Safety monitoring of disposable medical products

In 1988 medical devices have become a part of the German AMG. According to this law safety monitoring similar to the one with drugs should be introduced. In the United States the so called medical device report regulation is responsible for safety monitoring. They have demonstrated that the risks of these instrument cannot be neglected. Therefore medical organisations or technical supervising institutions in Germany should take care of safety monitoring with medical devices, because otherwise supranational organisations, which are already present in different countries, or European community authorities will become responsible after the introduction of the free European market in 1992.     

Recombinant therapeutic proteins: production platforms and challenges

Since the approval of insulin in 1982, more than 120 recombinant drug substances have been approved and become available as extremely valuable therapeutic options. Exact copying of the most common human form is no longer a value per se, as challenges, primarily related to the pharmacokinetics of artificial recombinant drugs, can be overcome by diverging from the original. However, relatively minor changes in manufacturing or packaging may impact safety of therapeutic proteins. A major achievement is the development of recombinant proteins capable of entering a cell. Such drugs open up completely new opportunities by targeting intracellular mechanisms or by substituting intracellularly operating enzymes. Concerns that protein variants would cause an intolerable immune response turned out to be exaggerated. Although most recombinant drugs provoke some immune response, they are still well tolerated. This knowledge might result in a change in attitude towards antibody formation, i.e., neutralizing antibody activity (in vitro) may be overcome by dosing consistently on the basis of antibody titers and not only on body weight. As with other drugs, efficacy and safety of therapeutic proteins have to be demonstrated in clinical studies, and superiority over available products has to be proven instead of just claimed.     

Ancianos frágiles polimedicados: ¿es la deprescripción de medicamentos la salida?

Deprescribing is the process of reconstructing multiple medication use by review and analysis and which concludes with dose modification, replacement or elimination of some drugs or adding others. Its development is intended to resolve tensions and contradictions between two sets of questions: 1/is life expectancy shorter than the time the drug takes to obtain a benefit?, and 2/are the goals of prescribing-deprescribing consistent with those of care? The validity of the rationale on deprescribing is based on scientific and ethical reasons. The usefulness and safety of many drugs that frail elderly or terminally ill takes is unknown, and other drugs may cause troublesome or severe side effects. Thus, in some cases their removal could be justified, being substantially safe doing so.     

动物病理学在新药开发风险控制中的作用

目的 进行临床前研究的主要原因在于,保证研究中新药探索实验中尤其是研发早期试验人群的安全,因为只是减少健康志愿者身上的风险无益于保证（所有）受试者的安全.内容 本文从新药研发的两个阶段分别对病理学在临床前风险控制研究中的作用进行了讨论.结论 在非临床前新药研发阶段的风险控制中,让病理学家参与到新药研发的风险管理队伍中来,帮助研发、监控研发,是成功研发与优良的风险管理策略相衔接的关键.     

Safe composition levels of transgenic crops assessed via a clinical medicine model

Substantial equivalence has become established as a foundation concept in the safety evaluation of transgenic crops. In the case of a food and feed crop, no single variety is considered the standard for safety or nutrition, so the substantial equivalence of transgenic crops is investigated relative to the array of commercial crop varieties with a history of safe consumption. Although used extensively in clinical medicine to compare new generic drugs with brand-name drugs, equivalence limits are shown to be a poor model for comparing transgenic crops with an array of reference crop varieties. We suggest an alternate model, also analogous to that used in clinical medicine, where reference intervals are constructed for a healthy heterogeneous population. Specifically, we advocate the use of distribution-free tolerance intervals calculated across a large amount of publicly available compositional data such as is found in the International Life Sciences Institute Crop Composition Database.     

Habit,prejudice, power and politics: issues in the conversion of H2-receptor antagonists to over-the-counter use.

H2-receptor antagonists have been widely prescribed in the last 20 years and are considered to rank among the safest drugs known. In several countries they have been switched to over-the-counter (OTC) status, and a similar move is under consideration in Canada. Some concerns have been raised as to the effectiveness of these drugs in the treatment of dyspepsia and heartburn, their safety when taken for self-diagnosed symptoms, and the potential for their use to delay diagnosis or mask serious disease. The author presents evidence to support the use of OTC H2-receptor antagonists in the treatment of dyspepsia. He argues that the safety record of these drugs is reassuring and that they are unlikely to mask gastric cancer. Finally, he describes the appropriate place of OTC H2-receptor antagonists in the overall management of acid-related disorders.     

Regulatory issues in aging pharmacology

Many current drugs increase the average lifespan by preventing fatal diseases or by slowing down the progressive degenerative diseases that increase mortality. The existing strategies and guidelines for the development and regulatory approval of new drugs are designed for such compounds. Rapid advances in understanding molecular mechanisms of aging make it possible to envisage future drugs that extend the lifespan by regulating aging mechanism outside of disease pathways. Strategies for development and regulatory approval of such drugs remain to be defined. Since the drug candidates will be given to healthy, elderly subjects, safety requirements will be extremely high. Clinical studies of many years' duration will be necessary to prove changes in longevity. These time intervals may exceed those of patent protection and thus minimize commercial incentives. Despite these challenges, two broadly defined pathways are feasible. First, it may be possible to obtain public funding for studies with voluntary participation of humans consuming existing drugs or natural compounds in the 'expected to be safe' category. Second, the development of novel drugs may proceed on the basis of well-defined biomarkers of aging that can serve as surrogate end points in clinical studies. The emerging approaches will prompt the regulatory agencies into taking the first steps towards regulatory guidance.     

