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.     

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.     

Drug surveillance data in a Canadian hospital.

Comparison of results of a Canadian hospital-based drug surveillance program with data from centres in the United States and Israel showed no important difference in the rate of drug exposures or adverse reactions. Drugs for symptomatic relief were frequently used in the Canadian centre. Women received more drugs and had more adverse reactions than men. Life-threatening and potentially fatal reactions were caused by commonly used drugs; autopsy findings may detect previously unsuspected relations between drug events and mechanisms of death. Voluntary reporting and intensive monitoring are both important in the field of adverse drug reactions.     

Variation in two phases of post‐winter development of a butterfly

The temporal aspects of life cycle characteristics, such as diapause development, are under strong selection in seasonal environments. Fine‐tuning of the life cycle may be particularly important to match the phenology of potential mates and resources as well as for optimizing abiotic conditions at eclosion. Here, we experimentally study the spring phenology of the orange tip butterfly, Anthocharis cardamines, by analysing post‐winter pupal development in three populations along a latitudinal cline in each of Sweden and the United Kingdom. These countries differ substantially in their seasonal temperature profile. By repeatedly recording pupal weights, we established that post‐winter development has two separate phases, with a more rapid weight loss in the second phase than in the first, likely corresponding to a ramping up of the rate of development. Variation in the duration of the first phase contributed more strongly than the second phase to the differences in phenology between the localities and sexes. We found that insects from Sweden had a faster overall rate of development than those from the United Kingdom, which is consistent with countergradient variation, as Sweden is colder during the spring than the United Kingdom. Similar trends were not observed at the within‐country scale, however. A cogradient pattern was found within Sweden, with populations from the north developing more slowly, and there was no clear latitudinal trend within the United Kingdom. In all localities, males developed faster than females. Our results point to the importance of variation in the progression of post‐winter development for spring phenology.     

Third EU report on the statistics on animals used for experimental and other scientific purposes: trends, problems, conclusions

A brief overview is given of the data published in the third report on the number of animals used for scientific purposes in the European Union (EU), in 1999. In comparison to the second EU statistical report, the meaningfulness of the data has been greatly improved, since 14 EU Member States have now used the "EU tables". Even though the total number of animals officially reported in the EU for 1999 (9.81 million animals) is lower than the number reported for 1996 in the second report (11.65 million animals), an increase in animal numbers was observed in several Member States. Repeatedly, the use of transgenic animals was considered to be the cause for this. Most national authorities provided some comments on the data they submitted. However, the quality of these accompanying notes varies considerably, with the comments provided by The Netherlands, Finland, Sweden, Austria, Denmark and the United Kingdom containing the most-detailed remarks on their data.     

The regional drug information service: a factor in health care?

Most regional health authorities throughout the United Kingdom have established drug information units to provide health service staff with a wide range of information about drugs and drug use. The units, which are staffed by drug information pharmacists, provide their service mainly by answering inquiries, although some disseminate information more positively through lectures and bulletins.An analysis of inquiries received by regional information units during 1976 showed that most were submitted by hospital doctors or pharmacists; comparatively few were received from general practitioners. Topics of inquiry included adverse effects of drugs, source of supply and identification, current treatment, dosage, route, precautions, and pharmaceutical problems such as stability or formulation of drug preparations. A more detailed analysis of the inquiries received by the North-western Regional Drug Information Service at Manchester over three years showed that the number of inquiries gradually increased and that more were received from general practitioners after a programme of lectures had been introduced to tell them about the service. The North-western service also received more requests from hospital pharmacists than other units, though many originated from clinicians.The regional drug information units consulted widely with clinical and other specialists in answering questions, but about a quarter of all inquiries were pharmaceutical, relating to stability and incompatibility. A multidisciplinary approach therefore seems necessary to provide a comprehensive and advisory drug information service.     

On the state of the public ill health: premature mortality in the United Kingdom and Europe.

Recently published data on mortality in the European Economic Community and Scandinavia convincingly showed that mortality among men and women aged 45-64 was considerably higher in the United Kingdom than elsewhere. This applied to deaths due to circulatory and respiratory disease, cancer, and all causes. For example, in 1980 in Scotland twice as many, or more, women aged 55-64 per 100 000 died of heart disease than in Belgium, Denmark, France, Greece, West Germany, the Netherlands, Norway, and Sweden. Reductions in mortality from all causes during 1950-80 in the United Kingdom did not match those in other countries, such as Finland and France. Whether the public in the United Kingdom knows about its relatively poor mortality state is doubtful. To secure improved funding of appropriate preventive and treatment services directed at reducing premature mortality, public awareness should be raised urgently so that politicians and political parties will respond quickly in a way that the problem demands.     

Dyspnoea,asthma, and bronchospasm in relation to treatment with angiotensin converting enzyme inhibitors.

