Control of Organic Impurities in Semisynthetic Antibiotics

In 2012, the European Medicines Agency (EMA) adopted a guideline, which divided all antibiotics into groups according to the manufacturing process and established acceptance criteria for organic impurities for each of the groups.The aim of the study was to justify the requirements and methodological approaches to setting the limits for organic impurities in semisynthetic antibiotics.Materials and methods: the authors analysed the requirements established by the leading world pharmacopoeias and the State Pharmacopoeia of the Russian Federation regarding the control of organic impurities in semisynthetic antibiotics, using the example of four semisynthetic antibiotics: doxycyline hyclate, clarithromycin, meropenem, and ceftriaxone. The study used the methods of comparative analysis and content analysis. Results: the study demonstrated that the organic impurity profiles of the analysed active substances and the corresponding finished medicinal products often differ significantly across the leading pharmacopoeias, either qualitatively or quantitatively. The Russian, European, and United States pharmacopoeias provide for the use of impurity reference standards in the test procedures for the determination of impurities in active substances of the semisynthetic antibiotics in question, whereas the Japanese Pharmacopoeia allows the use of non-compendial reference substances in the assessment of the chromatographic system separation power.Conclusions: the ability of a pharmacopoeial text to cover a variety of medicinal products coming to the Russian market from different countries has become a vital issue. This includes covering the impurity determination procedures, reference standards, and limits used, because general-purpose methods and limits do not always allow for correct assessment of impurity profiles in substances produced by different manufacturing processes. The current USP practice is to include various impurity control procedures in monographs on medicinal products, and the limits may also vary. This approach may be applied in the State Pharmacopoeia of the Russian Federation as well

Контроль органических примесей в полусинтетических антибиотиках

In 2012, the European Medicines Agency (EMA) adopted a guideline, which divided all antibiotics into groups according to the manufacturing process and established acceptance criteria for organic impurities for each of the groups.The aim of the study was to justify the requirements and methodological approaches to setting the limits for organic impurities in semisynthetic antibiotics.Materials and methods: the authors analysed the requirements established by the leading world pharmacopoeias and the State Pharmacopoeia of the Russian Federation regarding the control of organic impurities in semisynthetic antibiotics, using the example of four semisynthetic antibiotics: doxycyline hyclate, clarithromycin, meropenem, and ceftriaxone. The study used the methods of comparative analysis and content analysis. Results: the study demonstrated that the organic impurity profiles of the analysed active substances and the corresponding finished medicinal products often differ significantly across the leading pharmacopoeias, either qualitatively or quantitatively. The Russian, European, and United States pharmacopoeias provide for the use of impurity reference standards in the test procedures for the determination of impurities in active substances of the semisynthetic antibiotics in question, whereas the Japanese Pharmacopoeia allows the use of non-compendial reference substances in the assessment of the chromatographic system separation power.Conclusions: the ability of a pharmacopoeial text to cover a variety of medicinal products coming to the Russian market from different countries has become a vital issue. This includes covering the impurity determination procedures, reference standards, and limits used, because general-purpose methods and limits do not always allow for correct assessment of impurity profiles in substances produced by different manufacturing processes. The current USP practice is to include various impurity control procedures in monographs on medicinal products, and the limits may also vary. This approach may be applied in the State Pharmacopoeia of the Russian Federation as well.В 2012 г. Европейским агентством по лекарственным средствам (European Medicines Agency, ЕМА) утверждено руководство, согласно которому все антибиотики разделены на группы в соответствии с технологией их получения. Для каждой группы установлены критерии приемлемости содержания органических примесей.Цель работы: обосновать требования и методические подходы к контролю органических примесей в лекарственных средствах полусинтетических антибиотиков.Материалы и методы: проведен анализ требований отечественной и ведущих зарубежных фармакопей к допустимому содержанию органических примесей в полусинтетических антибиотиках на примере четырех из них: доксициклина хиклат, кларитромицин, меропенем и цефтриаксон. В работе использовали методы сравнительного информационно-аналитического исследования и контент-анализа.Результаты: показано, что профиль органических примесей в монографиях ведущих зарубежных фармакопей на одноименную фармацевтическую субстанцию, а также лекарственный препарат, для каждого из исследуемых лекарственных средств, как правило, различается либо качественно, либо количественно. В методиках определения примесей для фармацевтических субстанций рассматриваемых полусинтетических антибиотиков согласно Государственной фармакопее Российской Федерации (ГФ РФ), Европейской фармакопее и Фармакопее США предусмотрено применение стандартных образцов примесей, тогда как Японская фармакопея для оценки разделительной способности хроматографической системы допускает использование веществ, которые не являются фармакопейными стандартными образцами.Выводы: актуальным вопросом становится способность фармакопейного стандарта учитывать многообразие лекарственных средств, поступающих на российский рынок из разных стран. Это касается используемых методик определения примесей, применения стандартных образцов, норм, поскольку единая методика и нормы не всегда позволяют корректно оценивать профиль примесей в субстанциях, полученных различным способом. Фармакопея США в настоящее время практикует включение в монографии на лекарственные средства различных методик для контроля примесей, при этом могут различаться также и нормы. Такой подход может быть применен и в ГФ РФ

