Sunscreens Part 2: Regulation and Safety.

The second part of this CME article discusses sunscreen regulation and safety considerations for humans and the environment. First, we provide an overview of the history of the United States Food and Drug Administration's regulation of sunscreen. Recent Food and Drug Administration studies clearly demonstrate that organic ultraviolet filters are systemically absorbed during routine sunscreen use, but to date there is no evidence of associated negative health effects. We also review the current evidence of sunscreen's association with vitamin D levels and frontal fibrosing alopecia, and recent concerns regarding benzene contamination. Finally, we review the possible environmental effects of ultraviolet filters, particularly coral bleaching. While climate change has been shown to be the primary driver of coral bleaching, laboratory-based studies suggest that organic ultraviolet filters represent an additional contributing factor, which led several localities to ban certain organic filters.

Quality parameters for the medicinal plant Drosera rotundifolia L.: A new approach with established techniques.

Monographs of the European Pharmacopoeia (Ph. Eur.) are the basis for quality control of medicinal plants and therefore important to ensure the consistency, quality, safety, and efficacy of phytopharmaceuticals. The traditional medicinal plant sundew (Drosera sp.) has disappeared from therapy due to nature conservation, but can now be cultivated sustainably on rewetted peatland. However, currently there is no valid Ph. Eur. monograph for the quality control of Droserae herba. In this study, sundew material from different species and sources was investigated with the aim of developing quality control methods based on the Ph. Eur. and defining a uniform quality standard for Droserae herba. It was possible to distinguish between sundew species of different quality, using macroscopic, microscopic, and chromatographic methods. Special emphasis was laid on the content of flavonoids and naphthoquinones as important quality parameters as their content differed between the sundew species. The differences in content and toxicity result in the recommendation that only round-leaved sundew (Drosera rotundifolia L.) should be used as a medicinal plant for the production of phytopharmaceuticals in the future.

Preliminary clinical pharmacokinetic evaluation of bemotrizinol - A new sunscreen active ingredient being considered for inclusion under FDA's over-the-counter (OTC) sunscreen monograph.

Protection against sunburn, skin damage and the carcinogenic effects of ultraviolet light are the primary health benefits associated with UV filters used in topical sunscreen drug products. Countries such as Europe have 30+ UV filters approved for sunscreen products while the US has about 10, greatly reducing the options to provide diverse, effective sun protection products. Bemotrizinol (BEMT) is the first new sunscreen active ingredient to be evaluated for inclusion in the Over-The-Counter (OTC) sunscreen monograph using FDA's new Generally Recognized as Safe and Effective (GRASE) testing guidelines. An in vitro skin permeation test (IVPT) and clinical pilot pharmacokinetic Maximum Usage Trial (MUsT) were completed to support the GRASE determination for 6% BEMT. IVPT results indicated an oil +10% ethanol as the model sunscreen intervention for the pilot MUsT. The open-label trial revealed: BEMT concentrations rarely exceeded FDA's defined threshold (0.5 ng/mL) in plasma; no evidence for BEMT accumulation or steady-state concentrations above threshold; only one moderate and few mild treatment emergent adverse events (TEAEs). Therefore, maximal topical applications of 6% BEMT in a model sunscreen formulation did not contribute to meaningful systemic exposure. These results support the safety of BEMT 6% for human sunscreen use.

Ensuring the quality of medicines in India: An update on the development, modernization, and harmonization of drug standards in the Indian Pharmacopoeia.

India has a sparkling pharmaceutical sector that holds a distinguished place by producing and supplying high-quality and affordable medicines across the globe. Ensuring the quality and safety of the marketed medicinal products is one of the most important components of the drug regulatory framework and assessment of the quality of medicines is usually achieved by referring to the public standards of the official Pharmacopoeia. In India, the Indian Pharmacopoeia (IP) is published at regular intervals to fulfill the requirements of the Drugs and Cosmetics Act, 1940 to ensure the quality of medicines being manufactured and/or marketed in India. The present article aims to provide an overview of the history of the IP, its standards-setting process, and the current status of monographs in the 9th edition of the IP 2022. Special focus is placed on the newly added and upgraded general chapters and monographs within the IP 2022. There are a total of 223 general chapters and 3152 drug monographs available under various categories in the IP 2022. This study also highlights a total of 92 new drug monograph additions and 412 monograph revisions in the IP 2022. It is anticipated that the standards laid down in the IP 2022 will play an imperative role in delivering quality medicines to patients within and outside India.

