bluuebunny/crossref_metadata_2025 huggingface dataset:
Assesment of arsenic effects on cytosolic heme status using tryptophan pyrrolase as an index
Authors: Cebrián M. E. , Albores A. , Connelly J. C. , Bridges J. W.
Published: October 2006

Acute arsenic (As) administration produced in rat liver a decrease in the heme saturation of tryptophan pyrrolase (TP), accompanied by dose‐related increases in 5‐aminolevulinate synthetase (ALAS) and heme oxygenase (HO) activities, along with a corresponding decrease in cytochrome P‐450 (P‐450) concentration. The relationship between heme synthesis and degradation was altered as a result of As treatment. The magnitude of these effects was related to the oxidation state of arsenic, sodium arsenite (AsIII) being more potent than sodium arsenate (AsV). These results support the contention that the heme saturation of TP is sensitive to treatments that modify liver heme concentration. The increase in HO activity produced by As appears to be mediated by a mechanism largely or entirely independent of heme. The main effects of continuous exposure to AsIII were an initial decrease in the heme saturation of TP, which remained constant during the period of treatment, and an initial increase in ALAS activity, which after ten days of exposure dropped somewhat but remained above control values. No significant effects on HO or P‐450 concentration were observed. These results were interpreted as indicative that a new balance between heme synthesis and degradation had been reached and that an adaptive response to the subchronic effects of AsIII was taking place.
Reaction of tobacco smoke aldehydes with human hemoglobin
Authors: Hoberman Henry D. , George Richard C. San
Published: October 2006

Formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, and acrolein, all of which are constituents of tobacco smoke, were reacted in 5 mM concentration with the purified major fraction of normal adult human hemoglobin (hemoglobin Ao) in 1 mM concentration. A cigarette smoke condensate, diluted to contain 5 mM total aldehydes, was also reacted with 1 mM hemoglobin Ao. Cationic exchange high‐performance liquid chromatography (HPLC) showed that the products formed from simple aliphatic aldehydes, with the exception of formaldehyde, were analogues of those formed from acetaldehyde, earlier shown by us to be imidazolidinone derivatives, that is, cyclic addition products of the N‐terminal aminoamide function of α and β chains. Formaldehyde and acrolein produced a heterogeneous mixture of derivatives including crosslinked hemoglobin dimers. The greater proportion of modified hemoglobins produced by condensate aldehydes resembled those formed from acetaldehyde, the most abundant aldehyde in the condensate. A smaller fraction consisted of crosslinked hemoglobin dimers, presumably due to the action of formaldehyde. Mass spectrometric and HPLC analyses of the 2,4‐dinitrophenylhydrazones precipitated from the condensate documented the presence of formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, furfsral, and methylfurfural. The toxicity of aldehydes is briefly discussed in the context of the findings of this study.
Expression profiling of BEN regulated genes in mouse embryonic fibroblasts
Authors: Chimge Nyam‐Osor , Mungunsukh Ognoon , Ruddle Frank , Bayarsaihan Dashzeveg
Published: October 2006

BEN is a member of the TFII‐I family of helix–loop–helix transcription factors. Both TFII‐I and BEN are involved in gene regulation through interactions with tissue‐specific transcription factors and chromatin remodeling complexes. Identification of the downstream target genes of TFII‐I proteins is critical in delineating the regulatory effects of these proteins. In this study, we conducted a microarray analysis to determine gene expression alterations following the overexpression of BEN in primary mouse embryonic fibroblasts (MEFs). We found the BEN‐dependent modulation in the expression of large groups of genes representing a wide variety of functional categories including genes important in the immune response, cell cycle, transcriptional regulation and cell signaling. A set of genes identified by the microarray analysis was validated by independent real‐time PCR analysis. Among upregulated genes were Shrm, Tgfb2, Ube2l6, G1p2, Ccl7 while downregulated genes were Folr1, Tgfbr2, Csrp2, and Dlk1. These results support a versatile function of TFII‐I proteins in vertebrate physiology and lead to an increased understanding of the BEN‐dependent molecular events. J. Exp. Zool. (Mol. Dev. Evol.) 308B:209–224, 2007. © 2006 Wiley‐Liss, Inc.
Immunological characterization of a newly developed antibody for localization of a beta‐keratin in turtle epidermis
Authors: Alibardi Lorenzo , Toni Mattia
Published: October 2006

