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Biomedical subjects

N R Dunn

Publications and source records attributed to N R Dunn.

31 records · Page 2Linked to original sources
PubMed1999

Antidepressants and the serotonin syndrome in general practice.

BACKGROUND: As a consequence of the greater use of agents affecting the serotonergic system, a syndrome of serotonin hyperstimulation has been recognized more frequently. The serotonin syndrome is characterized by a constellation of symptoms that include mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, lack of coordination, and fever. Deaths have been reported. AIM: To identify cases of the serotonin syndrome among patients prescribed a new antidepressant in general practice, and to determine doctors' awareness of the syndrome. METHOD: Patients who were dispensed nefazodone in England between 1996 and 1997 were identified using dispensed prescription data. Prescribing doctors were sent questionnaires as part of a post-marketing surveillance study. Patients reported to have experienced two or more features of the serotonin syndrome were identified, and specific questionnaires were sent to their general practitioners. RESULTS: There was a 96.2% return rate of serotonin syndrome questionnaires. Nineteen cases met criteria for the syndrome (incidence = 0.4 cases per 1000 patient-months of treatment with nefazodone). Eight patients developed symptoms while taking nefazodone alone. Serotonergic symptoms were reported to a similar degree with five other antidepressants studied by the same method. In total, 85.4% of responding general practitioners were unaware of the serotonin syndrome. CONCLUSION: Improved awareness of the syndrome is needed within general practice. There is a need to distinguish the relatively minor serotonergic symptoms from those of a severe, life-threatening serotonin syndrome.

Adolescent↗
PubMed1999

Newer antidepressants: a comparison of tolerability in general practice.

BACKGROUND: An increasing number of antidepressants have been released on the United Kingdom market in recent years, and these are being prescribed more frequently in general practice. Clinical trials suggest that such agents have similar efficacy and the choice of drug is probably based on tolerability, toxicity in overdose, and cost. AIM: To compare the tolerability and safety profile of six, newly marketed antidepressants used in general practice. METHOD: Studies have been conducted for six antidepressants: fluoxetine, sertraline, paroxetine, moclobemide, venlafaxine, and nefazodone, using the technique of prescription-event monitoring. Patients were identified using incident dispensed prescription data. Questionnaires were sent to patients' general practitioners six months after the date of first prescription. Questionnaires asked for date of birth, sex, indication for prescribing each drug, and all events entered in the patients' records after the date of first prescription. RESULTS: Each cohort exceeded 10,000 patients. Nausea/vomiting was the most frequently reported event for all drugs. The difference in incidence rates for drowsiness/sedation, male sexual dysfunction, and hypertension is shown. Mortality data are also reported. CONCLUSION: Frequently reported events were similar for all six drugs but there were clinically and statistically significant differences for less frequently reported events. The adjusted mortality rate was identical between the six drugs. This study provides valuable comparative data for six, widely used antidepressants in general practice.

Adult↗
PubMed1998

Risk of non-fatal cardiac failure and ischaemic heart disease with long acting beta 2 agonists.

BACKGROUND: The long term safety of beta agonists, particularly in patients with heart disease, has not been fully established. METHODS: This study accessed the results of three cohort studies involving: 12,294 patients receiving at least one prescription for nedocromil between November 1986 and September 1988; 15,407 patients prescribed salmeterol between December 1990 and May 1991; and 8098 patients prescribed bambuterol between February 1993 and December 1995. Details of all dispensed prescriptions for these drugs prescribed by general practitioners in England soon after their launch were provided in confidence by the Prescription Pricing Authority. Questionnaires were sent to the prescriber asking for details of events occurring after the first prescription (prescription event monitoring). Rates and relative risks of non-fatal cardiac failure and ischaemic heart disease were calculated, comparing bambuterol and salmeterol with the reference drug nedocromil. RESULTS: The age and sex adjusted relative risk of non-fatal cardiac failure associated with bambuterol was 3.41 (95% confidence limits (CL) 1.99 to 5.86) when compared with nedocromil. When salmeterol was compared with nedocromil the adjusted relative risk of non-fatal cardiac failure was 1.10 (95% CL 0.63 to 1.91). The adjusted relative risk of non-fatal ischaemic heart disease was 1.23 (95% CL 0.73 to 2.08) and 1.07 (95% CL 0.69 to 1.66) for bambuterol and salmeterol, compared with nedocromil, respectively. However, in the first month of exposure the adjusted relative risk of non-fatal ischaemic heart disease was 3.95 (95% CL 1.38 to 11.31) when bambuterol was compared with nedocromil. CONCLUSIONS: Caution should be exercised when prescribing long acting oral beta agonists to patients at risk of cardiac failure. More definitive evidence would come from prospective randomised trials.