OBJECTIVE--To evaluate the occurrence of asthma and dyspnoea precipitated or worsened by angiotensin converting enzyme inhibitors. DESIGN--Summary of reports of adverse respiratory reaction in relation to treatment with angiotensin converting enzyme inhibitors that were submitted to Swedish Adverse Drug Reactions Advisory Committee and to World Health Organisation''s international drug information system until 1992. Sales of angiotensin converting enzyme inhibitors in Sweden were also summarised. SUBJECTS--Patients receiving angiotensin converting enzyme inhibitors who reported adverse respiratory reactions. MAIN OUTCOME MEASURES--Clinical characteristics of adverse reactions of asthma, bronchospasm, and dyspnoea. RESULTS--In Sweden 424 adverse respiratory reactions were reported, of which most (374) were coughing. However, 36 patients had adverse drug reactions diagnosed as asthma, bronchospasm, or dyspnoea. In 33 of these cases the indication for treatment with angiotensin converting enzyme inhibitors was hypertension, in only three heart failure. The respiratory symptoms occurred in about half of the patients within the first two weeks of treatment, and about one third needed hospitalisation or drug treatment. Dyspnoea symptoms occurred in conjunction with other symptoms from the airways or skin in 23 out of the 36 cases. In the WHO database there were 318 reports of asthma or bronchospasm, 516 reports of dyspnoea, and 7260 reports of cough in relation to 11 different angiotensin converting enzyme inhibitors. CONCLUSION--Symptoms of airway obstruction in relation to treatment with angiotensin converting enzyme inhibitors seem to be a rare but potentially serious reaction generally occurring within the first few weeks of treatment.     

Time required for approval of new drugs in Canada,Australia, Sweden,the United Kingdom and the United States in 1996-1998

BACKGROUND: The timeliness with which national regulatory agencies approve new drugs for marketing affects health care professionals and patients. An unnecessarily long approval process delays access to new medications that may improve patients'' health status. The author compared drug approval times in Canada, Australia, Sweden, the United Kingdom and the United States. METHODS: Application and approval dates of new chemical or biological substances (excluding diagnostic products, and new salts, esters, dosage forms and combinations of previously approved substances) approved for marketing in the 5 countries from January 1996 to December 1998 were requested from the relevant pharmaceutical companies. Data on new drug approvals during the study period were also obtained from the national drug regulatory agencies in Canada, Australia and Sweden and from publications of the US Food and Drug Administration. RESULTS: A total of 219 new drugs were identified as being approved in at least one of the countries during the study period: 23 (10.5%) in all 5 countries, 23 (10.5%) in 4, 27 (12.3%) in 3, 42 (19.2%) in 2, and 104 (47.5%) in 1 country. By individual nation, 97 drugs were identified as being approved in Canada, 94 in Australia, 107 in Sweden, 55 in the UK and 123 in the US. Approval times in Canada and Australia were similar (medians 518 and 526 days respectively), but both countries had significantly longer approval times than Sweden (median 371 days), the UK (median 308 days) and the US (median 369 days). This pattern was consistent across all 3 years and for the 23 new drugs approved in all 5 countries during the 3-year period. Median approval times in Canada were similar in all of the reviewing divisions of Health Canada''s Therapeutic Product Program (539-574 days) except the Central Nervous System Division (428 days) and the Bureau of Biologics and Radiopharmaceuticals (698 days). INTERPRETATION: Median drug approval times during 1996-1998 decreased by varying amounts from the 1995 values in all 5 countries. However, the median approval time in Canada continues to be significantly longer than the times achieved in Sweden, the UK and the US, and it remains considerably longer than Canada''s own target of 355 days for all new drugs.     

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.     

Generation of nitro radical anions of some 5-nitrofurans, 2- and 5-nitroimidazoles by norepinephrine, dopamine, and serotonin. A possible mechanism for neurotoxicity caused by nitroheterocyclic drugs

Catecholamine neurotransmitters such as norepinephrine, dopamine, and related catecholamine derivatives reduce nitroheterocyclic drugs such as nitrofurantoin, nifurtimox, nifuroxime, nitrofurazone, misonidazole, and metronidazole in slightly alkaline solutions. Drugs which contain 5-nitrofurans are reduced at lower pH than drugs which contain 2- and 5-nitroimidazoles. 5-Nitroimidazole derivatives such as metronidazole and ronidazole are known to be more difficult to reduce than 2-nitroimidazole derivatives, due to their lower redox potential. Catecholamines, when reducing nitro drugs, undergo concomitant oxidation to form semiquinone radicals. Both semiquinone radicals and nitro anion radicals formed in a reaction of nitro drug and catecholamine derivative were detected by electron spin resonance spectroscopy. Oxygen consumption studies in solutions containing nitro drug and catecholamine derivative showed that nitro anion radicals formed under aerobic conditions reduce oxygen to form the superoxide radical and hydrogen peroxide. Quinones formed in the reaction of catecholamine and nitro drug were detected by optical spectroscopy. Biosynthetic precursors and some metabolic products of catecholamines were also used in these studies, and they all exhibited reactions similar to catecholamines. Bovine chromaffin granules which synthesize and store catecholamines produced the nitrofurantoin anion radical when intact granules were treated with nitrofurantoin. These radicals formed inside the granules were observed by ESR spectroscopy. The formation of nitrofurantoin radical, semiquinone radicals of catecholamines, and oxygen-derived radicals by chromaffin granules is proposed to cause damage to adrenal medulla, and this process may lead to neurotoxicity.     

