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Biomedical subjects

G G Thompson

Publications and source records attributed to G G Thompson.

At least 37 records · Page 2Linked to original sources
PubMed1991

Cholelithiasis in patients with variegate porphyria.

Four patients with variegate porphyria (VP) who developed symptoms attributable to cholelithiasis are described. Elective cholecystectomy was performed uneventfully in two of these patients in whom the diagnosis of porphyria had previously been made. The third patient was not known to have porphyria at the time of surgery and developed a fulminating attack which proved fatal. The major haem precursor overproduced in VP is protoporphyrinogen and protoporphyrin was present in the gallstones available for analysis. Our experience suggests that patients with VP have an increased risk of cholelithiasis which may be related to the overproduction of protoporphyrinogen and increased bile concentration of protoporphyrin.

Adult↗
PubMed1991

Overconfidence among physicians and nurses: the 'micro-certainty, macro-uncertainty' phenomenon.

Overconfidence in clinicians was examined in two independently designed studies, each using a different research approach. The first study examined treatment choices of physicians in treating breast cancer, and the second rapid decision making among nurses working in Intensive Care Units. In both studies, individual respondents were highly confident they had made the right choice ('micro-certainty'), although there was no consensus across respondents as to what the optimal treatment would be ('macro-uncertainty'). The difference between micro-certainty of individuals and macro-uncertainty within the clinical community may cast some light on the persistence of practice variation. The implications of overconfidence in clinical treatment for patients, practitioners, and professional regulation are discussed.

Decision Making↗
PubMed1991

Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.

1. Potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol were evaluated in two double-blind, randomised, balanced, crossover studies employing the same six healthy males. 2. The first study examined the effect of repeated propranolol administration on the pharmacodynamics and pharmacokinetics of verapamil after single oral and intravenous doses. The second explored the pharmacodynamics and pharmacokinetics of verapamil and propranolol alone and in combination after single and repeated oral doses. 3. The magnitude of the prolongation of PR interval induced by oral and intravenous verapamil was not affected by pre-treatment with propranolol. When verapamil and propranolol were co-administered as single doses, effects on PR interval were additive but, following repeated doses, a trend towards greater than additive prolongation was seen. The arithmetic sum of the effects of the two drugs was 23% (95% C.I. 8-38%) but the measured increase after the combination was 40% (95% C.I. 26-54%). 4. The extent of reduction in heart rate and blood pressure at rest and after exercise following repeated doses of propranolol was not influenced by single oral or intravenous doses of verapamil. The heart rate and blood pressure responses to single and repeated oral doses of verapamil and propranolol in combination were significantly greater than those after either drug alone and approximated to the arithmetic sum of the individual responses. 5. Although repeated administration of propranolol reduced hepatic blood flow as assessed by indocyanine green clearance, there was no evidence of an interaction between the drugs at this level. 6. The pharmacokinetics of verapamil and norverapamil were not significantly affected by prior propranolol. After single doses of verapamil and propranolol in combination, the maximum plasma concentration of propranolol was increased and the oral clearance of verapamil reduced. No pharmacokinetic interaction was observed after repeated doses. 7. These findings provide little evidence of a pharmacodynamic or pharmacokinetic interaction between verapamil and propranolol in normal subjects. Most of the haemodynamic responses to these drugs in combination can be explained by additive drug effects but an interaction affecting AV conduction after repeated doses cannot be excluded. The minor pharmacokinetic interaction between the drugs is unlikely to be relevant to the pharmacodynamic changes.

Adult↗
PubMed1991

Health care in Canada: current trends and issues.

Canada's universal health care system is perceived as threatened by rising costs, an aging population, and technological growth. This popular and successful program has largely kept costs under control while maintaining quality and ensuring equity. However, its success demonstrates the limits of medical care; remaining health problems are less amenable to improvement by merely improving access to traditional services. A widening view of health implies a larger health role in other policy arenas, and a larger group of legitimate participants; coordinating an evolving and expanding system becomes increasingly difficult. Policy options include some combination of laissez faire, business as usual, managed care, manpower regulation, and system change. Change implies controversy and conflict. Hard decisions are clearly ahead.

Canada↗
PubMed1990

High-performance liquid chromatographic analyses of porphyrins in hamster Harderian glands.

Porphyrin content and 5-aminolaevulinate synthase activity of the Harderian gland were measured in intact and gonadectomized male and female hamsters; porphyrin profiles were analysed by high-pressure liquid chromatography. The total porphyrin content of the two female groups was similar, but enzyme activity in females ovariectomised for 20 weeks significantly decreased. Intact males have low porphyrin content and enzyme activity, while in castrates (6 weeks) both increased to female levels. Protoporphyrin IX formed 93% of total porphyrins in intact females, compared with 70% of total porphyrins in intact males. The remainder in both sexes was chiefly penta- and hexacarboxylic porphyrins and coproporphyrin and (in females) Harderoporphyrin. Gonadectomy in either sex resulted in protoporphyrin levels intermediate between male and female values.

