Intrauterine transfusion of twins.

Drug interactions are important causes of both unexpected toxic and therapeutic effects. Adverse reactions due to drug interaction are proportional to the number of drugs given and the duration of administration. Although drug interactions may be beneficial, they are most often recognized when they increase mortality or morbidity. The frequency of adverse drug interactions in clinical practice makes it mandatory for physicians to know the drugs and mechanisms involved.A drug may potentiate or antagonize the effects of another drug by direct chemical or physical combination, by altering gastrointestinal absorption, by influencing metabolism, transport, or renal clearance, by changing the activity of a drug at its receptor site, or by modifying the patient''s response to the drug by a variety of means.This article stresses the importance of avoiding multible drug therapy. When such treatment is unavoidable, patients must be carefully observed for evidence of intensified or diminished drug effect. Only this permits the detection and prevention of untoward drug interactions.     

Prevention. How much harm? How much benefit? 1. Influence of reporting methods on perception of benefits.

Before a physician or a patient can decide whether a preventive program is worth while, each must understand the nature and degree of its benefits and the frequency and magnitude of its adverse effects. Preventive interventions can be divided into two major categories: those with infrequent or minor adverse effects and those with adverse effects that are frequent or serious. Accident prevention, avoidance of high-risk behaviour and healthy lifestyle choices such as breast-feeding and moderate exercise are associated with few adverse consequences. By contrast, screening populations for disease, risk classification for the purpose of selective preventive interventions, dietary intervention and prophylactic drug treatment may lead to more frequent and serious adverse effects. When assessing whether the benefits of a preventive intervention outweigh the harm, one must be aware that the methods used to report benefits of clinical trials may distort the reader''s perception of their magnitude. The relative reduction of morbidity or mortality rate often grossly exaggerates benefits and should never be used as a basis for clinical decision making. More realistic ways of recording benefits are the absolute reduction of morbidity or mortality rate, the number of patients that need to be treated to avoid one adverse event, and the total cohort mortality rate.     

New perspectives in allergic asthma.

Major advances have recently been made in both the diagnosis and the treatment of allergic asthma. The radioallergosorbent test (RAST), which measures allergen specificity of lgE antibodies in vitro, offers as good results as direct skin tests for allergy, without the inconvenience, discomfort and risk for the patient of the latter. However, the RAST must be done in a radioisotope laboratory, and standardized extracts of test allergens are lacking. Several new drugs, administered by inhalation and relatively free from serious side effects, are highly effective in treating asthma. Disodium cromoglycate, believed to stabilize tissue mast cells, protects particularly against exercise- or antigen-induced bronchospasm, and often permits reduction or withdrawal of corticosteroid therapy. Some acetonides or esters of glucocorticoids, because of their greatly increased topical anti-inflammatory activity, are effective in doses too small to cause serious systemic side effects. With the most topically effective, beclomethasone dipropionate, systemic corticosteroid therapy can usually be reduced or withdrawn, but recovery of hypothalamic-pituitary-adrenal function may be delayed; the drug regimens should therefore overlap.     

Therapeutic strategies of dual-target small molecules to overcome drug resistance in cancer therapy

Despite some advances in targeted therapeutics of human cancers, curative cancer treatment still remains a tremendous challenge due to the occurrence of drug resistance. A variety of underlying resistance mechanisms to targeted cancer drugs have recently revealed that the dual-target therapeutic strategy would be an attractive avenue. Compared to drug combination strategies, one agent simultaneously modulating two druggable targets generally shows fewer adverse reactions and lower toxicity. As a consequence, the dual-target small molecule has been extensively explored to overcome drug resistance in cancer therapy. Thus, in this review, we focus on summarizing drug resistance mechanisms of cancer cells, such as enhanced drug efflux, deregulated cell death, DNA damage repair, and epigenetic alterations. Based upon the resistance mechanisms, we further discuss the current therapeutic strategies of dual-target small molecules to overcome drug resistance, which will shed new light on exploiting more intricate mechanisms and relevant dual-target drugs for future cancer therapeutics.     