Trends in sales of drugs for asthma in New Zealand,Australia, and the United Kingdom, 1975-81.

As part of an investigation into the recent epidemic of deaths from asthma in New Zealand, trends in the sales of drugs for asthma in New Zealand, Australia, and the United Kingdom during 1975-81 were examined. Data on sales of drugs were obtained from an international pharmaceutical market research organisation. A striking increase in sales of sympathomimetic aerosols, steroid aerosols, and theophylline per caput occurred in all three countries, with the greatest increase occurring in New Zealand. Sales of sodium cromoglycate also increased in New Zealand and the UK but fell in Australia. By 1981 New Zealand had the highest sales of all these drugs per caput. Explanations for the rising mortality from asthma in New Zealand despite large increases in drug sales need to be explored. Although the temporal association between mortality and sales of drugs suggests that direct drug toxicity is unlikely, there may be more subtle adverse effects of drug use.     

Occurrence and relatedness of vancomycin-resistant enterococci in animals, humans, and the environment in different European regions

Vancomycin-resistant enterococci (VRE) in Europe are thought to have emerged partly due to the use of the glycopeptide avoparcin in animal husbandry. We compared the occurrence of VRE in geographical regions of Europe in which until 1997 large amounts of avoparcin were used (Spain, United Kingdom, and Denmark) with the occurrence of VRE in Sweden, where avoparcin was banned in 1986. We also studied the relatedness between VRE strains from different regions and habitats. In total, 2,580 samples were collected from humans, animals, and the environment (soil, sewage, recipient water). VRE resistant to 20 microg/ml vancomycin were identified in 8.2% of the samples and were found most frequently in raw and treated urban sewage samples (means, 71% and 36% of the samples, respectively), pig manure (17%), and hospital sewage (16%). The proportions of VRE-positive sewage samples were similar in Sweden, Spain, and the United Kingdom, whereas pig feces and manure were more often positive in Spain than in Sweden (30% versus 1%). Most VRE were Enterococcus faecium carrying vanA, and computerized biochemical phenotyping of the isolates of different ecological origins showed a high degree of polyclonality. In conclusion, it seems that animal-associated VRE probably reflect the former use of avoparcin in animal production, whereas VRE in human-associated samples may be a result of antibiotic use in hospitals. Since there seems to be a reservoir of the resistance genes in all countries studied, precautions must be taken to limit the use of antibiotics and antibiotic-like feed additives.     

How good are articles on adverse drug reactions?

A study was carried out of the quality and completeness of articles on adverse drug reactions: 5737 articles from 80 countries published between 1972 and 1979 were studied. Only 61% of the articles included information on the number of patients treated and the number with adverse drug reactions, yet these are essential for calculating the incidence of adverse reactions. In only 55% could the incidence of a particular adverse reaction be calculated. Great importance is placed on articles on adverse reactions, particularly those that report on many patients. Authors and editors should ensure that articles include the following information: drug regimens, numbers of patients treated, numbers of patients developing adverse reactions, and nature and incidence of adverse reactions.     

Occurrence and Relatedness of Vancomycin-Resistant Enterococci in Animals, Humans, and the Environment in Different European Regions

Vancomycin-resistant enterococcci (VRE) in Europe are thought to have emerged partly due to the use of the glycopeptide avoparcin in animal husbandry. We compared the occurrence of VRE in geographical regions of Europe in which until 1997 large amounts of avoparcin were used (Spain, United Kingdom, and Denmark) with the occurrence of VRE in Sweden, where avoparcin was banned in 1986. We also studied the relatedness between VRE strains from different regions and habitats. In total, 2,580 samples were collected from humans, animals, and the environment (soil, sewage, recipient water). VRE resistant to 20 μg/ml vancomycin were identified in 8.2% of the samples and were found most frequently in raw and treated urban sewage samples (means, 71% and 36% of the samples, respectively), pig manure (17%), and hospital sewage (16%). The proportions of VRE-positive sewage samples were similar in Sweden, Spain, and the United Kingdom, whereas pig feces and manure were more often positive in Spain than in Sweden (30% versus 1%). Most VRE were Enterococcus faecium carrying vanA, and computerized biochemical phenotyping of the isolates of different ecological origins showed a high degree of polyclonality. In conclusion, it seems that animal-associated VRE probably reflect the former use of avoparcin in animal production, whereas VRE in human-associated samples may be a result of antibiotic use in hospitals. Since there seems to be a reservoir of the resistance genes in all countries studied, precautions must be taken to limit the use of antibiotics and antibiotic-like feed additives.