The impact of <em>CYP2C9</em>, <em>VKORC1</em>, and <em>CYP4F2</em> polymorphisms on warfarin dose requirement in Saudi patients

Copyright \ua9 2025 Jokhab, AlRasheed, Bakheet, AlMomen, AlAboud and Kamali. Background: Limited data are available on factors that affect warfarin dose requirement in Saudi patients. Saudis are among the underrepresented ethnic groups in warfarin pharmacogenetics research. The present study investigated the frequency of CYP2C9*2 and*3, CYP4F2 (G1347A) and VKORC1 –1639G&gt;A genotypes and their impact on warfarin dose requirement in a cohort of Saudi patients requiring anticoagulation therapy. Methods: 193 patients on chronic warfarin therapy and with stable anticoagulation took part in the study. Genotyping for VKORC1 1639G&gt;A, CYP4F2 G1347A, CYP2C9*2 430C&gt;T and CYP2C9*3 1075A&gt;C were performed using TaqMan genotyping assays. Analysis of variance was carried out to determine the association between CYP2C9, CYP4F2, and VKORC1 genotype and warfarin dose requirement in two groups based on target INR range. Backward linear regression analysis identified genetic and clinical factors influencing doe requirements. Results: Patients with CYP2C9 and VKORC1 polymorphisms required significantly lower warfarin doses compared to wild-type patients. Carriers of two mutant alleles required lower doses than those with one mutant allele. In contrast, CYP4F2 polymorphisms did not influence warfarin dose. Age and genetic variants in CYP2C9 and VKORC1 were negatively correlated with dose requirements, while body surface area (BSA) was positively correlated. Conclusion: Saudi patients with polymorphisms in CYP2C9 and VKORC1 required lower warfarin doses than those with the wild-type allele. CYP4F2 polymorphism had no effect on warfarin dose requirement. Integrating patient clinical factors, including age and BSA, and genetic polymorphisms in CYP2C9 and VKORC1 provides the best estimation of factors contributing to warfarin dose in the Saudi patient population

Oral manifestations associated with Novel Coronavirus Disease - 2019 (COVID-19): A questionnaire based hypothetical study [version 2; peer review: 2 approved]

Background: Since the Coronavirus disease 2019 (COVID-19) outbreak in 2019, the virus has evolved drastically, presenting with sets of mutations that influence its properties, including transmissibility and antigenicity. The oral mucosa is postulated as probable portal entry and several oral manifestations have been identified, which places dental professionals in a position to recognize probable COVID-19 patients depending on oral signs and symptoms in the initial phases of the disease itself. As co-existing with COVID-19 seems to be a new reality, greater understanding is required regarding early oral signs and symptoms which can be predictors for timely intervention and prevention of complications in COVID-19 patients. The objective of the study is to identify the distinguishing oral signs and symptoms among COVID-19 patients and to establish possible correlation between severity of COVID-19 infection and oral symptoms. Methods: This study recruited 179 ambulatory, non-hospitalized COVID-19 patients from the Kingdom of Saudi Arabia’s Eastern Province's designated hotels for COVID-19 and home isolated patients from the same region using a convenience sample method. Data was collected by qualified and experienced investigators, including two physicians and three dentists, using a validated comprehensive questionnaire through telephonic interviews with the participants. The X2 was used to assess the categorical variables, and odd's ratio was calculated to determine the strength of the association between general symptoms and oral manifestations. Results: Oral and nasopharyngeal lesions or conditions like loss of smell and taste, xerostomia, sore throat, and burning sensation were predictors of COVID-19-related systemic symptoms such as cough, fatigue, fever, and nasal congestion were identified to be statistically significant (p<0.05). Conclusions: The study reveals the occurrence of olfactory or taste dysfunction, dry mouth, sore throat, and burning sensation along with COVID-19 generic symptoms, should be considered as suggestive yet not conclusive indicators of COVID-19

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients

Background: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. Methods: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA\uae, Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. Results: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean&nbsp;\ub1&nbsp;standard deviation (SD) increase in MCF was 5.8&nbsp;\ub1&nbsp;2.5&nbsp;mm one hour after the first HFC infusion (mean&nbsp;\ub1&nbsp;SD dose, 61.88&nbsp;\ub1&nbsp;11.73&nbsp;mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80&nbsp;mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. Conclusions: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia

Obesity-induced cofilin1 pathway dysregulation: Possible molecular links between neuroinflammation, cognitive decline, and Alzheimer's disease biomarkers

Obesity is a growing concern globally, particularly among young populations. Cofilin1, a major actin-depolymerizing factor (ADF) isoform in the CNS, acts as a stress protein that triggers neuroinflammation and correlates with the onset of Alzheimer's disease (AD). However, its role in obesity has not yet been identified. In this study, we investigated the influence of diet-induced obesity on cofilin1 dysregulation in the brain and its correlation to neurobehavioral deficiencies, neuroinflammation, synaptic dysfunction, and AD biomarkers. Male C57BL/6 mice were fed a regular diet (control) or a high-fat diet (HFD, obese) for 7 weeks to induce obesity. Our data demonstrate that the activation of cofilin1 in the hippocampus region of HFD mice brains is mediated by Slingshot homolog-1 (SSH1) overactivation and LIM kinase-1 (LIMK1) inactivation. However, pcofilin1 is also increased, but this increase might be mediated by mechanisms other than an actin-dependent mechanism. Cofilin1 pathway dysregulation in HFD-fed mice was correlated with cognitive decline, as assessed using the Morris water maze (MWM) and Y-maze, and increased astrocytic activation protein and synaptotoxicity by downregulating pre- and post-synaptic markers. It also correlates with the significant upregulation of AD biomarkers (pTauSer396) in the brain, saliva, and serum. At the systemic level, our results showed dysregulation of the gut microbiota, characterized by a ∼53 % increase in the Firmicutes: Bacteroidetes ratio in HFD-fed mice. HFD-fed mice also exhibited a significant increase in certain inflammatory and anti-inflammatory blood cytokines. Our findings suggest that active cofilin1 plays a significant role in diet-induced obesity and may become a potential therapeutic target

A Facile Synthesis and Molecular Characterization of Certain New Anti-Proliferative Indole-Based Chemical Entities

Cancer cells frequently develop drug resistance, which leads to chemotherapeutic treatment failure. Additionally, chemotherapies are hindered by their high toxicity. Therefore, the development of new chemotherapeutic drugs with improved clinical outcomes and low toxicity is a major priority. Several indole derivatives exhibit distinctive anti-cancer mechanisms which have been associated with various molecular targets. In this study, target compounds&nbsp;4a&ndash;q were obtained through the reaction of substituted benzyl chloride with hydrazine hydrate, which produces benzyl hydrazine. Subsequently, the appropriate substituted benzyl hydrazine was allowed to react with 1H-indole-2-carboxylic acid or 5-methoxy-1H-indole-2-carboxylic acid using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as a coupling agent. All compounds exhibited cytotoxicity in three cell lines, namely, MCF-7, A549, and HCT. Compound&nbsp;4e exhibited the highest cytotoxicity, with an average IC50 of 2 &micro;M. Moreover, a flow cytometry study revealed a significantly increased prevalence of Annexin-V and 7-AAD positive cell populations. Several derivatives of&nbsp;4a&ndash;q showed moderate to high cytotoxicity against the tested cell lines, with compound&nbsp;4e having the highest cytotoxicity, indicating that it may possess potential apoptosis-inducing capabilities