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Background/Objectives: For locally applied, locally acting generic drug products, comparison to an originator product based on systemic exposure is usually not feasible due to low plasma concentrations and inadequate reflection of local exposure at the site of action. Where a validated PD model exists, a comparative clinical study can be performed in healthy subjects; where no surrogate endpoint is available, patients with the relevant indication need to be enrolled, with all the associated factors which could result in lack of sensitivity. Even though the need for alternative in vitro approaches has been acknowledged by both industry and regulatory bodies, the complexity of in vivo drug delivery processes makes the development of guidance documents particularly difficult. Our objective was to present in vitro approaches less classically used and to address in vivo relevance of the selected tests. Methods: This article analyses current regulatory approaches in Europe and the U.S., and highlights the key advantages of in vitro tests in terms of their sensitivity, reliability, reproducibility and in vivo relevance using locally applied flurbiprofen in various formulations. Results: The in vitro esophageal retention (IVOR) model demonstrates that the first 6-10 min after application of different flurbiprofen formulations is important for their comparison and also offers the best correlation with in vivo data using the partial area under the concentration-time curves (pAUCs). Rheological evaluations further demonstrated that the mucoadhesive properties of the gel spray formulation are based on interaction with mucin. Conclusions: Designing a relevant in vitro test requires adequate evaluation of the complexity of the drug substance, drug product, dosing conditions and delivery processes.
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Background: The optimal treatment regimen for patients with Hughes syndrome remains unclear. Therefore, the authors sought to compare the outcomes of warfarin vs. factor Xa inhibitors in patients with Hughes syndrome. Methods: MEDLINE, Embase, and Cochrane Central databases were searched for randomized controlled trials (RCTs) comparing 8 efficacy and safety of warfarin and factor Xa inhibitors in patients with Hughes syndrome. Recurrent thrombosis, all-cause mortality, stroke, adverse reactions, and bleeding were among 10 outcomes of interest. Mantel-Haenszel weighted random-effects model was used to calculate 11 relative risks (RRs) with 95% CIs. Results: The analysis included 625 patients from four RCTs and one post-hoc analysis. Meta-analysis showed a statistically non-significant difference between factor Xa inhibitors and warfarin in the recurrent thrombosis risk (arterial or venous) [RR 2.77 (95%, CI 0.79, 9.65); P=0.11, I2=50%]. Consistent results were revealed among patients with a previous history of arterial thrombosis [RR 2.76 (95% CI 0.93, 8.16); P=0.75, I2=0%], venous thrombosis [RR 1.71 (95% CI 0.60, 4.84); P=0.31, I2=15%] and patients who were triple antiphospholipid antibodies (aPL) positive [RR 4.12 (95% CI 0.46, 37.10); 21 P=0.21, I2=58%]. Factor Xa inhibitors were significantly associated with an increased risk of stroke [RR 8.51 (95% CI 2.35, 13.82); P=0.47, I2=0%]. Conclusion: Factor Xa inhibitors exhibited an increased risk of stroke among patients with Hughes syndrome. In addition, although not significant, the higher RRs among patients on factor Xa inhibitors may indicate a higher risk of thrombotic events associated with factor Xa inhibitors.
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Abdominal tuberculosis (TB) is a common form of extrapulmonary TB (EXPTB). It is being reported increasingly, especially in high-burden regions of the world. We present a case of a 37-year-old male who presented to the emergency department with clinical features suggestive of bowel obstruction. On clinical examination, the patient exhibited generalized tenderness in the abdomen. A subsequent CT scan revealed features consistent with small bowel obstruction. The patient underwent a diagnostic laparoscopy, which was converted to an exploratory laparotomy due to intraoperative findings of adhesions. Notably, there were extensive peritoneal deposits and adhesions between bowel loops. Peritoneal biopsies were obtained and subjected to the acid-fast bacillus (AFB) smear and culture, which demonstrated the growth of the Mycobacterium tuberculosis complex. As a result, the patient was initiated on antituberculous therapy.