PubMed Health⌕ Search

Biomedical subjects

A P Fletcher

Publications and source records attributed to A P Fletcher.

At least 19 recordsLinked to original sources
PubMed1992

An appraisal of spontaneous adverse event monitoring.

Awareness of the need to continue the safety assessment of new drugs into the post-marketing period has continued to increase over the past few years. The stage has been reached where there is, for all practical purposes, unanimous agreement that all new drugs, particularly those intended for widespread use and/or long-term administration, be subjected to some form of post-marketing monitoring. In many cases nationally sponsored spontaneous reporting systems are claimed to be sufficient to meet the needs without any critical appraisal being made of the suitability or reliability of this method. The adoption of 'pharmacovigilance' (spontaneous reporting) as the system for the whole European Community (EC) emphasizes the faith that has been placed in the system. At a recent symposium (Management Forum, 9-10 March, 1992) on post-marketing safety evaluation, more than half of the 16 papers presented were entirely or predominantly concerned with spontaneous reporting systems, which is a pattern common to other meetings on this topic. The Committee on Safety of Medicines (CSM) has referred to spontaneous reporting as the cornerstone of post-marketing surveillance which has further endorsed a general feeling of confidence that the system will meet our societal needs even though its scientific capability may be deficient. It is the purpose of this paper to challenge these assumptions and to make an objective appraisal of the various methods available.

Adverse Drug Reaction Reporting Systems↗
PubMed1991

Spontaneous adverse drug reaction reporting vs event monitoring: a comparison.

Spontaneous adverse drug reaction (ADR) reporting is the mainstay of national and international drug safety evaluation in the post-approval phase. A major criticism of the method has been a high, but essentially unquantifiable, level of under-reporting by doctors. A direct comparison has been made between spontaneous ADR reporting and an observational event monitoring system for a group of more than 44,000 patients receiving one or other of a group of seven new drugs. The data suggests that under-reporting by the spontaneous system may be as high as 98% for several clinical events believed to be associated with drug treatment.

Drug-Related Side Effects and Adverse Reactions↗
PubMed1990

Profile of a large-scale cohort study.

An event-monitoring, observational cohort study was conducted in 10,800 patients treated with the nonsteroidal anti-inflammatory agent (NSAID) nabumetone and in 2005 patients treated with a selection of other NSAIDs. A total of 2986 doctors in general practice in the UK participated in the study, which involved the provision of a registration report at the beginning of the study and follow-up reports at 1, 3, 6, and 12 months. The methodology which was developed was successful in collecting demographic, diagnostic, drug use, clinical event and adverse reaction data in everyday medical practice.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Blood coagulation in postmenopausal women given estrogen treatment: comparison of transdermal and oral administration.

The responses of the blood coagulation and related systems were studied in 23 postmenopausal women, all of whom received, in randomized order, therapy with conjugated oral estrogens (0.625 and 1.25 mg daily) and transdermally administered estradiol in doses of 25, 50, 100, and 200 micrograms/24 hr. Neither plasma fibrinopeptide A determinations nor plasma fibrinogen chromatographic findings were altered; thus there is no evidence of accelerated fibrinogen turnover with either form of therapy. However, alpha 1-antitrypsin and plasminogen concentrations were significantly increased with the higher dosage of oral but not with transdermally administered estrogen. Similarly, ceruloplasmin concentration was significantly elevated with both oral doses but was unchanged by transdermal therapy.

Administration, Cutaneous↗
PubMed1987

Course and resolution of the coagulopathy in nephrotic children.