Juvenile animal studies and pediatric drug development retrospective review: use in regulatory decisions and labeling

Juvenile animal toxicity studies are conducted to support applications for drugs intended for use in children. They are designed to address specific questions of potential toxicity in the growing animal or provide data about long-term safety effects of drugs that cannot be obtained from clinical trials. Decisions to conduct a juvenile animal study are based on existing data, such as a safety signal already identified in adult studies, or previous knowledge of the drug or chemical class for its potential to impair growth or developmental milestones. In 2006, the FDA issued an industry guidance in which considerations for determining when a juvenile animal study is warranted were outlined. A retrospective study was conducted covering years both before and after the issued guideline to examine the contribution of juvenile animal toxicity studies to the risk/benefit assessment of pediatric drugs at the FDA. The initial findings were presented as part of the May 2010 HESI workshop on the value of juvenile animal studies. The objective of the review was to better understand the value that the juvenile animal study contributes to regulatory decision making for pediatric drug development by looking at when the studies have been included in the product assessment; what, if any, impact the studies had on the regulatory decisions made; and whether the data were incorporated into the label. The data described below represent a first look at impact of the juvenile animal study since the pediatric legislation and the juvenile animal guidance were issued in the US.     

Cytochromes P450 and drug resistance

Cytochromes P450 are the key enzymes for activating and inactivating many drugs, in particular anticancer drugs. Therefore, individual expression levels of cytochromes P450 may play a crucial role in drug safety and drug efficacy. Overexpression of cytochrome P450 may yield rapid turnover and elimination of drugs before the target site was reached and any pharmacological effect is observed. Therefore, it may be vital to know the individual cytochrome P450 status in order to select the appropriate drug before drug resistance occurs. Expression levels and activity of cytochromes P450 depend on many different factors. These factors include tissue and organ specific expression, sex- and age-dependent expression, genetic differences yielding polymorphic forms, competitive inhibition or induction of cytochromes P450 due to multiple drug interaction, nutrition and diet. Genetically engineered test cells defined for cytochromes P450 are available for studying drugs for metabolic activation and for identifying the metabolically competent cytochrome P450 isoform.     

The chemical restraint of apes and monkeys by means of phencyclidine or ketamine.

The anesthetic effects of two drugs, namely, Phencyclidine and Ketamine, used alone or in combination with atropine, were compared during clinical and experimental procedures on different primate species ranging from gorillas, orangutans, white-faced and dwarf chimpanzees, baboons, cercopithecus monkeys to new--world monkeys. It is concluded that both these anesthetics are very good and safe drugs for restraint and anesthesia. Ketamine appeared to be superior to Phencyclidine for use among apes and monkeys in so far as it is shorter acting, has wider safety margin and shorter recovery time, provides better muscle relaxation and is practically without side effects. But Phencyclidine has definite advantage in so far as it is needed is smaller quantity to produce comparable effect of anesthesia.     

Where Failure Is Not an Option –Personalized Medicine in Astronauts

Drug safety and efficacy are highly variable among patients. Most patients will experience the desired drug effect, but some may suffer from adverse drug reactions or gain no benefit. Pharmacogenetic testing serves as a pre-treatment diagnostic option in situations where failure or adverse events should be avoided at all costs. One such situation is human space flight. On the international space station (ISS), a list of drugs is available to cover typical emergency settings, as well as the long-term treatment of common conditions for the use in self-medicating common ailments developing over a definite period. Here, we scrutinized the list of the 78 drugs permanently available at the ISS (year 2014) to determine the extent to which their metabolism may be affected by genetic polymorphisms, potentially requiring genotype-specific dosing or choice of an alternative drug. The purpose of this analysis was to estimate the potential benefit of pharmacogenetic diagnostics in astronauts to prevent therapy failure or side effects.     

三唑类抗真菌新药泊沙康唑和伏立康唑简介

随着侵袭性真菌感染的发病率和死亡率逐年增多,新近问世的新型抗真菌药物也越来越多。新一代广谱三唑类抗真菌药物泊沙康唑和伏立康唑,在体内和体外均有较强的抗真菌活性,临床上用其来预防和治疗侵袭性真菌感染。两药具有共有的作用机制,在抗真菌活性、药物代谢及安全性方面有着各自特点。分子结构上泊沙康唑和伏立康唑优于原有药物伊曲康唑和氟康唑,从而具备更强、更广的抗菌谱。两药的研发和应用表明抗真菌药物研究正朝着高效、广谱、低毒的方向发展,成为治疗各种类型真菌感染新的有力手段。然而,两药在临床研究和血药浓度监测方面仍待深入探究。本文将从分子结构、作用机制、适应症和药代动力学方面介绍两药,并对两药在未来的临床应用进行展望,为临床应用提供帮助。     

