Identification of adverse reactions to new drugs. I: What have been the important adverse reactions since thalidomide?

A consensus process was used to establish an agreed list of important adverse reactions to drugs identified since thalidomide. Ten physicians working in medicine in Britain and 10 physicians responsible for drug regulatory agencies in different countries were asked to list 10 important adverse reactions to drugs since thalidomide. From these 20 lists a measure of agreement was apparent. Eighteen important adverse reactions were identified for further study of the discovery processes now operating and of the delays occurring from marketing to alerting, from alerting to verification, and from verification to regulatory action. The results suggest that an empirical review of this type is necessary as a starting point for discussion of better systems to reduce delays in the discovery of adverse reactions to new drugs.     

Predisposing Factors in Adverse Reactions to Drugs

Predisposing factors were sought in 118 patients who developed adverse drug reactions in hospital. Significantly more patients of 60 years and over, and more women than men, developed adverse drug reactions. Patients with reactions had more drugs before the development of the reaction than patients who did not develop reactions. A previous adverse drug reaction and a history of allergic disease were significant factors, while a history of jaundice or the presence of diabetes mellitus and renal disease was not.     

Admissions to Hospital due to Drugs

In a survey of adverse drug reactions in wards of two Belfast hospitals for 52 weeks in 1965–6, 2·9% of 1,268 patients seen were admitted to hospital because of adverse reactions to drugs taken for therapeutic reasons and 2·1% were admitted because of self-poisoning. Patients admitted because of adverse drug reactions were older than those admitted because of self-poisoning and stayed in hospital longer. Among the drugs which caused the adverse reactions were digitalis preparations, antibiotics, corticosteroids, anticoagulants, analgesics, and tranquillizers. Hypersensitivity and side-effect types of reactions were the most common. Barbiturates were the most frequently used drugs in suicidal attempts.     

A Method of Determining Patterns of Use of Antibacterial Drugs

A hospital chart review system using standard IBM punch cards was designed to review patterns of use of antibacterial drugs in a large Canadian general hospital. Review of the charts of 4894 patients during an eight-month period showed that this method provided an inexpensive and accurate summary of many of the details of use of antibacterial drugs, including indications accepted for drug use, specific drugs selected, the manner in which the drugs were used and the precautions taken to avoid adverse reactions. This method of review should be valuable in delineating drug misuse and overuse, and hence in the continuing education of the physician.     

Intensive Hospital Monitoring of Adverse Reactions to Drugs

A total of 1,268 patients admitted to hospital wards were kept under surveillance by one observer throughout their stay in hospital. All drugs given to them and the occurrence of adverse reactions were recorded.Drug reactions were found in 10·2% of the 1,160 patients who received drug therapy. Most reactions were due to known pharmacological actions of the drugs. Though only four reactions were of life-threatening seriousness, 80% of the 129 reactions observed were of moderate severity. Digitalis preparations, bronchodilator drugs, and ampicillin had the highest reaction rates. It is suggested that larger surveys of adverse reactions in relation to drug usage would make a useful contribution to the problem.     

A Pharmacovigilance Approach for Post-Marketing in Japan Using the Japanese Adverse Drug Event Report (JADER) Database and Association Analysis

BackgroundRapid dissemination of information regarding adverse drug reactions is a key aspect for improving pharmacovigilance. There is a possibility that unknown adverse drug reactions will become apparent through post-marketing administration. Currently, although there have been studies evaluating the relationships between a drug and adverse drug reactions using the JADER database which collects reported spontaneous adverse drug reactions, an efficient approach to assess the association between adverse drug reactions of drugs with the same indications as well as the influence of demographics (e.g. gender) has not been proposed.ConclusionsDifferent combinations of adverse drug reactions were noted between the antidepressants. In addition, the reported adverse drug reactions differed by gender. This approach using a large database for examining the associations can improve safety monitoring during the post-marketing phase.     

The role of polymorphic cytochrome P450 enzymes in drug design,development and drug interactions with a special emphasis on phenotyping

Inhibitors of some cytochrome P450s (CYPs) are used to design target-specific drugs. CYPs belonging to families 1–4 play important roles in drug metabolism and therapeutics. Some isozymes of CYPs also activate pro-carcinogens into their carcinogenic forms. Approximately 40–50% human CYP-dependent drug metabolism is carried out by polymorphic CYPs resulting in therapeutic failure and adverse reactions. Phenotyping of CYPs involved in the metabolism of a drug is important to understand the potential of clinical interactions and to predict the possible individual variations due to genetic polymorphisms of certain CYPs.     