Adrenergic beta-Agonists↗
PubMed1997

Haploinsufficient phenotypes in Bmp4 heterozygous null mice and modification by mutations in Gli3 and Alx4.

Bone morphogenetic protein 4 (Bmp4), a vertebrate homolog of Drosophila decapentaplegic (dpp), encodes a signaling protein with multiple functions during embryogenesis. Most mouse embryos homozygous for the Bmp4(tm1blh) null allele die around the time of gastrulation, with little or no mesoderm. Two independently derived Bmp4(tm1) mutations were backcrossed onto the C57BL/6 genetic background. Several independently expressed, incompletely penetrant abnormalities were observed in heterozygotes, including cystic kidney, craniofacial malformations, microphthalmia, and preaxial polydactyly of the right hindlimb. In addition, heterozygotes were consistently underrepresented at weaning. These results indicate that Bmp4 gene dosage is essential for the normal development of a variety of organs and for neonatal viability. Two mutations that enhance the penetrance and expressivity of the polydactylous phenotype were identified: Gli3(XtJ), a deletion mutation involving a gene encoding a zinc-finger protein related to Drosophila cubitus interruptus, and Alx4(tm1rwm), a targeted null mutation in a gene encoding a paired class homeoprotein related to Drosophila aristaless. All double Bmp4(tm1); Gli3(XtJ) heterozygotes have extensive anterior digit abnormalities of both fore- and hindlimbs, while all double Bmp4(tm1); Alx4(tm1) heterozygotes display ectopic anterior digits only on the hindlimbs. These genetic interactions suggest a model for the multigenic control of anterior digit patterning during vertebrate limb development.

Animals↗
PubMed1997

A comparison of fluvoxamine, fluoxetine, sertraline and paroxetine examined by observational cohort studies.

OBJECTIVE: To compare the safety and side-effect profiles of the four selective serotonin reuptake inhibitor antidepressants (SSRIs), fluvoxamine, fluoxetine, sertraline and paroxetine. METHODS: The results from four observational cohort studies of the four SSRIs were compared. Each of these studies was conducted by Prescription-Event Monitoring (PEM). The exposure data were derived from general practitioner (GP) prescriptions confidentially supplied by the Prescription Pricing Authority (PPA) in England. Outcome data were obtained from questionnaires (green forms) on which the prescribing doctor recorded event data. The main findings comprised demographic information, including patients' date of birth and sex; the indication for prescribing the monitored drug; the effectiveness of the drug as perceived by the GP; the reasons for stopping treatment and all events recorded during and after treatment. RESULTS: The final cohort for each of the four SSRIs exceeded 10,000 patients. The sex, age distributions and indications for prescribing the four SSRIs were very similar. Only 36% of the GPs expressing an opinion reported fluvoxamine as effective, compared with approximately 60% for fluoxetine, sertraline and paroxetine. Fluvoxamine was associated with a higher incidence of adverse events than the other three SSRIs. Nausea/vomiting was both the most frequent clinical reason for stopping all four SSRIs and the most frequently reported clinical event. Adverse events reported in patients aged 70 years and over were comparable with the events reported for the total cohorts. Differences were identified between the four SSRIs for less frequently reported adverse events. Withdrawal symptoms were significantly more frequent with paroxetine than the other three SSRIs. CONCLUSIONS: The data from the four studies were comparable in terms of age distribution, sex of patients and indication for prescribing the drugs. Fluvoxamine had a considerably higher incidence of side-effects associated with its use than the other three SSRIs. The side-effect profiles of the four SSRIs were comparable for frequently reported events. Important differences were identified between the four SSRIs in respect of less frequently reported events. This study suggests that fluvoxamine compares unfavourably with fluoxetine, sertraline and paroxetine, both in terms of reported effectiveness and the incidence of adverse events. Biases possibly affecting the comparisons involved in this study are unlikely to account for the observed differences between fluvoxamine and the other three SSRIs.