Turtle scutes are made of hard (beta)‐keratins. In order to study size and localization of beta‐keratins in turtle shell, we produced a rat polyclonal antiserum against a turtle scute beta‐keratin of 13–16 kDa, which allowed the immunolocalization of the protein in the epidermis. In immunoblots the antiserum recognized turtle beta‐keratins but showed variable cross‐reactivity with lizard, snake, and avian beta‐keratins. The turtle antiserum appears less cross‐reactive than a chicken scale antiserum (Beta‐1). In bidimensional immunoblots, three main protein spots at 15–16 kDa with pI at 7.3, 6.8, 6.4, and an unresolved large spot at 40–45 kDa with pI around 5 were more constantly obtained. The latter may result from the aggregation of the smaller beta‐keratin protein. The corneous layer of the carapace and plastron of various species of chelonians appeared immunofluorescent. The ultrastructural immunolocalization showed sparse labeling over beta‐keratin filaments of cells of the horny layer of both carapace and plastron. The study for the first time shows that the isolated protein band derived from a component of the beta‐keratin filaments of the corneous layer of turtles. This antibody can be used for further studies on beta‐keratin expression and sequencing in chelonian shell. No labeling was present over other cell organelles or layers of turtle epidermis and it was absent in non‐epidermal cells. The specificity for turtle beta‐keratin suggests that the antiserum recognizes some epitope/s specific for chelonians beta‐keratins, and that it also variably recognizes other reptilian and avian beta‐keratins. J. Exp. Zool. (Mol. Dev. Evol.) 306B, 2006. © 2006 Wiley‐Liss, Inc.
Non‐steroidal anti‐inflammatory drugs and acute renal disease: A case control study
Authors: Beard Keith , Lawson David H. , MacFarlane Gary J.
Published: October 2006

Objectives: To quantify the risk of acute renal disease in patients exposed to non‐steroidal anti‐inflammatory drugs (NSAIDs). Design: Matched case control study. Subjects: All patients who underwent renal biopsy in Glasgow Royal Infirmary and the Western Infirmary, Glasgow, in 1986 and 1987 were considered as possible cases. Patients with chronic disease, with disease that was clearly not drug‐related, and whose records could not be traced were excluded. For each case in the final group, two controls were matched for age, sex and general practice. All drug exposures in the year before the diagnosis of renal disease were obtained from the general practitioners' records. Results: 27 of the 88 cases (31%) and 38 of the 176 controls (22%) were exposed to NSAIDs (odds ratio (OR) = 1.6; 95% confidence interval (CI) = 0.9, 3.0). No difference in exposure to bronchodilators, tranquillizers, antihistamines or antacids was found between cases and controls. A significant increase in OR was found with histamine (H2) receptor blockers. Of cases where interstitial nephritis was part of the pathological appearance, two were thought to be definitely and six possibly related to NSAIDs. Conclusions: The present study shows that in previously healthy persons, the risk of clinically apparent acute renal disease caused by these commonly used drugs is likely to be extremely small. The attributable risk of acute renal disease is of the order of one case in 100,000 patients treated with NSAIDs.
Scientific and ethical standards in pharmaceutical medicine should be self‐regulated
Authors: Stonier Peter
Published: October 2006

This report summarizes a debate which was convened by the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the United Kingdom at its first Annual Meeting on 10 December 1990, at the Royal College of Physicians, London, and moderated by Dr Richard Rondel, Registrar of the Faculty.
Sudden unexplained death in young persons with primary epilepsy
Authors: Jick S. S. , Cole T. B. , Mesher R. A. , Tennis P. , Jick H.
Published: October 2006

A population based study was carried out at Group Health Cooperative of Puget Sound (GHC) to estimate the incidence of sudden unexplained death occurring in individuals 15–49 years of age with presumed chronic primary epilepsy. Eleven deaths, considered to be sudden and unexplained, occurred in an estimated 8460 person years at risk for an estimated rate of 1.3 per 1000 years at risk.
Unsuspected patterns of drug utilization revealed by interrogation of a regional general practitioner prescribing database
Authors: McGavock H. , Wilson‐Davis K. , Niblock R. W. F.
Published: October 2006

The classification of drugs according to the specificity of their use has been shown to reveal unsuspected patterns of GP prescribing (McGavock, 1988). The present aim was to define the frequency distribution of rate of issue and cost of prescriptions of (a) drugs used to treat proven pathology, (b) drugs used mainly to relieve symptoms, and (c) drugs like antibiotics, whose use should be specific, but which are often used presumptively. Prescribing data were retrieved from the GP prescription pricing database, specific for individual practices and at the level of the therapeutic group (e.g. hypnotics). A new microcomputer program sorted these data into categories (a), (b) and (c), and produced frequency distributions for all practices in Northern Ireland. The distributions in all three categories were unimodal, positively skewed. A seven–tenfold range in the rate of prescribing was seen in all three categories (cost showed a threefold range), between lowest and highest practices. For each practice, prescribing rate and cost in each category were displayed, with the Northern Ireland average for comparison. This revealed the emphasis placed by each practice on the use of symptomatic treatment and the doctors' tendency to use category (c) drugs. Above all, it revealed the frequency of prescribing of drugs for proven pathology (a) which, prima facie, should be directly related to the diagnoses of diseases such as diabetes, asthma and hypertension. The interpretation of these patterns for practice audit is discussed, together with problems and caveats.
Diuretic treatment in those dying from a myocardial infarction
Authors: Battersby Clare , Daymond Margot , Styles William M. , Struthers Allan D. , Rowley‐Jones David , Bulpitt Christopher J.
Published: October 2006