The role of pharmacogenetics in treating central nervous system disorders

Symptoms of central nervous system (CNS) disorders include abnormalities in both physical and psychological domains. Many drugs indicated for the treatment of CNS disorders are fraught with side effects and/or poor efficacy which impact patients' quality of life and drives non-compliance. Moreover, for many CNS drugs such as antidepressants and antipsychotics, it takes time to determine whether a particular drug is efficacious in an individual patient. To optimize drug treatment for each patient, prescribing physicians often need to raise or lower doses, switch drug classes, or prescribe additional drugs to mitigate side effects, often in a "trial and error" fashion. Pharmacogenetic (PGx) testing, particularly in the realm of CNS therapy, can reduce the unpredictability of this process. By determining a patient's genetic profile, individual therapy parameters may be predicted pre-treatment for drug efficacy, optimal drug dose, and the risk of adverse drug reactions (ADRs). The intent of this review is to highlight the power of PGx testing to predict the likelihood of ADRs and efficacy during the treatment of the following CNS disorders: epilepsy, bipolar disorder, schizophrenia and depression.     

经皮给药纳米载体及靶向系统治疗类风湿关节炎研究进展

类风湿关节炎(RA)是全世界难治性自身免疫疾病,其治疗药物虽不断发展,但病灶药物浓度达不到有效水平导致药物疗效不理想或存在各种毒副反应,因此,基于新技术、新方法研究开发针对RA的安全、高效新型制剂是必要的.研究表明,纳米技术的运用可提高药物生物利用度,经皮给药可改善口服和注射带来的毒副作用.对近年来基于经皮给药系统治疗...     

Cognitive impairments and cancer chemotherapy: Translational research at a crossroads

Cancer chemotherapy is often associated with cognitive deficits which may remain after the treatment has ended. As more people survive cancer, concern is increasing about the impact of these problems with memory and executive function when they return to everyday life. When chemotherapeutic drugs are administered to healthy animals in dosing regimens modeling those used in humans, cognitive deficits also occur, and these preclinical studies can provide information about the biological mechanisms by which the cancer fighting drugs affect the brain. Evidence from animal studies points to damage to hippocampus, particularly a disruption of neurogenesis, whereas human studies emphasize cognitive deficits associated with impairments in frontal cortical function. This discrepancy may be due more to the tasks selected by researchers, and the choice of biochemical endpoints than inherently different effects of chemotherapy in humans and rodents. These differences in approach must be reconciled if common underlying mechanisms are to be identified, with the hope of leading to novel drug or non-pharmacological treatments. This may be achieved by broadening the scope of human and animal studies, and by looking outside the topic of chemotherapy-induced cancer deficits to learn from the advances being made by studying the effects of stress and somatic disease on brain function, and the cognitive impairments now recognized to result from a wide range of mental and physical illnesses.     

Current understanding of synergistic interplay of chitosan nanoparticles and anticancer drugs: merits and challenges

Recent advances have been made in cancer chemotherapy through the development of conjugates for anticancer drugs. Many drugs have problems of poor stability, water insolubility, low selectivity, high toxicity, and side effects. Most of the chitosan nanoparticles showed to be good drug carriers because of their biocompatibility, biodegradability, and it can be readily modified. The anticancer drug with chitosan nanoparticles displays efficient anticancer effects with a decrease in the adverse effects of the original drug due to the predominant distribution into the tumor site and a gradual release of free drug from the conjugate which enhances drug solubility, stability, and efficiency. In this review, we discuss wider applications of numerous modified chitosan nanoparticles against different tumors and also focusing on the administration of anticancer drugs through various routes. We propose the interaction between nanosized drug carrier and tumor tissue to understand the synergistic interplay. Finally, we elaborate merits of drug delivery system at the tumor site, with emphasizing future challenges in cancer chemotherapy.     

Chemical genetics and drug screening in Drosophila cancer models

Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.     

Chemical genetics and drug screening in Drosophila cancer models

Drug candidates often fail in preclinical and clinical testing because of reasons of efficacy and/or safety.It would be time- and cost-efficient to have screening models that reduce the rate of such false positive candidates that appear promising at first but fail later.In this regard,it would be particularly useful to have a rapid and inexpensive whole animal model that can pre-select hits from high-throughput screens but before testing in costly rodent assays.Drosophila melanogaster has emerged as a potential whole animal model for drug screening.Of particular interest have been drugs that must act in the context of multi-cellularity such as those for neurological disorders and cancer.A recent review provides a comprehensive summary of drug screening in Drosophila,but with an emphasis on neurodegenerative disorders.Here,we review Drosophila screens in the literature aimed at cancer therapeutics.     