Human parvovirus B19 infection and hydrops fetalis in Rio de Janeiro, Brazil

Formalin-fixed paraffin embedded lung and liver tissue from 23 cases of non immune hydrops fetalis and five control cases, in which hydrops were due to syphilis (3) and genetic causes (2), were examined for the presence of human parvovirus B19 by DNA hybridisation. Using in situ hybridisation with a biotynilated probe one positive case was detected. Using 32P-labelled probes in a dot blot assay format, five further positives were obtained. These were all confirmed as positive by a nested polymerase chain reaction assay. Electron microscopy revealed virus in all these five positive cases. The six B19 DNA positive cases of hydrops fetalis were from 1974, 1980, 1982, 1987 and 1988, four of which occurred during the second half of the year, confirming the seasonality of the disease

The re emergence of early congenital syphilis

Acta Paediatrica Scandinavica626601-607APSV

Supplementary Material for: Cumulative Effects of Foraging Behavior and Social Dominance on Brain Development in a Facultatively Social Bee <b><i>(Ceratina australensis)</i></b>

In social insects, both task performance (foraging) and dominance are associated with increased brain investment, particularly in the mushroom bodies. Whether and how these factors interact is unknown. Here we present data on a system where task performance and social behavior can be analyzed simultaneously: the small carpenter bee <i>Ceratina australensis.</i> We show that foraging and dominance have separate and combined cumulative effects on mushroom body calyx investment. Female<i> C. australensis</i> nest solitarily and socially in the same populations at the same time. Social colonies comprise two sisters: the social primary, which monopolizes foraging and reproduction, and the social secondary, which is neither a forager nor reproductive but rather remains at the nest as a guard. We compare the brains of solitary females that forage and reproduce but do not engage in social interactions with those of social individuals while controlling for age, reproductive status, and foraging experience. Mushroom body calyx volume was positively correlated with wing wear, a proxy for foraging experience. We also found that, although total brain volume did not vary among reproductive strategies (solitary vs. social nesters), socially dominant primaries had larger mushroom body calyx volumes (corrected for both brain and body size variation) than solitary females; socially subordinate secondaries (that are neither dominant nor foragers) had the least-developed mushroom body calyces. These data demonstrate that sociality itself does not explain mushroom body volume; however, achieving and maintaining dominance status in a group was associated with mushroom body calyx enlargement. Dominance and foraging effects were cumulative; dominant social primary foragers had larger mushroom body volumes than solitary foragers, and solitary foragers had larger mushroom body volumes than nonforaging social secondary guards. This is the first evidence for cumulative effects on brain development by dominance and task performance

Sex and social costs of escaping in the striped plateau lizard Sceloporus virgatus

As a predator approaches, prey base decisions about when to flee on a balance between degree of predation risk and costs of escaping. Lost opportunities to perform activities that may increase fitness are major escape costs. Paramount among these are chances to increase fitness by courting and mating and by driving away sexual rivals. Because sexual selection imposes different social demands on the sexes, social opportunities can have different consequences for males and females, but effects of sex differences in social opportunity costs on escape behavior are unknown. We conducted a field experiment showing that male striped plateau lizards (Sceloporus virgatus) given the opportunity to court or perform aggressive behavior permit closer approach before fleeing, but females do not. Males allowed a simulated predator to approach closer before initiating escape if a tethered male or female rather than a control stimulus was introduced to them, but females initiated escape at similar distances in all conditions. For males, a trade-off between the greater predation risk accepted before fleeing due to the likelihood of enhancing fitness by sexual or aggressive behavior accounts for closer approach allowed in the presence of conspecifics. Mating opportunities are not limiting for females in most species and females often have little to gain by interacting aggressively with other females. Therefore, presence of a conspecific male or female may not justify taking greater risk. Results confirm the prediction of optimal escape theory that flight initiation decreases as cost of escaping increases. The sex difference in effect of presence of conspecifics on flight initiation distance is a consequence of the sex difference in costs of escaping. Copyright 2007, Oxford University Press.