Blood coagulation function was serially studied in 84 children with nephrotic syndrome. Fifty-eight had minimal change disease, six had focal glomerulosclerosis and 20 had other forms of renal disease associated with the nephrotic syndrome. Qualitatively similar abnormalities in fibrinogen metabolism were present in all groups with clinically overt nephrotic syndrome; plasma fibrinogen concentration and high molecular weight fibrin(ogen) complexes (HMWFC) were grossly elevated (P less than 0.001 in most groups). With disease remission fibrinogen and HMWFC concentrations decreased to the normal range, usually with concomitant transient increase in plasma fibrinolytic activity (P less than 0.02). Alterations in concentrations of other proteins involved in coagulation and fibrinolysis differed depending on the underlying cause for the nephrotic syndrome. Antithrombin III concentration was normal except in the focal glomerulosclerosis group. The results demonstrate that a coagulopathy characterized by pathological degree of thrombin action on fibrinogen complicates the nephrotic state and may be initiated by different mechanisms. It is suggested that this coagulopathy, which remits with clinical improvement, is consequent upon local intrarenal activation of the blood coagulation system.

Adolescent↗
PubMed1986

Biologic effects of transdermal estradiol.

We conducted a dose-response study in 23 postmenopausal women to compare the physiologic effects of transdermal estradiol and oral conjugated equine estrogens. The doses studied were 25, 50, 100, and 200 micrograms of transdermal estradiol per 24 hours, and 0.625 and 1.25 mg of oral conjugated estrogens. Transdermal estradiol increased circulating concentrations of estradiol and estrone. Oral conjugated estrogens also raised the levels of estrogen, particularly estrone. Both preparations lowered gonadotropin levels, decreased the percentages of vaginal parabasal cells, increased the percentage of superficial cells, and lowered urinary calcium excretion. The effects of 0.625 and 1.25 mg of oral estrogens were similar to those of 50 and 100 micrograms of transdermal estradiol per 24 hours, respectively. Oral estrogens significantly increased circulating levels of renin substrate, sex-hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin; transdermal estradiol had no effect. The higher dose of oral estrogens had favorable effects on concentrations of low-density and high-density lipoproteins, but transdermal estradiol did not. Neither preparation affected any of the four clotting factors studied. These data indicate that transdermal estradiol can elicit many of the desirable actions of estrogen while avoiding the pharmacologic effects of oral estrogens on hepatic proteins.

Administration, Oral↗
PubMed1983

Formation of soluble fibrin oligomers in purified systems and in plasma.

The kinetic parameters for release of fibrinopeptide A (FPA) from human fibrinogen by thrombin are: Km = 2.3 X 10(-6)M and Vmax. = 1.1 X 10(-10)mol of FPA/s per unit of thrombin; for fibrin formation, Km is similar to that for FPA release, but, the conditions of the present study, Vmax. was approximately half of that for FPA release. The formation of fibrin polymer before the sol-gel transition was studied by gel-permeation chromatography combined with effluent analysis for fibrinogen antigen and residual FPA. Polymer formation in purified fibrinogen incubated with thrombin proceeded as a bimolecular association of exposed sites in a manner predicted by probability calculations and assuming random FPA cleavage. Each oligomer consisted of n molecules of fibrin monomer and two fibrinogen molecules, each of the latter lacking one FPA molecule, i.e. each oligomer, regardless of molecular size, retains two FPA molecules. The addition of 5 mM-CaCl2 to the reaction mixture changed the rate of polymer formation, so that dimer was no longer the prevalent oligomer; in the presence of Ca2+, the trimer was the oligomer in highest concentration. The polymers formed in the presence of calcium were similar in composition to those without, i.e. 2 mol of FPA/mol of oligomer. EDTA-treated plasma samples incubated for short periods of time, 30s or less, with thrombin ranging in concentration up to 1 N.I.H. unit/ml did not form clots during the 10-15 min period of observation until they were applied to the column, though a large proportion of the available FPA was cleaved (maximum 45%). The soluble polymers in plasma were mostly of the high-Mr variety (tetramer and greater); these high-Mr polymers contained less than 2 mol of FPA/mol of polymer, whereas dimer and trimer in plasma were similar to those in the purified systems, i.e. 2 mol of FPA/mol.

Biopolymers↗
PubMed1979

Blood coagulation system pathophysiology in acute myocardial infarction: the influence of anticoagulant treatment on laboratory findings.