The relative risk of dying from a myocardial infarction according to diuretic therapy was estimated in a case control study for 189 cases, 144 dead controls and 349 living controls. The controls were matched for age (±2.5 years), sex and general practice. The study was community‐based; the cases were identified from death certificates and the death certificates of the dead controls had no mention of ischaemic heart disease. The relative risk was estimated from the odds ratio and was similar whether dead or living controls were considered. Against all controls combined, the odds ratio for dying while taking a potassium‐losing diuretic at 1 month prior to death (R1) was 1.5 (95 per cent CI 0.9, 2.4) and for a combined potassium‐losing + sparing diuretic (RL+S) was 2.0 (95 per cent CI 1.1, 3.4). Potassium‐sparing diuretics may be given more frequently to patients at greater risk of dying, thus masking a benefit, but the data could not provide evidence for a benefit from the addition of a potassium‐sparing diuretic.
The status and future of pharmacoepidemiology (part 1)
Authors: Jones Judith K.
Published: October 2006

The study of the effects and use of pharmaceuticals in populations, or pharmacoepidemiology, is in its formative years. The field is growing due to many factors, including access to large data resources. Current research is applied, emanating from the pharmaceutical industry and drug regulatory agencies, with limited presence in academia. Accomplishments include a growing use of many large population databases and an increased understanding and acceptance of drug risk, e.g. for agranulocytosis, which may explain the presence of certain drugs with defined risk remaining on the market. In the next decade, international consensus will be needed on acceptable methods and data standards, development of new data resources, and efforts made to assure database maintenance and quality. Further, the field must develop bases for a clear identity and scientific credibility to enable development of academic status. In the future, pharmacoepidemiology has considerable potential for applications in drug regulatory reform, drug development, risk management, pharmaceutical benefit and cost assessment, and drug utilization review, as well as for understanding drug‐associated disease.
Handling of drug safety alerts in the European commmunity
Authors: Wood Susan M.
Published: October 2006

A Rapid Alert procedure for the communication and assessment of serious drug safety hazards within the European Community was initiated in 1988. The procedures adopted by member states, the Commission and the CPMP for handling these alerts are described and the early experience is reviewed.
Micturin and torsades de pointe — experience of a post‐marketing alert
Authors: Wild R. N.
Published: October 2006

On 13 September 1991 Micturin® (terodiline hydrochloride), was temporarily withdrawn worldwide after the discovery of an association with serious cardiac arrhythmias, notably a rare form of ventricular tachycardia known as torsades de pointe. This paper describes the events and actions leading up to the withdrawal and discusses the reasoning behind it.
Risk of death from human insulin
Authors: Suissa S. , Spitzer W. O. , Abenhaim L. , Downey W. , Gardiner R. J. , Fitzgerald D.
Published: October 2006

In response to growing concerns surrounding the risks of human insulin, we conducted a 13‐year historical cohort study of 4925 insulin users less than 40 years of age. This cohort was formed from the population of Saskatchewan, Canada, from 1978–90, using the computerized databases arising from the universal health insurance plan of this Province of 1.1 million inhabitants. Of 101 deaths, 53 occurred within the defined one‐month time window of effect. The cohort resulted in 14,600 person‐years of exposure to insulin use. The overall rate of death was 3.6 per 1000 person‐years of insulin use (95% CI: 2.7–4.6). This death rate remained stable throughout the 13‐year study period and did not increase after 1984, the year of introduction of human insulin in Saskatchewan. We found 46 deaths for animal insulin (4.0/1000/year) and 7 deaths for human insulin (2.3/1000/year). Among the latter 7 deaths, 1 death occurred in the group treated solely with human insulin (1.2/1000/year), and 6 deaths in those who were switched from animal to human insulin (2.8/1000/year). These observed differences are not statistically significant. The data from this rapid response pharmacoepidemiological study, which took 8 months to complete, do not support allegations that treatment with human insulin increases the risk of death. They do not however exclude the possibility that human insulin is associated with an elevated risk of fatal or non‐fatal hypoglycaemia.
Some patient experiences with drugs and adverse drug reactions in an African teaching hospital
Authors: Magunje S. , Simooya O. O.
Published: October 2006

One hundred and seventy patients regularly attending a general medical outpatients' clinic at the Parirenyatwa Central Hospital (PCH) in Harare, Zimbabwe were interviewed about their knowledge of their present drug therapy and possible adverse drug reactions (ADRs), history of previous ADRs and action taken on experiencing them, information source and satisfaction with their therapy. Sixty seven patients knew what drugs they were taking and this level of awareness was associated with age, occupation and level of education of the patient. Only 19 patients knew about the possible ADRs of their drugs and this knowledge was associated with language ability, disease knowledge and knowledge of what drugs they were taking. Seventy eight patients had experienced ADRs and this was linked to age and knowledge of ADRs. Eighty one patients said that they would continue their drug treatment on experiencing ADRs, and this behaviour was associated with knowledge of disease and ADRs. More than half of the patients were not satisfied with the information given about their drugs, and very few had read about this subject. These results suggest that overall knowledge of drugs and ADRs amongst patients at the PCH is low, and that there is a need to increase patient education regarding therapy. This training should take into account the patient's demographic and socioeconomic background. Knowledge of ADRs was shown to increase the potential for compliance.
Severe hypoglycaemia in Chinese patients with non‐insulin‐dependent diabetes treated with insulin or sulphonylureas
Authors: Chan Thomas Y. K. , Chan Juliana C. N. , Critchley Julian A. J. H.
Published: October 2006

