ABSTRACT
Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control limits for nitrosamine impurities in pharmaceuticals. In this review, nitrosation pathways and possible root causes of nitrosamine formation in pharmaceuticals are discussed. The control limits of nitrosamine impurities in pharmaceuticals proposed by national regulatory authorities are presented. Additionally, a practical and science-based strategy for implementing the well-established control limits is notably reviewed in terms of an alternative approach for drug product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, a novel risk evaluation strategy for predicting and investigating the possible nitrosation of amine precursors and amine pharmaceuticals as powerful prevention of nitrosamine contamination is addressed.
ABSTRACT
BACKGROUND: Worldwide, the prescribing pattern of the Nonsteroidal Anti-inflammatory Drugs (NSAIDs) has increased. They are considered highly effective medications in controlling various conditions including inflammatory diseases. They are associated with various adverse effects including gastrointestinal bleeding and ulcer and renal toxicity though. These adverse effects are generally potentiated when NSAIDs are co-prescribed with other drugs that share similar adverse effects and toxicities. Developing severe side effects from NSAIDs is more prone among elderly patients. Hence, it is crucial to evaluate prescribing pattern of these agents to prevent/decrease the number of unwanted side effects caused by NSAIDs. AIM: The aim of this study is to assess the prescribing pattern of NSAIDs among elderly and the co-prescribing of NSAIDs and different interacting drugs, which could lead to more incidences of NSAIDs-induced toxicities among Jordanian elderly patients. SETTINGS AND METHODOLOGY: A multicenter retrospective study was performed during a three months period in Jordan. The study involves a total number of (n = 5916) elderly patient's records obtained from Four governmental hospitals in Jordan. RESULTS: A total number of (n = 20450) drugs were prescribed and dispensed for patient. NSAIDs drugs prescribing percentage was 10.3% of total medications number. Aspirin was the most commonly prescribed NSAIDs among patients (70.4%), followed by Diclofenac sodium in all dosage forms (25.1%) and oral Ibuprofen (3.1%. In addition, Aspirin was the highest NSAIDs co-prescribed with ACEI (e.g., Enalapril), ARBs (e.g. Candesartan and Losartan), Diuretics (Furosemide, Indapamide, Hydrochlorothiazide, Amiloride, and Spironolactone), Warfarin and antiplatelets (Clopidogreal and Ticagrelor) followed by Diclofenac and other NSAIDs. CONCLUSION: NSAIDs prescribing rate among elderly patients was high. Additionally the co-prescribing of NSAIDs especially Aspirin with other agents, which contributes to NSAIDs nephrotoxicity and gastrointestinal toxicity, were high. Strict measurements and action plans should be taken by prescribers to optimize the medical treatment in elderly through maximizing the benefits and decreasing the unwanted side effects.
ABSTRACT
Background: The Saudi Food and Drug Authority (SFDA) requires marketing authorization holders to submit a PIL in both Arabic and English language. However, the readability of imprinted and disseminated Patient information leaflets (PILs) was not assessed extensively in Saudi Arabia. This study aims to assess the readability of PIL of antihypertensive drugs in both Arabic and English languages. Method: This study was a descriptive quantitative analysis conducted in Saudi Arabia in August 2021. PILs of all oral antihypertensive medications in Saudi Arabia were included in the study. The Arabic and English PILs were extracted from the Saudi Drugs Information System (SDI) and pharmaceutical companies' registration documents. The study used Flesch-Kincaid grade level to assess the readability of English and sentence length to assess the Arabic texts. Descriptive analyses were used to assess the readability scores and the mean differences. Results: It was found that almost 88% of English PILs were above recommended readability level compared to 79% of Arabic PILs. About 89% of English PILs of generic and 86% of brand-name medications were above the readability cutoff point compared with 83% of Arabic PILs of generic and 68% of brand-name medications. The means of grade level for readability of PILs for the widely used antihypertensive medications including angiotensin II receptor blockers (ARBs), antiadrenergic, diuretics, Beta-blockers (BBs), calcium channel blockers (CCBs), and combination antihypertensive medications, and CCBs were higher than the recommended readability level (p < 0.05). The highest mean grade level for readability among English PILs was for combinations of antihypertensive agents (9.35 ± 1.38, p 0.01) and among Arabic PILs was for ARBs (6.15 ± 1.62, p < 0.01). Conclusions: The majority of PILs of antihypertensive medications were above the recommended readability level that can be understood by the majority of the public, especially among generic medications and the most widely used antihypertensive medications. The study findings highlight the need of implementing guidelines to improve the readability of information imprinted in PILs and adopt new regulations requiring readability assessment for manufactures before submitting the PILs to the SFDA.