The safety of psychotropic drug use during pregnancy: a review

A substantial number of women of childbearing age are prescribed psychotropic drugs, and because nearly 50% of pregnancies are unplanned, many women are still taking them upon becoming pregnant. This article reviews the various classes of psychotropic drugs that are commonly used to treat psychiatric disorders--antidepressants, benzodiazepines, antipsychotics, antiepileptics, lithium and monoamine oxidase (MAO) inhibitors--in terms of their safety during pregnancy. Evidence-based information from epidemiologic studies indicates that most psychotropic drugs are relatively safe for use during pregnancy. There is also an increasingly large body of evidence-based information in the literature indicating that it may be more harmful to both the mother and her baby if she is not treated appropriately when suffering from a severe psychiatric disorder. Therefore, it is important for women with psychiatric disorders and their healthcare providers to have access to evidenced-based information about the safety of these drugs when taken during pregnancy to ensure that women make an informed decision as to whether they should continue with the pharmacotherapy they have been using to treat their condition.     

Classifying Drugs by their Arrhythmogenic Risk Using Machine Learning

All medications have adverse effects. Among the most serious of these are cardiac arrhythmias. Current paradigms for drug safety evaluation are costly, lengthy, conservative, and impede efficient drug development. Here, we combine multiscale experiment and simulation, high-performance computing, and machine learning to create a risk estimator to stratify new and existing drugs according to their proarrhythmic potential. We capitalize on recent developments in machine learning and integrate information across 10 orders of magnitude in space and time to provide a holistic picture of the effects of drugs, either individually or in combination with other drugs. We show, both experimentally and computationally, that drug-induced arrhythmias are dominated by the interplay between two currents with opposing effects: the rapid delayed rectifier potassium current and the L-type calcium current. Using Gaussian process classification, we create a classifier that stratifies drugs into safe and arrhythmic domains for any combinations of these two currents. We demonstrate that our classifier correctly identifies the risk categories of 22 common drugs exclusively on the basis of their concentrations at 50% current block. Our new risk assessment tool explains under which conditions blocking the L-type calcium current can delay or even entirely suppress arrhythmogenic events. Using machine learning in drug safety evaluation can provide a more accurate and comprehensive mechanistic assessment of the proarrhythmic potential of new drugs. Our study paves the way toward establishing science-based criteria to accelerate drug development, design safer drugs, and reduce heart rhythm disorders.     

Preclinical pharmacokinetic and toxicological evaluation of MIF-1 peptidomimetic,PAOPA: Examining the pharmacology of a selective dopamine D2 receptor allosteric modulator for the treatment of schizophrenia

Schizophrenia is a mental illness characterized by a breakdown in cognition and emotion. Over the years, drug treatment for this disorder has mainly been compromised of orthosteric ligands that antagonize the active site of the dopamine D2 receptor. However, these drugs are limited in their use and often lead to the development of adverse movement and metabolic side effects. Allosteric modulators are an emerging class of therapeutics with significant advantages over orthosteric ligands, including an improved therapeutic and safety profile. This study investigates our newly developed allosteric modulator, PAOPA, which is a specific modulator of the dopamine D2 receptor. Previous studies have shown PAOPA to attenuate schizophrenia-like behavioral abnormalities in preclinical models. To advance this newly developed allosteric drug from the preclinical to clinical stage, this study examines the pharmacokinetic behavior and toxicological profile of PAOPA. Results from this study prove the effectiveness of PAOPA in reaching the implicated regions of the brain for therapeutic action, particularly the striatum. Pharmacokinetic parameters of PAOPA were found to be comparable to current market antipsychotic drugs. Necropsy and histopathological analyses showed no abnormalities in all examined organs. Acute and chronic treatment of PAOPA indicated no movement abnormalities commonly found with the use of current typical antipsychotic drugs. Moreover, acute and chronic PAOPA treatment revealed no hematological or metabolic abnormalities classically found with the use of atypical antipsychotic drugs. Findings from this study demonstrate a better safety profile of PAOPA, and necessitates the progression of this newly developed therapeutic for the treatment of schizophrenia.     

New anthelmintics

The anthelmintic drugs currently available are still relatively few in number. Many of them are limited in their usefulness because of narrow spectrum of action, safety, high cost or impractical delivery systems. Some of these will be discontinued because of unforseen problems such as occurrence of drug resistance which needs more attention than it presently receives.Drug development is costly and time consuming and requires exacting interdisciplinary interactions between researchers using the most stringent quantitative tests to determine toxicity, safety, mode of action and pharmacokinetics before a drug is ever used in clinical trials. A system of universal testing standards accepted by all involved in drug-development should be established. Scientists are beginning to apply rational design to the development of new compounds and this approach can be expected to be exploited more in the future.From the clinical standpoint, the future is beginning to look brighter for the millions of persons suffering from helminth diseases as a result of available broad spectrum compounds which can be used in clinics and mass-treatment programs.