Peptide hydrogels for affinity-controlled release of therapeutic cargo: Current and potential strategies

The development of devices for the precise and controlled delivery of therapeutics has grown rapidly over the last few decades. Drug delivery materials must provide a depot with delivery profiles that satisfy pharmacodynamic and pharmacokinetic requirements resulting in clinical benefit. Therapeutic efficacy can be limited due to short half-life and poor stability. Thus, to compensate for this, frequent administration and high doses are often required to achieve therapeutic effect, which in turn increases potential side effects and systemic toxicity. This can potentially be mitigated by using materials that can deliver drugs at controlled rates, and material design principles that allow this are continuously evolving. Affinity-based release strategies incorporate a myriad of reversible interactions into a gel network, which have affinities for the therapeutic of interest. Reversible binding to the gel network impacts the release profile of the drug. Such affinity-based interactions can be modulated to control the release profile to meet pharmacokinetic benchmarks. Much work has been done developing affinity-based control in the context of polymer-based materials. However, this strategy has not been widely implemented in peptide-based hydrogels. Herein, we present recent advances in the use of affinity-controlled peptide gel release systems and their associated mechanisms for applications in drug delivery.     

Improving understanding of chromatin regulatory proteins and potential implications for drug discovery

Many epigenetic-based therapeutics, including drugs such as histone deacetylase inhibitors, are now used in the clinic or are undergoing advanced clinical trials. The study of chromatin-modifying proteins has benefited from the rapid advances in high-throughput sequencing methods, the organized efforts of major consortiums and by individual groups to profile human epigenomes in diverse tissues and cell types. However, while such initiatives have carefully characterized healthy human tissue, disease epigenomes and drug–epigenome interactions remain very poorly understood. Reviewed here is how high-throughput sequencing improves our understanding of chromatin regulator proteins and the potential implications for the study of human disease and drug development and discovery.     

Combination therapeutics in complex diseases

The biological redundancies in molecular networks of complex diseases limit the efficacy of many single drug therapies. Combination therapeutics, as a common therapeutic method, involve pharmacological intervention using several drugs that interact with multiple targets in the molecular networks of diseases and may achieve better efficacy and/or less toxicity than monotherapy in practice. The development of combination therapeutics is complicated by several critical issues, including identifying multiple targets, targeting strategies and the drug combination. This review summarizes the current achievements in combination therapeutics, with a particular emphasis on the efforts to develop combination therapeutics for complex diseases.     

Network Neighbors of Drug Targets Contribute to Drug Side-Effect Similarity

In pharmacology, it is essential to identify the molecular mechanisms of drug action in order to understand adverse side effects. These adverse side effects have been used to infer whether two drugs share a target protein. However, side-effect similarity of drugs could also be caused by their target proteins being close in a molecular network, which as such could cause similar downstream effects. In this study, we investigated the proportion of side-effect similarities that is due to targets that are close in the network compared to shared drug targets. We found that only a minor fraction of side-effect similarities (5.8 %) are caused by drugs targeting proteins close in the network, compared to side-effect similarities caused by overlapping drug targets (64%). Moreover, these targets that cause similar side effects are more often in a linear part of the network, having two or less interactions, than drug targets in general. Based on the examples, we gained novel insight into the molecular mechanisms of side effects associated with several drug targets. Looking forward, such analyses will be extremely useful in the process of drug development to better understand adverse side effects.     

ATP depletion triggers acute myeloid leukemia differentiation through an ATR/Chk1 protein-dependent and p53 protein-independent pathway

Despite advances in oncology drug development, most commonly used cancer therapeutics exhibit serious adverse effects. Often the toxicities of chemotherapeutics are due to the induction of significant DNA damage that is necessary for their ability to kill cancer cells. In some clinical situations, the direct induction of significant cytotoxicity is not a requirement to meet clinical goals. For example, differentiation, growth arrest, and/or senescence is a valuable outcome in some cases. In fact, in the case of acute myeloid leukemia (AML), the use of the differentiation agent all-trans-retinoic acid (ATRA) has revolutionized the therapy for a subset of leukemia patients and led to a dramatic survival improvement. Remarkably, this therapeutic approach is possible even in many elderly patients, who would not be able to tolerate therapy with traditional cytotoxic chemotherapy. Because of the success of ATRA, there is widespread interest in identifying differentiation strategies that may be effective for the 90-95% of AML patients who do not clinically respond to ATRA. Utilizing an AML differentiation agent that is in development, we found that AML differentiation can be induced through ATP depletion and the subsequent activation of DNA damage signaling through an ATR/Chk1-dependent and p53-independent pathway. This study not only reveals mechanisms of AML differentiation but also suggests that further investigation is warranted to investigate the potential clinical use of low dose chemotherapeutics to induce differentiation instead of cytotoxicity. This therapeutic approach may be of particular benefit to patients, such as elderly AML patients, who often cannot tolerate traditional AML chemotherapy.     