[Heart Diseases by Professor Dmitry D. Pletnev (for the reprint of D.D. Pletnev's monograph "Heart Diseases", 1936)].

The article presents a brief review of Heart Diseases (1936), the monograph by one of the founders of domestic and world cardiology Dmitry Dmitrievich Pletnev. In the monograph, he summarized his clinical and experimental approach to the issues of heart diseases, addressed several fundamental problems of modern physiology and healthcare, introduced the concept of "functional unit" and "functional unity of the whole body", the concept of the extracardiac genesis of the chest frog, differential diagnosis of left and right ventricle myocardial infarction, semiotics and treatment of chronic heart failure, functional diagnosis of heart arrhythmias. All these approaches and concepts have long been included in the classics of world cardiology.

[By canceling out history of the Soviet medicine are we weather throwing the baby out with the bath water? (On the issue of how to study history of the USSR medicine)].

The article considers particular aspects of the problem of studying the history of medicine in the USSR as educational and scientific practical discipline. On one hand, the history of medicine as educational academic discipline can quite be "ideologized", since education implies not only learning but also education of young man as patriot and citizen. On the other hand, history of medicine as scientific practical discipline is to be delivered from politics and ideology. However, this is determined in greater degree not so much by totalitarian pressing or liberalism of social system as by professionalism and world view of researcher. The monograph by S. N. Zatravkin and E. A. Vishlenkova ""The Clubs" and "the ghetto" of the Soviet Health Care" (2022), dedicated to the Soviet health care and its ideological essence, also is considered. The high significance of the book for understanding of becoming of medicine in the USSR is emphasized. However, this scholar work does not consider medical care of population of the country in clinics of medical universities and academic research institutes of the USSR. Enough attention is not paid to the history of medicine in the USSR as a science. The role of scientific schools in creating foundation for development of medicine in Russia in the late XX and early XXI centuries.

[Significance of herbal/botanical monograph in international registration of Chinese medicine].

Herbal/botanical monograph, first emerging abroad, includes the scientific conclusions on safety and effectiveness of herbal medicine/botanical medicine, as it is often compiled by drug regulatory authorities. It is designed to unify the related technologies in this field and evaluation standards for review. Thus, herbal/botanical monograph is vital for the internationalization of Chinese medicine and being inscribed into the herbal/botanical monograph of target country is the first step for drug registration there. At the moment, there are few domestic studies on international herbal/botanical monographs, let alone the importance of the monographs in international registration of Chinese medicine preparations. This study first described international monographs on herbal/botanical medicine, then discussed the similarities and differences between international monographs and Chinese Pharmacopoeia, and finally analyzed the significance and value of the monographs in the international registration of Chinese medicine. On this basis, this study underscored the research on herbal/botanical monographs of key candidate countries for Chinese medicine registration, with a view to enhancing international recognition and laying the foundation for international registration and related policy formulation.

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium.

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

University presses and the impact of COVID-19.

University presses occupy a distinctive field of publishing, heavily tied to the fortunes of the universities and colleges in which they are usually situated. COVID-19 has catalysed their adoption of digital technologies; focused their commitments to social justice; and given new impetus to business models and formats that fully leverage the Internet, especially open access. Economic pressures on higher education that seem set only to increase are also driving university presses to more interdependent approaches and an emphasis on the contributions of the university press network to knowledge infrastructure for the humanities and social sciences. This article explores how university presses have reacted to the COVID-19 pandemic, with particular reference to the experiences of the University of Michigan Press. It concludes that the diversity of types of university presses is one of the greatest strengths of this field of publishing and makes it resilient in a time of unprecedented change.

The continued need for scientific monographs: an appreciation of John Rothwell's "Control of human voluntary movement".

Here I write a personal assessment of Professor John Rothwell's seminal book, "Control of Human Voluntary Movement". I focus on the second edition published in 1994, reflecting on its importance over the last 25 years and explaining why it remains highly relevant for the motor control field to this day. It is to be hoped that a third edition will be written that updates the physiology and unifies it with computational motor control. The book attests to the continuing importance of monographs in science, as they uniquely allow for long-form narrative and coherent synthesis.