Two hundred twenty patients admitted to a Coronary Care Unit were studied by serial plasma fibrinogen chromatography--a method for quantification of HMWFCs, native fibrinogen, and other fibrinogen derivatives in plasma. Enhanced formation of fibrin (intravascular coagulation/thrombosis) is reflected by elevation of plasma HMWFC. One hundred ten patients suffering from documented acute myocardial infarction showed early, sharp elevation of plasma HMWFC (p less than 0.001 when compared to normal and cardiac control groups), a finding which persisted for 10 to 20 days after infarction. Forty-three of the patients did not receive anticoagulant therapy, and the others received either initial heparin, heparin plus warfarin, or werfarin therapy. Plasma fibrinogen chromatographic findings, days 1 to 5, did not differ between the anticoagulated and nonanticoagulated treatment groups, although there were minor differences in the data for days 6 to 10. The results demonstrate that patients with acute myocardial infarction develop a coagulopathy characterized by enhanced fibrin formation, which is influenced to only a minor degree by conventional dosage anticoagulant therapy.

Anticoagulants↗
PubMed1977

Reduction of coagulation factor XIII concentration in patients with myocardial infarction, cerebral infarction, and other thromboembolic disorders.

Coagulation factor XIII and plasma fibrinogen chromatographic assays have been performed serially in patients suffering from acute myocardial and cerebral infarction, and in others with disseminated intravascular coagulation. The findings were compared with 2 groups of "controls"; normal clinically-well subjects and hospitalized patients with cerebral infarction who exhibited minimal, stable, or improving neurological deficits. Substantial depression of factor XIII concentrations developed in the 3 patient groups, together with concomitant significant increases in the proportion and concentration of plasma high molecular weight fibrin(ogen) complexes (HMWFC). An inverse correlation (p less than 0.05) between coagulation factor XIII concentration and percentage of HMWFC was demonstrated in the early stages of the illness. These findings suggest that depression of coagulation factor XIII concentration in these states, is secondary to extravascular or intravascular coagulation and may reflect its degree.

Adult↗
PubMed1977

Severe glomerulonephritis complicated by coagulopathy: treatment with anticoaguland and immunosuppresive drugs.

Serial determinations, using plasma fibrinogen gel chromatography as well as standard methodology, demonstrated that six children with severe glomerulonephritis, characterized on renal biopsy by glomerular necrosis and crescent formation, had persistent evidence of intravascular coagulation. Based on these observations, therapy with anticoagulants and azathicoagulants and azathioprine was instituted for one year; treatment with anticoagulants was continued for a second year. Anticoagulant therapy was initiated with heparin, followed by oral anticoagulation with phenindione and dipyridamole. In contrast to our earlier experience with similar patients, each of the present patients improved. Urinalyses returned to normal and glomerular filtration rates to near normal values in all patients at the end of the treatment period and have remained so for up to 3.9 years since treatment has been completed. Post-treatment biopsies showed remarkable improvement, with virtually no glomerulosclerosis even in patients who had had a high incidence of glomerular crescents before treatment. It is suggested that the therapeutic regimen favorably influenced the natural history of disease and that plasma fibrinogen chromatographic findings may be helpful in selecting patients likely to benefit from the use of anticoagulant therapy.

Acute Disease↗
PubMed1976

Pathophysiological response of the blood coagulation system in acute glomerulonephritis.

A new procedure, plasma fibrinogen chromatography, has been utilized, together with other blood coagulation assays, to quantify fibrin formation in 43 children with acute poststreptococcal glomerulonephritis (AGN) from the time of hospitalization until recovery. During the prediuretic phase of AGN, significant evidence for substantial increase in fibrin formation (intravascular coagulation) included gross increase in plasma high molecular weight fibrinogen complexes (HMWFC), the development of either hypo- or hyperfibrinogenemia and gross depression of coagulation factor XIII concentration and of alpha2-macroglobulin concentration. During the diuretic phase of the disease, these abnormalities regressed and evidence of enhanced plasma fibrinolytic activity, documented by an increase in fibrinogen first derivative, was detected. Concomitantly, urinary excretion of fibrin(ogen) degradation products (FDP) underwent substantial increase. With disease recovery, which occurred in all children, urinary FDP excretion ceased and all coagulation findings normalized.

Acute Disease↗