双膦酸盐类药物致不良反应回顾性分析

目的:分析双膦酸盐类药物所致不良反应情况。方法:检索中国期刊全文数据库(CNKI)、万方数据库(Wan Fang)、中文科技期刊数据库(VIP)2004年1月至2013年8月国内有关双膦酸盐致不良反应的个案报道,按年龄、性别、原发病、药物名称、给药途径、不良反应发生时间、临床表现症状、治疗与转归等进行分类统计分析。结果:48例不良反应包括运动系统、消化系统、感官系统、循环系统、神经系统及全身性损害,高年龄段与女性发生率较高。结论:临床上应重视双膦酸盐类药物所致不良反应,坚持合理用药。     

Adverse reactions to drugs in general practice.

Of 817 patients in a general-practice survey of adverse reactions to drugs, 41% were thought to have "certainly" or "probably" had a reaction to the drug prescribed. Adverse effects on the gastrointestinal and central nervous systems were the most frequently reported, and 90% of reactions had occurred by the fourth day of treatment. More patients given drugs acting on the central nervous system and antihistamines reported reactions than those in other categories. A higher incidence of adverse drug effects is shown in this general-practice survey than in other, mainly hospital-based, surveys. Further intensive surveillance for adverse effects of drugs is recommended to provide additional information on the burden of drug-induced disease in the community.     

Survey of colourings and preservatives in drugs.

OBJECTIVE--To assess the prevalence of colourings and preservatives in drug formulations in the United Kingdom. DESIGN--Postal survey. PARTICIPANTS--All pharmaceutical manufacturers in the United Kingdom were requested to supply data on drug formulations with particular regard to the content of colourings and preservatives. MAIN OUTCOME MEASURE--Prevalence in proprietary drugs of colourings or preservatives, or both, that have been implicated in adverse reactions. Computation of a list of formulations of bronchodilators, antihistamines, and antibiotics that are free of such additives. RESULTS--A total of 118 out of 120 pharmaceutical companies supplied the data requested. In all, 2204 drug formulations were analysed and found to contain 419 different additives, of which 52 were colourings and preservatives that have been implicated in adverse reactions; 930 formulations contained such an additive. Tartrazine was the fourth most commonly occurring colouring, being present in 124 drug formulations. CONCLUSION--Many drugs contain additives that help to identify them and prolong their shelf life but are implicated in adverse reactions in some people. Some form of labelling of drug additives would enable these people to avoid drugs containing such additives.     

Patients as a direct source of information on adverse drug reactions.

To determine whether patients should participate directly in detecting adverse reactions to drugs their ability to provide written reports of symptoms experienced during treatment with amoxycillin or trimethoprim-sulphamethoxazole was investigated. When compared with telephone interviews forms on which patients reported events were reliable (the observed agreement with the same statements posed during telephone calls was 85%, kappa = 0.56) and valid (sensitivity = 54%, specificity = 94%). Patients were also supplied with forms that invited them to report adverse reactions, and their perceptions were compared with those of a panel of experts, who were informed of all clinical events that had been reported during the detailed telephone interviews. Patients were more conservative than the experts in attributing clinical events to drug treatment. The extent of agreement varied and was notably poor for skin and bowel complaints (kappa = 0.13 in each case). The performance of event report forms and reaction report forms as instruments of detection was compared in a hypothetical situation in which the experts'' views represented the "truth" about adverse reactions to a new drug. Event reporting had a higher sensitivity than reaction reporting (42% v 24%) but a lower specificity (58% v 98%). National centres monitoring adverse drug reactions should probably resist pressure to accept reports of reactions directly from the public, but a system based on large scale reporting of events might be valuable in aiding the early detection of symptomatic reactions to new drugs.     

DRUG DANGERS AND REACTIONS

The protection of the consumer against dangerous, adulterated, and misbranded drugs provided by the Federal Food, Drug, and Cosmetic Act has failed in some instances. A general program of reporting adverse drug reactions has been initiated on a pilot basis. Arrangements are being made to extend this program into larger hospitals. Better and more complete reporting of adverse drug reactions together with tightening of the Food and Drug law regarding new drugs will improve this situation.Recently the president of the National Academy of Sciences appointed a committee at the request of the Secretary of Health, Education, and Welfare to review the policies and procedures used by the Food and Drug Administration in reaching decisions and to present recommendations. This committee has completed its work and has made specific recommendations that would give the Food and Drug Administration authority to require proof of efficacy as well as safety of all new drugs, and would provide it with sufficient resources to meet the responsibilities assigned to it.     