Pitfalls in the analysis of phytocannabinoids in cannabis inflorescence.

The chemical analysis of cannabis potency involves the qualitative and quantitative determination of the main phytocannabinoids: Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), etc. Although it might appear as a trivial analysis, it is rather a tricky task. Phytocannabinoids are present mostly as carboxylated species at the aromatic ring of the resorcinyl moiety. Their decarboxylation caused by heat leads to a greater analytical variability due to both reaction kinetics and possible decomposition. Moreover, the instability of cannabinoids and the variability in the sample preparation, extraction, and analysis, as well as the presence of isomeric forms of cannabinoids, complicates the scenario. A critical evaluation of the different analytical methods proposed in the literature points out that each of them has inherent limitations. The present review outlines all the possible pitfalls that can be encountered during the analysis of these compounds and aims to be a valuable help for the analytical chemist. Graphical abstract.

Recommendations for further revisions to improve the International Agency for Research on Cancer (IARC) Monograph program.

In 2019, the International Agency for Research on Cancer (IARC) "Preamble to the IARC Monographs" expanded guidance regarding the scientific approaches that should be employed in its monographs. These amendments to the monograph development process are an improvement but still fall short in several areas. While the revised Preamble lays out broad methods and approaches to evaluate scientific evidence, there is a lack of specificity with regard to how IARC Working Groups will conduct consistent evaluations in a standardized, objective, and transparent manner; document systematic review and evidence integration actions, and substantiate how these actions and decisions inform the ultimate classifications. Furthermore, no guidance is provided to ensure Working Groups consistently incorporate mechanistic evidence in a robust manner using a defined approach in the context of 21st century knowledge of modes of action. Nor are the conclusions of the working groups subjected to outside, independent scientific peer review. Continued improvements and modernization of the procedures for evaluating, presenting, and communicating study quality, and in the methods used to conduct and peer-review evidence-based decision making will benefit the Working Group members, the IARC Monographs Programme overall, and the international regulatory community and public who rely upon the monographs.

Lipoprotein(a) and the risk of cardiovascular disease in the European population: results from the BiomarCaRE consortium.

AIMS: As promising compounds to lower Lipoprotein(a) (Lp(a)) are emerging, the need for a precise characterization and comparability of the Lp(a)-associated cardiovascular risk is increasing. Therefore, we aimed to evaluate the distribution of Lp(a) concentrations across the European population, to characterize the association with cardiovascular outcomes and to provide high comparability of the Lp(a)-associated cardiovascular risk by use of centrally determined Lp(a) concentrations. METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE)-project, we analysed data of 56 804 participants from 7 prospective population-based cohorts across Europe with a maximum follow-up of 24 years. All Lp(a) measurements were performed in the central BiomarCaRE laboratory (Biokit Quantia Lp(a)-Test; Abbott Diagnostics). The three endpoints considered were incident major coronary events (MCE), incident cardiovascular disease (CVD) events, and total mortality. We found lower Lp(a) levels in Northern European cohorts (median 4.9 mg/dL) compared to central (median 7.9 mg/dL) and Southern European cohorts (10.9 mg/dL) (Jonckheere-Terpstra test P < 0.001). Kaplan-Meier curves showed the highest event rate of MCE and CVD events for Lp(a) levels ≥90th percentile (log-rank test: P < 0.001 for MCE and CVD). Cox regression models adjusted for age, sex, and cardiovascular risk factors revealed a significant association of Lp(a) levels with MCE and CVD with a hazard ratio (HR) of 1.30 for MCE [95% confidence interval (CI) 1.15‒1.46] and of 1.25 for CVD (95% CI 1.12‒1.39) for Lp(a) levels in the 67‒89th percentile and a HR of 1.49 for MCE (95% CI 1.29‒1.73) and of 1.44 for CVD (95% CI 1.25‒1.65) for Lp(a) levels ≥ 90th percentile vs. Lp(a) levels in the lowest third (P < 0.001 for all). There was no significant association between Lp(a) levels and total mortality. Subgroup analysis for a continuous version of cube root transformed Lp(a) identified the highest Lp(a)-associated risk in individuals with diabetes [HR for MCE 1.31 (95% CI 1.15‒1.50)] and for CVD 1.22 (95% CI 1.08‒1.38) compared to those without diabetes [HR for MCE 1.15 (95% CI 1.08‒1.21; HR for CVD 1.13 (1.07-1.19)] while no difference of the Lp(a)- associated risk were seen for other cardiovascular high risk states. The addition of Lp(a) levels to a prognostic model for MCE and CVD revealed only a marginal but significant C-index discrimination measure increase (0.001 for MCE and CVD; P < 0.05) and net reclassification improvement (0.010 for MCE and 0.011 for CVD). CONCLUSION: In this large dataset on harmonized Lp(a) determination, we observed regional differences within the European population. Elevated Lp(a) was robustly associated with an increased risk for MCE and CVD in particular among individuals with diabetes. These results may lead to better identification of target populations who might benefit from future Lp(a)-lowering therapies.