Journal Article↗
PubMed1997

Myocardial infarction and oral contraceptives, a retrospective case control study in England and Scotland ('MICA' Study).

Recent studies have shown that modern (third generation), oral contraceptives (OC) are associated with an increased incidence of venous thromboembolic disease compared to older (second generation), OC. It is not known, however, whether this association is also true for arterial thrombosis, in particular myocardial infarction. In fact, it has been suggested that third generation OC may even be protective against myocardial infarction (MI), compared to second generation OC. The protocol for a multicentre case-control study, involving the whole of England and Scotland, is described. Cases will be female patients aged 16-44 years, who suffered an MI between 1.10.93 and 1.10.95. Controls will be drawn from the community, using the GP list, to which the case belonged. Odds ratios will be calculated primarily to compare current users of third generation OC with current users of second generation OC.

Journal Article↗
PubMed1996

Standards of care of diabetic patients in a typical English community.

BACKGROUND: Poole has a well-established system of sharing care of patients with diabetes between hospital and general practitioners. Very few comprehensive audits of the effectiveness of such a system, which is being adopted in many areas of the UK, have been carried out. AIM: A study was set up to survey structure, process and outcome of care for as many diabetic patients in the Poole area as possible, and to feed the results back to individual practices. METHOD: Structure criteria were assessed by self-completion questionnaire. Process and outcome criteria were assessed by visits to practices and examination of individual patient notes. A total of 37 practices were visited and the notes of 3974 patients reviewed. Results were analysed by practice and for the district as a whole, and were sent to each practice for comparison. RESULTS: The overall prevalence of diabetes in the area was 1.61%, with a marked preponderance of elderly patients (14.1% were over 80). The overall male to female ratio was 1.2:1. The structure questionnaire pinpointed deficiencies in audit facilities, completeness of diabetic registers, and in general use of optometrists and chiropodists. Process criteria analysis showed that, within the last 13 months, 44% of patients under sole care of a general practitioner had undergone full eye examination, cholesterol levels had been checked in 25%, smoking status in 50%, and some foot inspection had been carried out in 57%. Glycaemic control and blood pressure had been measured in over 75% of patients. Outcome analysis showed, in those patients in which they were measured, mean glycosylated haemoglobin (Hba1c) to be 8.07% (upper limit of normal, ULN = 6.5%), some degree of retinopathy to be present in 17.3%, hypertension in 27%, and hypercholesterolaemia in 33%. CONCLUSION: Standards of care of diabetics by general practitioners in the Poole area are not optimal, although they are as good as those reported for other districts. Glycaemic control was generally poor, especially in those patients needing insulin to control the disease. Vascular disease risk factors need to be targeted, and eye examination systems and chiropody services improved.

Adolescent↗
PubMed1986

Unusually high-level expression of a foreign gene (hepatitis B virus core antigen) in Saccharomyces cerevisiae.

As a model system for the study of factors affecting gene expression, hepatitis B virus core antigen (HBcAg) has been expressed in the yeast Saccharomyces cerevisiae. The singularly high levels of expression achieved are approx. 40% of the soluble yeast protein. The HBcAg polypeptides are present as 28-nm particles which are morphologically indistinguishable from HBcAg particles in human plasma and are highly immunogenic in mice. The plasmid construction employed to achieve these very high levels of expression utilizes the constitutively active yeast promoter from the GAP491 gene which is fused in a way that all non-translated sequences flanking the HBcAg coding region are yeast-derived. Hybrid constructions containing 3'-nontranslated viral DNA (yeast 5') or 5'-nontranslated viral DNA (yeast 3') as well as a construction with both 5'- and 3'-nontranslated viral DNA also have been made. A comparison of these constructions for levels of HBcAg expression indicates that the strongest contributor to the high levels of protein is the presence of 5'-flanking sequences which are yeast-derived; secondarily, a significant improvement can be achieved if the 3'-flanking sequences also are yeast-derived. The high abundance of HBcAg in the highest producer is explicable in part on the basis of the very high stability in yeast cells of HBcAg polypeptides. Analysis of the HBcAg coding sequence reveals a very low index of codon bias for S. cerevisiae, largely discounting codon usage as a contributor to the high level of protein obtained.

Genes↗