Death after Taking Medicaments

A register of reported adverse reactions, recently made available to major hospitals and medical schools gives an indication of prescribing habits under the N.H.S. in England and Wales. An analysis is made here of the chief medicaments allegedly leading to death. Such data are incomplete because of lack of knowledge of the total use of each drug in the United Kingdom and because reporting of adverse reactions is very incomplete. Nevertheless, data about various groups of drugs do draw attention to some hazards and should encourage more widespread reporting of reactions to drugs and other medicaments.     

Recognizing and reporting adverse drug reactions.

Although physicians in practice are most likely to see patients with adverse drug reactions, they may fail to recognize an adverse effect or to attribute it to a drug effect and, when recognized, they may fail to report serious reactions to the US Food and Drug Administration (FDA). To recognize and attribute an adverse event to a drug effect, physicians should review the patient''s clinical course, looking at patient risk factors, the known adverse reactions to the suspected drug, and the likelihood of a causal relationship between the drug and the adverse event-based on the temporal relationship, response to stopping or restarting the drug, and whether other factors could explain the reaction. Once an adverse drug reaction has been identified, the patient should be informed and appropriate documentation made in the patient''s medical record. Serious known reactions and all reactions to newly released drugs or those not previously known to occur (even if the certainty is low) should be reported to the FDA.     

多模式术后镇痛在腹腔镜结肠手术中的应用

目的:理论上联合使用不同机制镇痛药较镇痛药单独使用镇痛效果更完善,在妇科、骨科等手术中已有结论;笔者观察比较腹腔镜结肠手术术使用单一止痛药及联合使用不同机制镇痛药在术后镇痛的效果以及各自不良反应的发生率。方法:择期腹腔镜结肠手术患者90例,随机分为3组,每组30例。A组使用地佐辛+氟比洛酚酯行术后镇痛为多模式镇痛组;B组使用地佐辛行术后镇痛;C组使用氟比洛酚酯行术后镇痛。记录每组术后4、8、12、24 h视觉模糊评分(VAS)及术后不良反应包括嗜睡、躁动、恶心呕吐的发生率。结果:A组术后4 h、8 h的VAS评分低于B、C两组,差异有显著性,A组无嗜睡及躁动发生,发生呕吐1例,不良反应发生率A组低于B、C两组,差异有显著性。结论:地佐辛+氟比洛酚酯联合用药可安全有效应用于腹腔镜结肠手术术后镇痛,是一种有效的多模式术后镇痛方式,在减弱疼痛的放大效应及对中枢神经的作用两方面起效,因而较单独使用地佐辛及氟比洛酚酯有更好的镇痛效果,且不良反应低于单独使用地佐辛及氟比洛酚酯。     

Web Resources for Pharmacogenomics

Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research,pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically changed the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings.     

Use of Optical Biosensor Technology to Study Immunological Cross-Reactivity between Different Sulfonamide Drugs

Adverse reactions to medications account for a substantial number of hospitalizations and in some cases fatalities. The nature of the many drug-drug interactions caused by the inhibition of drug-metabolizing enzymes can now be predicted and examined with a greater deal of accuracy due to research developments in the understanding of the drug-metabolizing enzymes. However, the more troubling aspects of drug-drug interactions are the idiosyncratic reactions that are unpredictable and quite often life-threatening. These reactions are often caused by a prior sensitization of a person's immune system to a given drug or class of drugs. The following work offers a technique to examine in a medium-throughput system the cross-reactivity of drugs to antibodies in order to predict if structures share the same antigenic potential toward a sensitized individual. Two commercially important sulfonamide drugs, sulfamethazine and furosemide, were taken and their binding to their respective antibodies were tested in the presence of other structurally related sulfonamide drugs. The BIACORE 3000 biosensor was used for the study and the solution-phase equilibrium assay principle was employed. The data obtained help us determine which drugs can react, and to what extent, with sulfamethazine and furosemide, giving rise to possible allergic or hypersensitivity reactions. Though sulfamethazine and furosemide were used in this study; this principle and methodology can be applied to study any drug molecule-antibody pair.     

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.