In 2404 emergency admissions to two general medical wards over a 1‐year period, 41 (1.7 per cent) were due to insulin‐ or to sulphonylurea‐induced hypoglycaemia. Thirty‐six of the episodes involved 33 Chinese patients with non‐insulin‐dependent diabetes (NIDDM). Of these admissions, 75 per cent (n = 27) were related to sulphonylurea therapy. Compared to a control group of NIDDM patients attending the outpatient clinic [mean ± standard deviation age: 55 ± 13 years, median (range) plasma creatinine concentrations: 79 (49–1085) μmol/1], the hypoglycaemic patients were significantly older (71 ± 10 years; p < 0.001) and had higher plasma creatinine concentrations [120 (50–656) μmol/1; p < 0.001]. These risk factors applied both to patients treated with sulphonylureas and with insulin. Thus, particular caution is required when prescribing either sulphonylureas or insulin for elderly diabetic patients with renal impairment. Our findings may also reflect the preponderance of NIDDM in the Chinese population in Hong Kong and the high prevalence of renal impairment among Chinese diabetic patients.
Role and place of causality assessment
Authors: Venulet Jan
Published: October 2006

For biological reasons a drug has either caused or contributed to the development of an adverse reaction or it has not. All intermediary evaluations like possible, probable, etc. are only approximations of the unknown truth. Three practical approaches to assessment are possible — unstructured, based solely on knowledge and experience; semi‐structured, based on certain descriptive criteria; and standardized, based on an operational logic. Nowadays, causality assessment is understood as one of the signaling and sorting parameters and the many drug regulatory agencies assess causality, although rarely using a standardized assessment. The globalization of drug monitoring efforts speaks for a wider acceptance of one method as it would help to understand better how and why a particular assessment was reached.
Causality assessment of suspected adverse drug reactions: A transatlantic view
Authors: Jones Judith K.
Published: October 2006

The European Community's (EC) pending requirement for a standard assessment of the causal association between a drug product and a reported drug‐associated event prompts a review of this aspect of pharmaceutical safety evaluation. Pharmaceutical manufacturers who use various methods, or no methods, may need to consider these EC definitions and their interpretation for evaluating their current procedures and planning any future changes. This paper first describes the EC classifications and their basis as one statement on the status of causality assessment in Europe. Reflecting the rather different view of causality assessment in North America, this paper then briefly reviews the evolution and uses of causality assessment over the last two decades. The controversies over causality are next discussed, followed by examination of the diverse uses of assessment by a pharmaceutical manufacturer or a regulator. Finally, the paper concludes with thoughts on applying causality concepts as tools for enhancing drug‐risk assessment.
Drug safety alerts — a review of ‘current problems’
Authors: Mann R. D.
Published: October 2006

A study of the ‘Current Problems’ publication of the Committee on Safety of Medicines in the UK has shown that many drug safety alerts or warnings are based upon a fairly small number of spontaneous adverse drug reaction reports. In terms of problems naming one drug and one serious reaction, or type of reaction, 24 (52%) of the 46 problems discussed in ‘Current Problems’ related to 10 or less yellow card reports. Nine (43%) of the 21 problems naming one drug and one non‐serious reaction, or type of reaction, were concerned with 10 or less reports. ‘Current Problems’ contain many entries other than this rather clear‐cut type of situation but, in respect of all other quantified entries in the publication that related to serious reactions, 13 (41%) of the 32 relevant problems were concerned with 10 or less yellow card reports. The situation seems to be different when non‐serious reactions are considered — as in general review articles or entries considering the whole range of reactions being reported in respect of a specific drug — when 9 (65%) of the 14 relevant ‘Current Problems’ entries were concerned with 51 or more yellow card reports.

Of the problems that named one drug and one serious reaction, or type of reaction, 12 of the 24 relevant ‘Current Problems’ entries were concerned with 4 or less yellow card reports. The relevant alerts and warnings seem, in view of subsequent experience, to have been justified. Nevertheless, there would seem to be much merit in investigating health hazard signals on computerized databases before publication takes place that may lead to differential reporting and subsequently bias the relevant data.
Estimation of the frequency of warfarin‐associated necrosis in a large in‐patient record‐linked database
Authors: Jones Judith K. , Staffa Judy A.
Published: October 2006

