Development and Validation of LC-MS/MS Method for the Determination of 1-Methyl-4-Nitrosopiperazine (MNP) in Multicomponent Products with Rifampicin-Analytical Challenges and Degradation Studies.

Rifampicin is an essential medicine for treating and preventing tuberculosis (TB). TB is a life-threatening infectious disease and its prevention and treatment are public health imperatives. In the time of a global crisis of nitrosamine contamination of medicinal products, patient safety and a reduction in the number of drug recalls at the same time are crucial. In this work, the LC-MS/MS method was developed for the determination of the 1-methyl-4-nitrosospiperazine (MNP), a genotoxic nitrosamine impurity in various products containing rifampicin at a 5.0 ppm limit level according to Food and Drug Administration (FDA). Extraction with neutralization was necessary due to the matrix and solvent effect associated with the complexity of the rifampicin product. The developed method was validated in accordance with regulatory guidelines. Specificity, accuracy, precision, limit of detection, and limit of quantification parameters were evaluated. The recovery of the MNP was 100.38 ± 3.24% and the intermediate precision was 2.52%. The contamination of MNP in Rifampicin originates in the manufacturing process of the drug. Furthermore, the results of the forced degradation experiments show that the formation of MNP is possible by two mechanisms: through degradation of rifampicin and the oxidation of 1-amino-4-methyl-piperazine. This article points out that it is necessary to monitor and describe degradation products and the mechanism of degradation of potentially affected active pharmaceutical ingredient (API) with respect to the formation of nitrosamines during stress testing, as it was done in the following work for rifampicin in multicomponent products.

Development of a Sensitive Screening Method for Simultaneous Determination of Nine Genotoxic Nitrosamines in Active Pharmaceutical Ingredients by GC-MS.

A worldwide crisis with nitrosamine contamination in medical products began in 2018. Therefore, trace-level analysis of nitrosamines is becoming an emerging topic of interest in the field of quality control. A novel GC-MS method with electron ionization and microextraction was developed and validated for simultaneous determination of nine carcinogenic nitrosamines (NDMA, NMEA, NDEA, NDBA, NMOR, NPYR, NPIP, NDPA, and N-methyl-npz) in active pharmaceutical ingredients (APIs): cilostazol, sunitinib malate, and olmesartan medoxomil. The method was validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, demonstrating good linearity in the range of LOQ up to 21.6 ng/mL (120% of specification limit). The limits of detection for the nine nitrosamines were determined to be in the range 0.15-1.00 ng/mL. The developed trace level GC-MS method turned out to be specific, accurate, and precise. The accuracy of all the tested APIs ranged from 94.09% to 111.22% and the precision evaluated by repeatability, intermediate precision, and system precision was RSD ≤ 7.65%. Nitrosamines were not detected in cilostazol and sunitinib, whereas in olmesartan medoxomil NDEA was detected at the level of LOQ. The novel protocol was successfully applied for nitrosamines determination in selected APIs and can be used for the routine quality control of APIs under Good Manufacturing Practices rules, ensuring the safety and effectiveness of pharmaceutical products.

Non-alcoholic fatty liver disease in patients with psoriasis: therapeutic implications.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver pathology in the western countries. Psoriatic patients are at higher risk of having NAFLD, and at higher risk of experiencing a more severe form of the disease with poorer outcomes. The components of the metabolic syndrome - obesity, lipid abnormalities, hypertension, and type 2 diabetes - significantly correlate with NAFLD progression. The inflammatory state present in psoriasis plays a significant role in development of NAFLD and the metabolic syndrome. All patients with psoriasis and insulin resistance and risk factors for metabolic syndrome should also been screened for NAFLD, and planning of the treatment options should always take into consideration the possible risks related to the liver, especially in patients with NAFLD.

Terry's Nails: A Sign of Systemic Disease.

Terry's nails are a type of apparent leukonychia, characterized by ground glass opacification of nearly the entire nail, obliteration of the lunula, and a narrow band of normal, pink nail bed at the distal border. The aim of this study is to guide clinical practice by reviewing all of the data concerning Terry's nail that have become available since the original description by Terry in 1954, with particular reference to all clinical features, associated medical conditions, pathogenesis, and necessary workup. PubMed was searched using the keywords "leukonychia" and "Terry nails." Although the abnormality can occur with normal aging, Terry's nails can also be an indication of an underlying medical condition, most notably, cirrhosis, chronic renal failure, and congestive heart failure. A change in nail bed vascularity, secondary to overgrowth of connective tissue, is thought to be responsible, with nail bed biopsy revealing telangiectasias in the distal band. The differential diagnosis for Terry's nails includes half-and-half nails (Lindsay's nails), Muehrcke's nails, and true leukonychia totalis/partialis. Having the ability to delineate these nail findings can be a valuable tool in clinical practice as each entity is associated with a different set of systemic conditions. Terry's nails highlight the intimate connection between nail changes and systemic disease as well as the importance of thorough nail inspection with every physical examination.