5-Aminolevulinate Synthetase↗
PubMed1990

Variations in breast cancer treatment decisions and their impact in mounting trials.

Clinical trials are often hindered by insufficient participation. Difficulties may arise if a clinician is generally reluctant to enroll patients in clinical trials, if the clinician is unwilling to enroll a patient in a particular trial, or if the patient refuses to participate. In our three-stage survey of clinicians treating breast cancer, we found that a favorable orientation to trials in principle can be attenuated when clinicians do not like the treatment regimens in a particular trial. We also found a lack of consensus as to appropriate treatment for breast cancer coupled with a high confidence by individual clinicians in their own treatment decisions (a phenomenon we term "micro-certainty/macro-uncertainty"). Accordingly, in the most controversial situations, it may be hardest to mount trials. Trial design is also complicated by the variation among clinicians in the importance they assign to various patient characteristics in making their treatment decisions. This variation can lead to difficulties in establishing patient subgroups that will be accepted by the clinical community. The trial designer will need to be alert to these considerations; efforts to build consensus on which data are necessary and which therapies are acceptable should improve the design and application of clinical trials.

Attitude of Health Personnel↗
PubMed1989

Analytic solution of a dynamic pool model incorporating constant marginal cost and discount rates.

A simple dynamic pool model is extended to describe the economics of a single-species fishery by incorporating constant marginal cost and discount rates. Assuming that the population has already come to equilibrium under an initial fishing mortality rate and that any change in that rate is to be sustained indefinitely, the model can be solved analytically to yield the optimal fishing mortality rate. When this rate is expressed as a proportion of the natural mortality rate, the solution takes the form of a third-degree polynomial whose coefficients are simple functions of four other parameters. The solution exhibits positive conservation effects as long as all four parameters are sufficiently high. These conservation effects may be great enough to warrant closing the fishery when the marginal cost rate exceeds a well-defined limit.

Animals↗
PubMed1988

Simple high-performance liquid chromatographic method for the measurement of amiloride in body fluids.

A simplified rapid high-performance liquid chromatographic (HPLC) procedure has been developed for the measurement of amiloride in plasma or urine. Solid-phase extraction columns provide quick, clean and simple sample preparation, allowing ten samples to be processed in less than 5 min. The HPLC system uses a standard reversed-phase (C18) column with detection by ultraviolet absorption at 365 nm. The assay has been used to define plasma amiloride concentration-time profiles and to quantitate urine amiloride recovery in healthy men after repeated administration at two doses.

Adult↗
PubMed1988

The effects of chronic carbamazepine treatment of haem biosynthesis in man and rat.

The anticonvulsant drug carbamazepine has been reported to produce a condition clinically and biochemically similar to acute intermittent porphyria (AIP). We have determined the effect of chronic carbamazepine treatment on the activities of the enzymes of haem biosynthesis in circulating blood cells and on the urinary excretion of porphyrins and their precursors in 53 epileptic patients receiving monotherapy and in 42 age- and sex-matched controls. In the patients the mean activity of leucocyte 5-aminolaevulinic acid (ALA) synthase, the rate-limiting enzyme of the pathway, was 218% of control values (p less than 0.001) and ALA-dehydratase activity was reduced by 37% (p less than 0.001). Circulating carbamazepine concentrations correlated negatively with ALA dehydratase (rs = -0.45; p less than 0.01). Porphobilinogen deaminase and uroporphyrinogen decarboxylase appeared unaffected by carbamazepine treatment. Significant quantitative increases in the urinary excretion of porphobilinogen and total porphyrins (both p less than 0.05) accompanied the changes in enzyme activity. Similar dose-dependent effects on ALA synthase and ALA dehydratase were shown to occur in rats treated for 5 days with 3 different doses of carbamazepine. These findings further support the porphyrinogenicity of carbamazepine, but the pattern of enzyme alteration differs from that found in AIP.

5-Aminolevulinate Synthetase↗
PubMed1988

Technology acquisition in Canada. Control in a regulated market.

The authors provide a detailed overview of how the national and provincial health systems of Canada exercise control over the diffusion of medical technology. In particular, they examine the diffusion of CT scanning and the adoption of non-ionic radio contrast media. While the nature of the parliamentary system theoretically allows the government, especially the executive, to exert more control over its policy agenda than in the United States, the authors believe that effective control is hampered by a lack of political will and insufficient "teeth" in the Ministry of Health's mandate and policy. The authors also conclude that the manipulation of reimbursement systems to encourage or discourage the diffusion of various medical technologies is not always effective, and that political clout often triumphs over rational decision making.

Canada↗
PubMed1988

Effects of sodium valproate on haem biosynthesis in man: implications for seizure management in the porphyric patient.