In an effort to estimate the frequency of warfarin‐associated necrosis in hospital, a cohort of 20,556 patients who had received warfarin during hospitalization between July 1984 through June 1987 was identified retrospectively using the Medimetrik Hospital Diagnosis and Therapy Audit database. Case‐finding began with two broad screening efforts (using ICD‐9CM codes), followed by concurrent clinical and algorithmic evaluations and chart abstract reviews by a panel of three experts in the field. Those cases designated by one or more experts as possible or probable cases of warfarin‐associated necrosis constituted the numerator; the denominator was an estimate of the number of hospitalized patients administered warfarin who remained in the hospital for at least four days. A total of six possible cases (no probable cases were identified) of warfarin‐associated necrosis were found in this population, representing a frequency of 33.5 per 100,000 with a 95 per cent confidence interval of 12.3 per 100,000 to 73.06 per 100,000. To our knowledge, this is the first observational study to estimate the frequency of warfarin‐associated necrosis. The estimated should be interpreted with caution, however, due to the absence of probable cases and lack of complete information on the length of warfarin therapy. It demonstrates the need for automated databases which allow identification of drug therapy both inside and outside the hospital setting.
Micturin (Terodiline Hydrochloride), Torsades de Pointe and other Arrhythmias — A Study using the VAMP Database
Authors: Hall G. C. , Chukwujindu J. , Richardson J. , Lis Y. , Wild R. N.
Published: October 2006

In a preliminary open study using the VAMP database only one confirmed case of torsades de pointe was identified from 9176 terodiline‐treated patients. The risk of torsades de pointe with terodiline is therefore 1.1 per 10,000.

This preliminary study was followed by a retrospective cohort study which compared the risk of a patient treated with terodiline developing torsades de pointe, or other arrhythmias, with the risk in a matched reference population. In this study the follow‐up period of the patients treated with terodiline averaged 5 months (range 2 weeks to 41 months) and that of the controls averaged 6 months (range 2 weeks to 40 months).

This comparative study showed that there was no significant difference in the risk of developing a cardiac arrhythmia between the cohort treated with terodiline and their reference patients. The incidence rate was 3.68 per 1000 in the group treated with terodiline and 3.33 per 1000 in the reference group. There was no significant difference in the risk of developing an arrhythmia in the terodiline‐treated patients compared with the controls (relative risk 1.1, 95% confidence intervals 0.64–1–90).
Completing the triangle — relationships between practice demography, general practitioner workload and prescribing
Authors: McGavock H. , Wilson‐Davis K. , Milligan Officer E. Administrative
Published: October 2006

The objective was to survey general practitioners' consulting workload and correlate workload with practice demography and prescribing. Two hundred and sixteen of the 345 Northern Irish practices completed a retrospective questionnaire of office consultations and home visits, November 1990. These data were amalgamated with the regional general practitioner prescribing database and statistical analyses were performed to reveal the frequency distribution of workload and to correlate workload with the number of partners, practice demography and prescribing. The consulting workload per doctor varied from 249 office consultations per month to 683. The commonest workload was 373 consultations per month. Single‐handed doctors had the largest workloads. The average length of consultation was 7.5 min a.m., 8.8 min p.m. Consulting workload correlated strongly with the number of patients over 60 (R = 0.72), mature adults 30–44 (R = 0.84) and children under 5 (R = 0.86), but weakly with the number of ‘officially‐deprived’ patients (R = 0.28). Workload could most precisely be predicted from practice demography using the equation:

No. of consultations per month (for a given practice) = 1.31 (children 0–4) + 0.63 (children 10–14) + 0.004 (persons 15–59) + 0.1 (persons > 60) − 0.06 (deprived persons) + κ

R = 0.9006 (R2 = 0.811, i.e. 81.1% of variability in workload is determined by differences in practice demography)

Where k is a categorical variable of number of partners in a practice.

Similarly practice demography can explain 90.0% of the total variation in monthly total prescriptions per practice and 91.3% of the variation in total monthly prescription costs.

Surgery workload correlated significantly with the number and cost of prescriptions (R = 0.35 to 0.50). This was true of specific prescribing (for proven pathology), for symptomatic prescribing and for prescribing of drugs often used less precisely than they should be (for presumptive diagnoses). On average, doctors issued 3.7 prescription items per consultation, with a net ingredient cost of £5.93 per prescription item. This study shows that general practitioner consulting workload is determined principally by the demography of the practice list and is itself a determinant of prescribing frequency and cost.
The systems for monitoring adverse drug reactions in Hong Kong
Authors: Chan Thomas Y. K. , Critchley Julian A. J. H.
Published: October 2006

Post‐marketing surveillance is essential for providing additional safety information on drugs. In Hong Kong, a scheme to monitor ADRs was introduced in October 1986. It relies on voluntary reporting by hospital doctors and general practitioners of suspected ADRs. There appeared to be gross under‐reporting as only 68 reports were received between 1986 to 1991. Although hospital‐based studies have provided us with information on the pattern of and the risk factors for ADRs, spontaneous reporting on a national scale remains the only feasible and inexpensive method for monitoring ADRs. In order to increase reporting, we hope to convince the medical profession in Hong Kong of the importance in reporting ADRs and to make it easier for them to report.
Towards an adverse drug reactions dictionary. Should existing terminologies be harmonized?
Authors: Benichou C.
Published: October 2006