ABSTRACT
BACKGROUND: Compared to angiotensin inhibition, angiotensin-neprilysin "blockade" improves mortality and reduces hospitalizations in patients with heart failure (HF) with reduced ejection fraction (EF). Sacubitril/valsartan is known to influence left ventricular (LV) reverse remodeling with systolic function improvement, although underlying mechanisms remain partially unclear. Our objectives were to evaluate whether sacubitril/valsartan promotes LV remodeling and improves LV ejection fraction (LVEF) (above the 35% threshold by echocardiographic evaluation) and to identify predictors of reverse remodeling in a real-world setting. METHODS: New York Heart Association (NYHA) class II-III patients with EF ≤ 35% were consecutively enrolled. All patients were on optimal medical therapy on the initiation of sacubitril/valsartan therapy. Full clinical and multi-parametric echocardiographic evaluation, electrocardiogram, and laboratory tests were performed at baseline and after 3, 6, 12, and 24 months. RESULTS: In total, 69 patients were recruited from July 2016 to August 2018. Reverse remodeling was observed in 57.7% (30/52) of patients, occurring within 3, 6, 12, and 24 months in 2, 11, 13, and 4 patients, respectively. Twenty-four (46%) patients showed LVEF improvement above the threshold of 35% during follow-up, occurring in 1, 10, 9, and 4 patients within 3, 6, 12, and 24 months, respectively. Primitive dilated cardiomyopathy and female gender were identified as significant predictors of reverse remodeling. NYHA class was improved in both remodeling and non-remodeling patients. CONCLUSION: Sacubitril/valsartan promotes favorable cardiac remodeling and significantly improves LVEF in a significant proportion of HF patients within 24 months, both in NYHA class II and III patients with HF.
ABSTRACT
Coronavirus disease 2019 (COVID-19) shows a wide variation in expression and severity of symptoms, from very mild or no symptoms, to flu-like symptoms, and in more severe cases, to pneumonia, acute respiratory distress syndrome, and even death. Large differences in outcome have also been observed between males and females. The causes for this variability are likely to be multifactorial, and to include genetics. The SARS-CoV-2 virus responsible for the infection depends on two human genes: the human receptor angiotensin converting enzyme 2 (ACE2) for cell invasion, and the serine protease TMPRSS2 for S protein priming. Genetic variation in these two genes may thus modulate an individual's genetic predisposition to infection and virus clearance. While genetic data on COVID-19 patients is being gathered, we carried out a phenome-wide association scan (PheWAS) to investigate the role of these genes in other human phenotypes in the general population. We examined 178 quantitative phenotypes including cytokines and cardio-metabolic biomarkers, as well as usage of 58 medications in 36,339 volunteers from the Lifelines population cohort, in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2. While none reached our threshold for significance, we observed several interesting suggestive associations. For example, single nucleotide polymorphisms (SNPs) near the TMPRSS2 genes were associated with thrombocytes count (p = 1.8 × 10-5). SNPs within the ACE2 gene were associated with (1) the use of angiotensin II receptor blockers (ARBs) combination therapies (p = 5.7 × 10-4), an association that is significantly stronger in females (p dif f = 0.01), and (2) with the use of non-steroid anti-inflammatory and antirheumatic products (p = 5.5 × 10-4). While these associations need to be confirmed in larger sample sizes, they suggest that these variants could play a role in diseases such as thrombocytopenia, hypertension, and chronic inflammation that are often observed in the more severe COVID-19 cases. Further investigation of these genetic variants in the context of COVID-19 is thus promising for better understanding of disease variability. Full results are available at https://covid19research.nl.