharmacogenomics among healthcare professionals (HCPs). Pharmacogenomics education is considered the most influential barrier to the successful implementation of PGx. In the Middle East and North Africa (MENA) region, several studies have highlighted the lack of PGx education among students and HCPs. This scoping review aims to provide an overview of the existing literature on how PGx is delivered in the curricula and its impact on knowledge acquisition among students and HCPs in the MENA region. A database search of PubMed, Embase, and CINAHL was conducted up to June 2023. Outcomes included PGx education availability, curriculum placement, mode of delivery, and knowledge level. Seven cross‐sectional studies were identified (2014–2023), with 57% from the Gulf region. PGx education is mostly taught to undergraduates (71%) through didactic lectures (100%), with only a few studies reporting a standalone course (29%). Participants demonstrated low (43%) to moderate (43%) knowledge levels, assessed using objective scales or subjective self‐assessment after completion of the course. Reported barriers to implementing PGx education included knowledge gaps, economic constraints, and system sustainability. PGx education in the MENA region is delivered mainly as an integrated course in professional programs including pharmacy and medicine, and the overall knowledge level was low to moderate. Future research could focus on providing more detailed reporting of the PGx educational landscape, developing standardized assessment tools, and evaluating actual knowledge acquisition among different professions.

Different dosing strategies exist to initiate warfarin, most commonly fixed warfarin dosing (FWD), clinical warfarin dosing (CWD), and genetic‐guided warfarin dosing (GWD). Landmark trials have shown GWD to be superior when compared to FWD in the EU‐PACT trial or CWD in the GIFT trial. COAG trial did not show differences between GWD and CWD. We aim to compare the anticoagulation quality outcomes of CWD and FWD. This is a prospective cohort study with a retrospective comparator. Recruited subjects in the CWD (prospective) arm were initiated on warfarin according to the clinical dosing component of the algorithm published in www.warfarindosing.org. The primary efficacy outcome was the percentage time in the therapeutic range (PTTR) from day 3 to 6 till day 28 to 35. The study enrolled 122 and 123 patients in the CWD and FWD, respectively. The PTTR did not differ statistically between CWD and FWD (62.2 ± 26.2% vs. 58 ± 25.4%, p = 0.2). There was also no difference between both arms in the percentage of visits with extreme subtherapeutic international normalized ratio (INR) (4; 7.7 ± 14.7% vs. 7.5 ± 12.4%, p = 0.92). We conclude that CWD did not improve the anticoagulation quality parameters compared to the FWD method.

Chronic hyperglycemia and excessive reactive oxygen species (ROS) production are defining features of endothelial dysfunction, a key driver of diabetic vascular complications such as diabetic nephropathy. Microvesicles (MV-enriched fraction), a subtype of extracellular vesicles, and the stress-responsive antioxidant protein Sestrin2 (SESN2) have emerged as important contributors to these processes. This study investigated the role of the MV-enriched fraction in endothelial cell communication under diabetic conditions, with a particular focus on oxidative stress signaling. To model diabetic injury, EA.hy926 endothelial cells were treated with methylglyoxal (MGO), and the resulting MV-enriched fraction was isolated and then applied to two recipient models: naïve endothelial cells and SESN2 knockdown (KD) cells. Protein expression of key antioxidant markers, including endothelial nitric oxide synthase (eNOS), was assessed by Western blot. Nitric oxide (NO) bioavailability was quantified via nitrite measurement using 2,3-diaminonaphthalene (DAN), while mitochondrial and cytosolic ROS levels were evaluated using MitoSOX and dihydroethidium (DHE), respectively. Results demonstrated that the MV-enriched fraction derived from diabetic conditions triggers a complex antioxidant response in healthy endothelial cells, characterized by upregulation of SESN2, superoxide dismutase 1 (SOD1), and heme oxygenase-1 (HO-1). This suggests a compensatory mechanism that mitigates oxidative stress. Notably, SESN2 KD cells exhibited increased ROS production and reduced NO levels upon MV treatment, underscoring the essential role of SESN2 in maintaining redox homeostasis. Overall, this study highlights the dual role of the MV-enriched fraction as a mediator of both protective and detrimental redox signaling in diabetic endothelial dysfunction and suggests potential therapeutic targets for managing diabetic vascular complications.

Background: Previous studies demonstrated the superiority of a genotype-guided warfarin dosing (GWD) method for warfarin initiation. International GWD models such as Gage et al model were validated in diverse populations but Arab patients were not well represented in these studies. Objective: To derive and validate a GWD model in an Arab population and compare the outcomes to Gage et al model. Methods: In this cross-sectional study, DNA was collected through saliva kits from a cohort of recruited Arab patients on warfarin . Clinical factors and demographics were recorded and genotyping for VKORC1 (−1639G > A) , CYP2C9*2 , CYP2C9*3 and CYP4F2*3 was performed. Subjects were randomly divided to derivation and validation cohorts. Simple and Multiple linear regression analyses were used to identify factors associated with warfarin dose and derive a warfarin dosing model. The warfarin dose was also calculated using Gage et al model. Accuracy of the 2 models were compared through the mean absolute error (MAE) and percentage of predicted warfarin doses within 20% of the actual warfarin dose Results: The Arab cohort included 405 patients. In the derivation cohort (n = 270), multiple regression analysis showed a dosing model consisting of VKORC1 (−1639G > A) , CYP2C9*2 & CYP2C9*3 genotypes, along with other clinical factors (R ² = 51.6%) (P < 0.05). When compared to Gage et al model, the Arab model had a significantly lower MAE of weekly warfarin dose (9.3 ± 7.6 mg/week vs 12.4 ± 10.4 mg/week, p = 0.03) Conclusion: A model derived and validated in an Arab population had better prediction accuracy compared to an internationally validated one.