Due to the worldwide marketing of drugs, centralization of information is mandatory. Several Adverse Drug Reactions (ADR) terminologies have been proposed. The most widely used are WHO‐ART and COSTART. However, because of cultural differences, all terms do not exist or do not have the same meaning in different languages or countries. Equivalence between terms of different terminologies are difficult to establish, since terms are proposed without definitions or precise guidelines for their use. Definitions given by medical dictionaries do not resolve this difficulty, since they are neither always concordant nor adapted to the level of information contained in spontaneous notifications. Therefore, it seems necessary to create a dictionary specific for ADR, listing all drug‐induced abnormalities and giving for each of them a definition adapted to the information usually available in pharmacovigilance. As most drug reactions are indistinguishable from non‐drug‐induced diseases, this dictionary must be created in concertation with experts in drug toxicity in each medical field, coming from different countries. An example of such an attempt is given; it was possible to draw a dictionary for liver and biliary disorders from an international consensus meeting of experts on definitions and criteria assessment of drug‐induced liver reactions. This approach could make unnecessary the harmonization of the various terminologies, since each of them would have to make a bridge towards a worldwide accepted ADR dictionary.
Delay and completeness of cancer registration in a post‐marketing surveillance study of cimetidine
Authors: Lucas T. , Beresford J. , Vessey M.
Published: October 2006

Data collected in a large multicentre post‐marketing surveillance study of cimetidine have been used to assess delay and completeness of cancer registration. With regard to delay, 44% of registrations in Nottingham were received within 2 years of the diagnosis of cancer but only 14% in Oxford and 6% in Portsmouth. By the end of the third year, these figures had become 82%, 62% and 62% respectively. With regard to completeness, in the period 3 to 10 years before the assessment date 9% of Nottingham, 36% of Oxford and 17% of Portsmouth neoplasms were still unregistered. Investigators using National Cancer Registry data for interpretation of their studies should be acquainted with the performance of the individual registries concerned.
PEM report number 3. Fluconazole
Authors: Inman William , Kubota Kiyoshi , Pearceb Gillian , Wilton Lynda
Published: October 2006

Three groups of patients who were prescribed the oral anti‐fungal drug fluconazole between September 1988 and January 1989 were studied by Prescription‐Event Monitoring (PEM). The largest group of 13,440 patients, including 560 men, had been treated with a single 150 mg capsule. A smaller group of 798, including 55 men, had received more than one 150 mg capsule and a third small group of 777 patients, including 261 men, had received a course of treatment with 50 mg capsules. The first group was studied between February and June 1989 and the second and third groups in January 1990.

In the two groups who had received single or multiple doses of 150 mg, the mean age of women was 34 and 35 years respectively and of men in both groups, 41 years. In the small group receiving 50 mg capsules the patients were considerably older, the males averaging 49 years and the females 46 years. While an overwhelming majority of females were treated for vaginal candidiasis, a significant number of men in the 150 mg groups and almost half the men in the 50 mg group had been treated for oral candidiasis. It was believed that a considerable number of men had been treated prophylactically while their partners were receiving treatment for vaginal candidiasis.

General practitioners reported that the single 150 mg capsule had been effective in 85%. As expected, there were many cases of re‐infection or recurrences during the three‐month period of observation.

The pattern of events was compared with data obtained from PEM studies of itraconazole and 31 other drugs. Upper respiratory tract and genito‐urinary infections were reported more frequently than with other drugs but the relationship was with the disease being treated rather than with the drug itself.

There were four cases of angioneurotic oedema, only two of which were considered to have been possibly related to the use of fluconazole. There were also four reports of liver dysfunction, none of which was considered to be drug related.

Although pregnancy is a contra‐indication, a total of 289 were reported. Thirty‐nine had terminated in spontaneous abortion and 38 were terminated therapeutically. Among women who used fluconazole prior to conception there were six abnormal pregnancies including four live births, one stillborn foetus with trisomy‐18 (Edwards' syndrome) and one anencephalic foetus. One mother had used fluconazole a week before conception. The baby had three short fingers on one hand. No abnormalities occurred in babies exposed during their mother's pregnancy.

One hundred and twenty‐five deaths were investigated. Eighty of the deaths were due to cancer, 26 to neurological, cardiac or respiratory disease and seven to AIDS. Other or undetermined causes accounted for a further 12 deaths. No death was attributed to treatment.

The overall conclusion reached after this study of more than 15,000 patients was that, while many events that had been recorded were attributable to the candidial infection, fluconazole was virtually free from recognizable side‐effects.
PEM report number 4. Ciprofloxacin
Authors: Inman William , Kubota Kiyoshi , Pearce Gillian , Wilton Lynda
Published: October 2006

The fluoroquinolone antibiotic ciprofloxacin has been studied by Prescription‐Event Monitoring (PEM) in 11,477 patients who had received prescriptions from general practitioners in England between November 1988 and January 1989. There were about 50% more females in the series than males and the average ages were 53.2 and 55.5 years respectively. Chest and urinary infections were the most common indications. Forty‐five per cent of the patients used 500 mg daily and 42% 1000 mg daily. Ciprofloxacin was said to have been effective in 90.3% of patients.

