Retrospective application of ICH M7 to anti-hypertensive drugs in Brazil: Risk assessment of potentially mutagenic impurities.

Potentially mutagenic impurities are likely to be formed in any drug substance, since their synthesis requires reactive intermediates which may also react with DNA. The ICH M7 guideline, which defines how to risk assess and control mutagenic impurities, was first published in 2014 and is not to be applied retrospectively; however, some impurities have been found above the permitted limits in drug products which were already on the market. This study assessed the implications of applying ICH M7 retrospectively to anti-hypertensive drugs marketed in Brazil by performing a risk assessment and establishing control strategies. The manufacturing processes of 15 drug substances were evaluated and 262 impurities were identified, from which 21% were classified as potentially mutagenic. Most of the impurities were identified below ICH M7 acceptable limits, except for impurities described in a pharmacopoeial monograph. Compendial specifications are defined based on scientific evidence and play an important role in setting quality and safety standards for pharmaceuticals, however there are opportunities for further alignment with ICH guidelines, aiming for a holistic assessment of the impurities profile to ensure the safety of medicines.

Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-Nitrosodiethylamine (NDEA).

The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines.

Design, Synthesis and Biological Evaluation of Betulinic Acid Derivatives as New Antitumor Agents for Leukemia.

BACKGROUND: Chronic myeloid leukemia (CML) is currently treated with imatinib, a Bcr-Abl inhibitor. However, resistance to this drug usually develops over time. Triptolide, a diterpenoid triepoxide, has been shown active against CML cells resistant to imatinib, acting mainly on the level of Bcr-Abl transcription inhibition. OBJECTIVE: Here, we used the triterpene betulinic acid, a known proteasome inhibitor with potential antileukemic activity, as a scaffold for the generation of analogues with predicted triptolide biological activity. METHOD: Betulinic acid derivatives were designed based on the structure-activity relationship of triptolide and evaluated for their cytotoxic effects in CML cells, lymphocytes and human keratinocytes (HaCaT), as well as against the proteasome complex. The main modification performed on betulinic acid was fluorination at C-28 and epoxidation, both of which are responsible for enhancing activity of triptolide. A total of 10 compounds were obtained: 6 previously described and 4 novel compounds. The cytotoxic activity over a CML cell line (K562) was assessed using flow cytometry and compared to lymphocytes and HaCaT. RESULT: The results show that betulinic acid was the most cytotoxic compound against CML cells, showing a good selectivity index for cancer over normal cells. The most important trend for the activity in betulinic acid derivatives is the presence of a free hydroxyl group at C-3 and a carboxyl group at C-28. Results also indicated that the epoxide is important for enhancing the activity, while modification at C-28 worsens the activity. CONCLUSION: Proteasome inhibition assays suggest that proteasome is the main target for betulinic acid and its derivatives.

Effects of low-level exposure to xenobiotics present in paints on oxidative stress in workers.

Paints are composed of an extensive variety of hazardous substances, such as organic solvents and heavy metals. Biomonitoring is an essential tool for assessing the risk to occupational health. Thus, this study analyzed the levels of biomarkers of exposure for toluene, xylene, styrene, ethylbenzene, and lead, as well as the oxidative stress biomarker alterations in painters of an industry. Lipid peroxidation biomarker (MDA), delta-aminolevulinate dehydratase (ALA-D), nonprotein thyol groups, superoxide dismutase and catalase (CAT) were analyzed in exposed and nonexposed subjects. We estimated which of the paint constituents have the greatest influence on the changes in the biomarkers of oxidative stress in this case of co-exposure. The results demonstrated that despite the fact that all the biomarkers of exposure were below the biological exposure limits, the MDA levels and antioxidant enzyme activities were increased, while nonprotein thyol groups and ALA-D levels were decreased in painters when compared with nonexposed subjects. After statistic test, toluene could be suggested as the principal factor responsible for increased lipid peroxidation and inhibition of ALA-D enzyme; however, further studies on the inhibition of ALA-D enzyme by toluene are necessary.

Avaliação comparativa entre o diâmetro de cones estandardizados e cones secundários b8 calibrados por régua calibradora, distando 1mm das suas pontas (d1) / Comparative evaluation between the diameter of standardized cones and secondary cones b8 calibrated by special scale, measuring 1mm from its tips (d1)

Introdução e Objetivo: O presente estudo teve por objetivo avaliar e comparar as medidas do diâmetro D1 de cones estandardizados e secundários calibrados com régua calibradora através da medição do primeiro milímetro dos cones, com um paquímetro digital. Material e Métodos: utilizou-se dez cones de guta-percha estandardizados de cada calibre #25, #30, #35 e #40 das marcas Dentsply/Maillefer e Tanari, e cones secundários B8 calibrados por régua calibradora, perfazendo um total de 160 cones. Com o auxílio de um paquímetro digital eletrônico foi verificado o diâmetro a um milímetro da ponta do cone (D1). Resultados: obteve-se que em uma das marcas houve diferença significativa entre os cones padronizados e os calibrados. Quando comparado o calibre dos cones padronizados das duas marcas, também ocorreu diferença estatística, não ocorrendo quando os cones foram calibrados por régua calibradora. Conclusão: os cones Tanari, em média, tiveram um resultado superior aos cones calibrados e Dentsply, nessa ordem.

Introduction and Objective: The present study had for objective to evaluate and to compare the measures of the D1 diameter of calibrated standardized and secondary cones calibrated using a special scale through the measurement of the first millimeter of the cones, with one digital caliper. Material and Methods: Ten standardized gutta-percha cones of each type had been used: #25, #30, #35 and #40. The manufacturers were Dentsply/Maillefer and Tanari, and secondary cones B8 calibrated by a special scale, making a total of 160 cones. With the aid of a digital electronic caliper was verified the diameter to the one millimeter back from the tip of the cone (D1). Results: one of the manufacturers brand had significant difference between the standardized cones and the calibrated ones. When compared, the caliber of the standardized cones of both brands presented difference in statistics, not occurring when the cones had been calibrated by the special scale. Conclusion: the Tanari cones, on average, had a superior result compared to the calibrated cones and Dentsply, in this order.