Troponin I and cardiovascular risk prediction in the general population: the BiomarCaRE consortium.

AIMS: Our aims were to evaluate the distribution of troponin I concentrations in population cohorts across Europe, to characterize the association with cardiovascular outcomes, to determine the predictive value beyond the variables used in the ESC SCORE, to test a potentially clinically relevant cut-off value, and to evaluate the improved eligibility for statin therapy based on elevated troponin I concentrations retrospectively. METHODS AND RESULTS: Based on the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, we analysed individual level data from 10 prospective population-based studies including 74 738 participants. We investigated the value of adding troponin I levels to conventional risk factors for prediction of cardiovascular disease by calculating measures of discrimination (C-index) and net reclassification improvement (NRI). We further tested the clinical implication of statin therapy based on troponin concentration in 12 956 individuals free of cardiovascular disease in the JUPITER study. Troponin I remained an independent predictor with a hazard ratio of 1.37 for cardiovascular mortality, 1.23 for cardiovascular disease, and 1.24 for total mortality. The addition of troponin I information to a prognostic model for cardiovascular death constructed of ESC SCORE variables increased the C-index discrimination measure by 0.007 and yielded an NRI of 0.048, whereas the addition to prognostic models for cardiovascular disease and total mortality led to lesser C-index discrimination and NRI increment. In individuals above 6 ng/L of troponin I, a concentration near the upper quintile in BiomarCaRE (5.9 ng/L) and JUPITER (5.8 ng/L), rosuvastatin therapy resulted in higher absolute risk reduction compared with individuals <6 ng/L of troponin I, whereas the relative risk reduction was similar. CONCLUSION: In individuals free of cardiovascular disease, the addition of troponin I to variables of established risk score improves prediction of cardiovascular death and cardiovascular disease.

[Analysis of difficult problems on European Union laws and regulations of traditional herbal medicinal products].

Registration of Chinese patent medicine in European Union (EU) is of great significance to the internationalization of traditional Chinese medicine as EU market acts as an important position in the global botanical market. In retrospect, the domestic studies on EU regulations of traditional herbal medicinal products have been conducted for more than 10 years, but there is still some cognitive bias and lack of research. In this paper, a review of the relevant research progress and the main misunderstanding problems about Directive 2004/24/EC, like the centralized and decentralized supervision system of traditional herbal medicinal products in the EU, marketing authorization procedures for traditional herbal medicinal products, Community Herbal Monograph and List Entries, would be systematically analyzed, so as to provide reference for the registration of Chinese patent medicine in EU.

Issues and approaches for ensuring effective communication on acceptable daily exposure (ADE) values applied to pharmaceutical cleaning.

This manuscript centers on communication with key stakeholders of the concepts and program goals involved in the application of health-based pharmaceutical cleaning limits. Implementation of health-based cleaning limits, as distinct from other standards such as 1/1000th of the lowest clinical dose, is a concept recently introduced into regulatory domains. While there is a great deal of technical detail in the written framework underpinning the use of Acceptable Daily Exposures (ADEs) in cleaning (for example ISPE, 2010; Sargent et al., 2013), little is available to explain how to practically create a program which meets regulatory needs while also fulfilling good manufacturing practice (GMP) and other expectations. The lack of a harmonized approach for program implementation and communication across stakeholders can ultimately foster inappropriate application of these concepts. Thus, this period in time (2014-2017) could be considered transitional with respect to influencing best practice related to establishing health-based cleaning limits. Suggestions offered in this manuscript are intended to encourage full and accurate communication regarding both scientific and administrative elements of health-based ADE values used in pharmaceutical cleaning practice. This is a large and complex effort that requires: 1) clearly explaining key terms and definitions, 2) identification of stakeholders, 3) assessment of stakeholders' subject matter knowledge, 4) formulation of key messages fit to stakeholder needs, 5) identification of effective and timely means for communication, and 6) allocation of time, energy, and motivation for initiating and carrying through with communications.

