Identification of adverse reactions to new drugs. IV--Verification of suspected adverse reactions.

The verification processes were assessed for 18 important adverse drug reactions. Verification when achieved by formal studies was not obtained through cohort studies such as postmarketing surveillance or other follow up of drug users but through case-control studies or a similar disease orientated approach. When not achieved in this way the most useful aspects of uncontrolled studies were rechallenge and dose-response data. Analysis of the data and of the characteristics of different methods of verification suggested that there were four approaches to earlier discovery. (1) The best system seemed to be some form of record linkage, capable of providing at the same time data on incidence of adverse reactions and on prevalence of drug usage in patients with disease suspected of being drug induced. Until such a system can be established the relative efficacy of alternative approaches appears to be (2) review of all published first alerts, with prompt initiation of case-control or disease orientated studies for verification, (3) postmarketing surveillance of cohorts of drug users, and (4) voluntary reporting systems.     

Identification of adverse reactions to new drugs. II--How were 18 important adverse reactions discovered and with what delays?

The process of discovery of 18 important adverse drug reactions was reviewed. For each adverse reaction the dates were noted of the report which first alerted the medical profession to the suspected reaction, the report which resulted in verification of causality beyond reasonable doubt, and the first regulatory action or warning to the medical profession in Britain by the Committee on the Safety of Medicines.     

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.     

The effect of diabetes mellitus on pharmacokinetics,pharmacodynamics and adverse drug reactions of anticancer drugs

Diabetes mellitus (DM) and cancer are global problems carrying huge human, social, and economic impact. Type 2 diabetes (T2DM) is associated with an increased risk for a number of cancers, including breast, pancreatic, and liver cancer. Moreover, adverse drug reactions are higher in paitents with cancer with T2DM compared to cancer patients without T2DM. Cellular mechanisms of hyperglycemia and chemotherapy efficacy may be different depending upon the particular cancer type and the condition of the patient. This review evaluates the effect of DM on the pharmacokinetic, pharmacodynamic, and adverse drug reactions of commonly used anticancer drugs such as cisplatin, methotrexate, paclitaxel, doxorubicin, and adriamycin in both clinical and animal models. A literature search was conducted in scientific databases including Web of Science, PubMed, Scopus, and Google Scholar including the relevant keywords. The results of the effectiveness of anticancer therapies in patients with DM are, however, inconsistent because DM can negatively impact multiple diverse entities including nerves and vascular structures, insulin-like growth factor 1, the function of the innate immune system, drug pharmacokinetics, the expression levels of hepatic CYP₄₅₀, Mdr _1b and enzymes that then lead to drug toxicity. However, in a few circumstances, DM led to attenuation of the toxicity of anticancer drugs secondary to attenuation of the energy-dependent renal uptake process. Overall, the impact of DM on patients with cancer is variable because of the diverse types of cancers and the spectrum of anticancer drugs. With respect to the evidence for cancer involvement in DM pathophysiology and the response to anticancer treatment in patients with DM, many questions still remain and further clinical trials are needed.     

Lymphocyte reactions at early periods after heart transplantation]

The authors determined the quantitative and qualitative composition of the white blood and dehydrogenase activity of lymphocytes in the blood from the afferent and afferent vessels of the transplanted heart at the early postoperative periods in dogs. There was noted a reduction of the lymphocyte count in the blood flowing from the transplanted heart on account of retention of these cells in the transplant, and also an inversion of the mitochondrial dehydrogenases activity due to the lymphocyte contact with foreign antigens of the transplanted heart. A hypothesis is put forward that the inversion mechanism was connected with the lymphocyte functions in the capacity of immunocompetent cells.     

Functional characterization of the creatine phosphokinase reactions in heart mitochondria and myofibrils]

The kinetic properties of MM-isozyme of creatine phosphokinase (CPK) bound to heart myofibrils have been determined experimentally. It has been shown that CPK isozymes bound to the heart myofibrils and mitochondria are electrophoretically different, but have very similar kinetic properties. For both isozymes the ATP formation reaction is preferable. However, in heart mitochondria the kinetic properties of CPK are compensated for by a tight functional coupling with ATP-ADP translocase. Due to this coupling the ATP formed in the course of oxidative phosphorylation can be used completely for creatine phosphate production in mitochondria. On the other hand, the kinetic properties of myofibrillar CPK isozyme are such that they provide for the effective utilization of creatine phosphate produced in mitochondria for rephosphorylation of AKP formed in the myofibrils during contraction. It is concluded that in the heart cells energy can be transferred from the mitochondria to the myofibrils by creatine phosphate molecules.