The events were compared with those reported in 25 other studies in order to obtain some impression of the background rates in a population of more than a quarter of a million patients monitored by PEM. The events most frequently reported were related to the infections that were being treated and the most common side‐effects were those affecting the gastrointestinal system. There were three definite and one doubtful case of photosensitivy. Among the psychiatric events, only depression and malaise or lassitude occurred at a rate which exceeded one per 1000 patients during the first 13 weeks of follow‐up. Fourteen patients suffered convulsions but only two cases were considered to be possibly related either to treatment or to pyrexia associated with urinary tract infection. No cases of pseudomem‐branous colitis were identified although diarrhoea was the most common gastrointestinal event. Following the withdrawal of temafloxacin, the ciprofloxacin data were searched for evidence of hepatic or renal damage or hypoglycaemia, but no evidence was found with ciprofloxacin, or in, as yet uncompleted, studies of enoxacin, ofloxacin or norfloxacin. No serious adverse reactions (ADRs) or deaths attributable to ciprofloxacin were recorded and no previously unrecognized hazards were identified.

The PEM data were compared with selected results from clinical trials. For the most part the incidence of events encountered during a three‐month period resembled those in clinical trials very closely.

It was concluded that ciprofloxacin is a safe and effective antibiotic prescribed in general practice.
PEM report number 8. Cisapride
Authors: Inman William , Kubota Kiyoshi , Pearce Gillian , Wilton Lynda
Published: October 2006

The gastrointestinal prokinetic agent cisapride has been studied by Prescription‐Event Monitoring (PEM) in 13,234 patients who had received prescriptions from general practitioners in England between October 1990 and April 1991. There were 58% female and 41% male; the average age was 56 years. The most common indications were oesophageal reflux, dyspepsia and hiatus hernia.

The events were compared with pooled data from a population of 332,402 patients in 33 PEM studies including those of omeprazole, nizatidine and famotidine which were used to provide estimates of background rates. The events most frequently reported were related to the conditions that were being treated, mainly those affecting the gastrointestinal tract. Diarrhoea was the most noteworthy among events identified as adverse reactions to cisapride. Dermatalogical, hepatic, cardiovascular and other sub‐groups of events were examined with particular care and no unacceptable hazards were detected.

The PEM data were also compared with those from clinical trials involving treatment periods from four weeks to one year in similar patients. The pattern of events revealed by the PEM study closely matched the findings of clinical trials.

It was concluded that cisapride is a safe and effective prokinetic agent causing few serious side‐effects when prescribed in general practice.
PEM report number 10. Zopiclone
Authors: Inman William , Kubota Kiyoshi , Pearce Gillian , Welton Lynda
Published: October 2006

The short‐acting, non‐benzodiazepine hypnotic, zopiclone, first marketed as ‘Zimovane’ in the United Kingdom in 1989, has been studied by Prescription‐Event Monitoring (PEM) in 13,177 patients. Of more than 24,000 forms that had been posted to general practitioners 55% were returned, the response ranging from 68% by doctors who had been sent only a single form to 19% from those who had been sent more than 30 forms. The mean ages of the patients were 53 and 54 or males and females respectively; 22% were aged over 70 years.

Eighty‐five per cent of the patients were prescribed a dose of one tablet (7·5 mg). A large number of patients were using other psychotropic drugs concurrently — antidepressants, 12%; other hypnotics and sedatives, 8%.

A subjective opinion of efficacy was favourable to the drug in 86% of patients.

The pattern of events was compared with those encountered in a similar study of flunitrazepam, conducted eight years earlier, and with data from 31 other PEM studies. A large number of psychiatric events were noted, mostly attributable to concurrent disorders, some of which were clearly the reason for the patient's insomnia.

There were only seven cases of possible dependence including three reported to the Committee on Safety of Medicines (CSM), for which no details were supplied to the Drug Safety Research Unit (DSRU). In this study there were no confirmed cases of dependence on zopiclone.

Twenty patients overdosed deliberately with zopiclone alone, suffering no more than transient drowsiness. A further 16 took simultaneous overdoses of zopiclone and other drugs including one patient who took 28 tablets of zopiclone and 100 of co‐proxamol and died. Thirty‐seven patients overdosed with other drugs, with three deaths.

PEM confirms that zopiclone has a very low risk of dependence and is safe in overdose.
Estimation of the signal generating value of spontaneous reports of adverse reactions
Authors: Biron Pierre , Balency Dominique
Published: October 2006

The main function of drug adverse reaction spontaneous reporting systems is the generation of early signals of previously undocumented serious reactions to recently marketed products. To quantify the signal generating value of case reports we first score them on a 6‐level causality/completeness scale combining the French and the European community assessment methods; prior documentation is scored on a 5‐level scale inspired from the French method. Then the prior documentation value is subtracted from the imputability value and the resulting difference is considered as a signal generating value. The result is a scale of ranks ranging from 1 to 10, averaging 4.8 in the database of our regional program. It may serve to compare the usefulness of spontaneous reports originating from different sources and it may encourage clinicans to submit more informative case reports.
Adverse drug reactions in HIV seropositive patients
Authors: Benichou C. , Eliaszewicz M. , Flahault A.
Published: October 2006

Patients infected with the human immunodeficiency virus (HIV) will receive a number of drugs intended to fight the HIV infection itself or to avoid and treat its complications. In these patients, adverse drug reactions (ADRs) are unusual in their frequency, not in their type. They may involve all the systems and reduce the already limited therapeutic possibilities. The frequent absence of therapeutic alternatives may require, for certain reactions, the continuation of the suspected drug.