Polypharmacology and supercomputer-based docking: opportunities and challenges

Polypharmacology, the ability of drugs to interact with multiple targets, is a fundamental concept of interest to the pharmaceutical industry in its efforts to solve the current issues of the rise in the cost of drug development and decline in productivity. Polypharmacology has the potential to greatly benefit drug repurposing, bringing existing pharmaceuticals on the market to treat different ailments quicker and more affordably than developing new drugs, and may also facilitate the development of new, potent pharmaceuticals with reduced negative off-target effects and adverse side effects. Present day computational power, when combined with applications such as supercomputer-based virtual high-throughput screening (docking) will enable these advances on a massive chemogenomic level, potentially transforming the pharmaceutical industry. However, while the potential of supercomputing-based drug discovery is unequivocal, the technical and fundamental challenges are considerable.     

The mammalian clock and chronopharmacology

Increases in our understanding of the molecular control of circadian rhythms and subsequent signaling pathways has allowed for new therapeutic drug targets to be identified as well as for a better understanding of how to more efficaciously and safely utilize current drugs. Here, we review recent advances in targeting components of the molecular clock in mammals for the development of novel therapeutics as well as describe the impact of the circadian rhythm on drug efficacy and toxicity.     

Medications in older patients.

Adverse drug reactions are common in persons aged 65 and older and are associated with increased morbidity and mortality. A heightened susceptibility to adverse reactions is due to a number of factors, including an increased incidence of disease, multiple drug use, and altered pharmacokinetic and pharmacodynamic properties of many drugs. The risk of drug interactions increases with the number of medications taken. Adverse drug reactions can be prevented through prudent prescribing practices, patient education, and adequate monitoring of drug efficacy and side effects. Several types of medications are of particular concern, including many antihypertensive agents, drugs with anticholinergic effects, psychoactive medications, and nonsteroidal anti-inflammatory drugs. Some drugs, such as histamine H2-receptor antagonists, are relatively safe but are overprescribed. Data regarding the risks associated with these problem drugs are presented, with recommendations for safe and effective treatment alternatives.     

Conceptualizing Cancer Drugs as Classifiers

Cancer and healthy cells have distinct distributions of molecular properties and thus respond differently to drugs. Cancer drugs ideally kill cancer cells while limiting harm to healthy cells. However, the inherent variance among cells in both cancer and healthy cell populations increases the difficulty of selective drug action. Here we formalize a classification framework based on the idea that an ideal cancer drug should maximally discriminate between cancer and healthy cells. More specifically, this discrimination should be performed on the basis of measurable cell markers. We divide the problem into three parts which we explore with examples. First, molecular markers should discriminate cancer cells from healthy cells at the single-cell level. Second, the effects of drugs should be statistically predicted by these molecular markers. Third, drugs should be optimized for classification performance. We find that expression levels of a handful of genes suffice to discriminate well between individual cells in cancer and healthy tissue. We also find that gene expression predicts the efficacy of some cancer drugs, suggesting that these cancer drugs act as suboptimal classifiers using gene profiles. Finally, we formulate a framework that defines an optimal drug, and predicts drug cocktails that may target cancer more accurately than the individual drugs alone. Conceptualizing cancer drugs as solving a discrimination problem in the high-dimensional space of molecular markers promises to inform the design of new cancer drugs and drug cocktails.     

Cancer drug resistance: A fleet to conquer

Cancer is a disease that claims millions of lives each year across the world. Despite advancement in technologies and therapeutics for treating the disease, these modes are often found to turn ineffective during the course of treatment. The resistance against drugs in cancer patients stems from multiple factors, which constitute genetic heterogeneity like gene mutations, tumor microenvironment, exosomes, miRNAs, high rate of drug efflux from cells, and so on. This review attempts to collate all such known and reported factors that influence cancer drug resistance and may help researchers with information that might be useful in developing better therapeutics in near future to enable better management of several cancers across the world.