High population prevalence of cardiac troponin I measured by a high-sensitivity assay and cardiovascular risk estimation: the MORGAM Biomarker Project Scottish Cohort.

AIMS: Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population. METHODS AND RESULTS: High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort (n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I (P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic (P < 0.0001) and net reclassification (P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events. CONCLUSION: Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

A Review of Probiotic Ingredient Safety Supporting Monograph Development Conducted by the United States Pharmacopeia (USP).

The United States Pharmacopeia (USP) is an independent, nonprofit science-based organization whose mission is to improve global health through public standards and related products for medicines, food and dietary supplements. Probiotic-based dietary supplements are increasingly popular in the marketplace and USP has developed fourteen monographs specific to probiotic ingredients, including representatives from the Genera Lactobacillus, Bacillus, Streptococcus, and Bifidobacterium. These monographs include the definition of the article, tests for identification, quantification assays (enumeration in the case of probiotics), limits for contaminants, and other quality parameters when appropriate. In addition to quality, the USP also considers the safety of probiotics for monograph development. This report includes an overview of the USP admission evaluation process for probiotics as well as a tabular summary of the probiotic monographs currently available. Pharmacopeia monographs can guide manufacturers and brand owners and protect consumers through establishment of quality standards.

Standardization and preliminary characterization of an ayurvedic stress-relieving head massage oil of Nardostachys jatamansi DC.

BACKGROUND: Jatamansi/Nardostachys jatamansi (NJ) is an important aromatic shrub widely used by Ayurvedic practitioners for centuries due to its usefulness in intellect-enhancing (Medhya), strengthening (Balya), and skin disorders. Several classical dosage forms like hot or cold infusion, decoction, distillate, powders, etc. have been mentioned for NJ. Clinical trials of Jatamansi Oil (JO) as a head massage conducted by clinicians and therapists have shown encouraging results in de-stressing/stress management of cancer patients through head anointing treatment. OBJECTIVE: Such effective proprietary formulation needs assessment of its characteristics using modern analytical technologies to comprehend the Ayurvedic concept of dermal pharmacology. MATERIALS AND METHODS: Triplicate batches of JO were prepared by evaporating its decoction in sesame oil (SO). Basic physicochemical analysis of the raw material, in-process samples, and finished products was carried out to develop a monograph. Further, raw SO and finished product JO were subjected to TLC, and extracted in hexane and dichloromethane separately for Gas Chromatography-Mass Spectrometry (GC-MS) analysis to profile several bioactive molecules from NJ in the final product, JO. RESULTS: Standard Operating Procedure was developed and a basic monograph was prepared for JO. GC-MS analysis revealed several phytocompounds dissolved/dispersed in SO after processing, while 18 additional distinct peaks were observed in JO as compared to SO. CONCLUSION: This preliminary analysis supports the Ayurvedic concept of lipid-based formulations. The plausible phytocompounds anticipated based on retention times can be further quantified and studied for their probable action as anointing treatment. A detailed experimental strategy for understanding the phytochemical changes during the entire process needs to be planned and performed.

Advice to the US FDA to Allow US Pharmacopeia to Create Biological Product Specifications (BPS) to Remove Side-by-Side Analytical Comparisons of Biosimilars with Reference Products.

Pharmacopeia monographs are not intended to establish biosimilarity. However, the US Food and Drug Administration (FDA) has stopped the US Pharmacopeia (USP) from creating monographs for biological drugs due to the need for side-by-side comparisons with the reference products. The USP can create Biological Product Specifications (BPS), not to be labeled as monographs, based on the analytical testing of reference products and validated test methods that will remove the need for side-by-side analytical testing of biosimilars with reference products. Scientific arguments confirm that this plan is logical and capable of creating global quality standards for biosimilars to allow their interchangeability with other biosimilars. While the regulatory agencies have waived many high-cost biosimilar tests, analytical assessment is the most sensitive test; reducing its cost will further enhance the entry of biosimilars with no clinically meaningful difference.