The study of these patients may provide better comprehension of the mechanisms responsible for ADRs occurring in immuno‐competent patients, since the association of certain diseases with certain drugs increases the risk of drug reactions. The search for an enhancing, synergistic or at least a non‐neutralizing mechanism may improve the study or the prevention of all ADRs.

The spread of HIV infection and the attempt to maintain the infected patient at home means that any physician is likely to be confronted with the diagnosis and treatment of a drug‐related toxicity in an HIV‐positive patient.

In May 1993, a certain number of physicians who had specialized in the treatment of HIV‐infection and/or in management of ADRs, met to discuss the different toxicities observed with the drugs most often employed in this illness. The description, the incidences and the recommendations which are presented in this report reflect the opinion of a large majority — and often the unanimity — of the participants.
The impact and treatment of arthritis in general practice
Authors: Blackburn S. C. F. , Ellis R. , George C. F. , Kirwan J. R.
Published: October 2006

Fifty‐two general practitioners from a variety of practice settings recorded clinical information on 1964 patients with arthritis who independently completed questionnaires about their treatment, joints affected and disability. Of 1871 analysed, 79.4 per cent had osteoarthritis (OA) and 15.3 per cent rheumatoid arthritis (RA). Half of those with OA were under 65 years old, 60 per cent were obese and two‐thirds were women. The knee was the site most commonly affected. Mean disability scores (HAQ) were greater in RA than OA (1.28 versus 0.87) but 34 per cent of patients with OA were moderately disabled (score > 1) and 6 per cent severely disabled (score > 2), even after allowing for comorbid conditions. Disability increased markedly in patients over 75 years. Although these older OA patients were treated increasingly with simple analgesics alone, 69 per cent were taking non steroidal anti‐inflammatory drugs often in combination. Physiotherapy was not used frequently.

These results illustrate the huge burden of disability caused by OA in the community and the opportunities to improve treatment.
Communication in pharmacovigilance
Authors: Moore N. , Montero D. , Coulson R. , De Abajo F. , Kreft‐Jais C. , Biron A. , Palop R.
Published: October 2006

Pharmacovigilance is a field where communication is paramount. Information, such as single case reports, is transferred from health professionals to National Regulatory Administrations and between administrations and industry. The cumulation of reports may be used for information purposes, and to assist in the identification of possible signals. These are then assessed by the analysis of individual and aggregate cases, the latter being exchanged between administrations for multinational analysis at the European level. Once a decision has been made on a possible alert, the decisions and the reasons thereof must be transmitted to administrations and to other correspondents, such as health professionals, the pharmaceutical industry and WHO.

Within the CARE project of the DGXIII European Nervous System telematics research programme, the Pharmacovigilance Pilot, consisting of representatives of the French, Spanish, and UK pharmacovigilance systems, set out to identify and describe the messages corresponding to these communication needs, and the methods best suited to effective telematic transmission.

The messages identified concern: the transmission of individual case reports, the transmission of cumulative and aggregate case reports, and of regulatory decisions.

Each of these information messages have been structured for future inclusion into a network for electronic data interchange between administrations in pharmacovigilance. In time they should provide a common electronic vocabulary enabling all parties involved in pharmacovigilance to communicate telematically. Transmission options have been considered also. In view of the large number of existing and potential partners involved in the communication processes in pharmacovigilance, EDI (electronic data interchange) seems the most appropriate method to exchange these messages. Two of these, concerning the single case and the aggregate cases (rapid alerts) have been submitted to the Western European EDIFACT Board MD9 for integration into EDIFACT (as MEDADR and MEDPHV).
Electronic transmission of rapid alerts in pharmacovigilance: A pilot EC experiment
Authors: Montero D. , Moore N. , Coulson R. , Zabala J. L. , De Abajo F. , Kreft‐Jais C. , Wigglesworth K. , Biron A. , Monteagudo J. L.
Published: October 2006

Though electronic communication and transfer of data is becoming commonplace, it is still rare between administrations. This is why CEC DGXIII started the European Nervous System (ENS) programme, to promote the use of telematics to facilitate the work of administrations. Pharmacovigilance is one of the pilots of CARE, an ENS project in health care. This pilot involves Instituto de Salud Carlos III (Spain), Medicines Control Agency (UK), and the French Pharmacovigilance System (France) along with Norsistemas Consultores (Spain). Its objective is to explore the possibilities of telematic transmission of Pharmacovigilance data between national administrations.

The technical approach has tested the transmission of urgent drug alerts, information equivalent to that of the existing Rapid Alert scheme, up to now transmitted by fax. The network using international standards (Unix, X400, and EDI, based on X25 networks) has been set up between the three participating countries. The data structure for the drug alerts has been described and submitted to future European users. The message structure itself has been entered into the registration and validation process for EDIFACT certification. The application for message transmission has been written and is being tested and re‐evaluated. The information contained in these messages will be initially entered manually, but could be generated from national databases. Though this network at the present only concerns three countries, it is expected that most EC countries will be linked in the near future.