The short-term effects of sodium valproate (VPA) on haem biosynthesis were assessed in a placebo-controlled crossover trial in eight healthy male subjects who ingested VPA 500 mg t.i.d. and matched placebo for 5 days. All showed augmented activity of leucocyte 5-aminolaevulinate synthase (ALA-S) activity, the rate-limiting enzyme of the haem biosynthetic pathway, following 3 and 5 days of VPA treatment (P less than 0.001). This was accompanied by increased urinary excretion of 5-aminolaevulinic acid (ALA; P less than 0.02) and total porphyrins (P less than 0.01). Mean (+/- SD) total VPA concentrations on day 3 (89 +/- 16 mg 1-1) and day 5 (91 +/- 22 mg 1-1) were within the target range for the drug. The long-term effects of VPA administration were examined in epileptic patients on established monotherapy. Leucocyte ALA-S activity (P less than 0.001), and daily urinary excretion of porphobilinogen (P less than 0.01) and total porphyrins (P less than 0.01) were all higher than in age-matched controls. No significant differences in erythrocyte ALA-dehydratase, porphobilinogen deaminase and uroporphyrinogen decarboxylase activities were found between the groups. These data suggest that VPA is porphyrinogenic in man and cannot be recommended as safe for seizure management in the porphyric patient.

5-Aminolevulinate Synthetase↗
PubMed1987

Antipyrine metabolism in acute hepatic porphyria in relapse and remission.

Antipyrine kinetics following a single oral dose were obtained in porphyric patients in attack and in remission and in controls. The clearance of antipyrine was significantly lower during an acute porphyric attack (median: 0.34 ml min-1 kg-1; range: 0.1-0.71, P less than 0.05) than in patients in remission (median: 0.53 ml min-1 kg-1; range: 0.28-0.87) or controls (median: 0.52 ml min-1 kg-1; range: 0.32-0.93). There was a significant negative correlation between weight-adjusted antipyrine clearance and the urinary excretion of the porphyrin precursors, delta-aminolaevulinic acid (r = 0.86, P less than 0.001) and porphobilinogen (r = 0.82, P less than 0.002). These data suggest that the more severe the porphyric attack, the greater the impairment of hepatic monooxygenase activity.

5-Aminolevulinate Synthetase↗
PubMed1987

Effect of rifampicin on haem and bilirubin metabolism in man.

Haem and bilirubin metabolism was studied in seven healthy volunteers during 4 weeks treatment with rifampicin 600 mg at night. The serum unconjugated bilirubin concentration increased 2-3 fold in the first 24 h of treatment (P less than 0.01) and subsequently fell to below pretreatment values (P less than 0.05) during the third and fourth weeks of rifampicin therapy. In each subject, the activity in leucocytes of delta-aminolaevulinic acid (ALA) synthase increased and that of protoporphyrinogen (proto) oxidase decreased during the first week of therapy. The mean ALA synthase activity was most markedly increased on day 4 being seven-fold its pretreatment value (P less than 0.01), and the mean proto oxidase activity most depressed on day 2 at 50% its pretreatment value (P less than 0.02). There was increased urinary excretion of porphobilinogen (PBG) during the first week of therapy and increased excretion of porphyrins and PBG during the third week of treatment. The increase in ALA synthase activity and haem precursor excretion can be explained by the combination of increased haem demand for haemoprotein induction and partial block in haem synthesis due to reduced proto oxidase activity.

Adult↗
PubMed1987

Studies in laboratory animals to assess the safety of anti-inflammatory agents in acute porphyria.

The safety of various anti-inflammatory drugs in acute porphyria was assessed by examining their effect on rat hepatic haem synthesis. Azapropazone, chloroquine, and gold increased delta-aminolaevulinic acid (ALA) synthase activity, indicating that they are liable to precipitate porphyric crises. Aspirin, ibuprofen, indomethacin, ketoprofen, flurbiprofen, phenylbutazone, naproxen, prednisolone, and penicillamine did not increase ALA synthase activity and should be safe in porphyria. Though these animal studies can be used as a guide to prescribing in patients with acute porphyria, some caution is still required as species may vary in their response to inducing agents.

5-Aminolevulinate Synthetase↗
PubMed1987

Porphyrin metabolism and haem biosynthesis in Gilbert's syndrome.

Studies in 14 patients with unconjugated hyperbilirubinaemia caused by Gilbert's syndrome have revealed abnormalities of the enzymes of haem biosynthesis measured in peripheral blood cells. The activity of the penultimate enzyme of haem biosynthesis protoporphyrinogen (PROTO) oxidase was reduced at 3.1 +/- 2.6 nmol PROTO/g protein/h (mean +/- ISD) compared with 8.2 +/- 5.1 in controls (p less than 0.005). This was associated with a compensatory increase in the activity of the initial and rate controlling enzyme of the pathway delta-aminolaevulinic acid (ALA) synthase at 866 +/- 636 nmol ALA/g/protein/h compared with 156 +/- 63 in controls (p less than 0.001). Unlike variegate porphyria in which there is a genetic deficiency of PROTO oxidase there was no increased excretion of porphyrins or their precursors in Gilbert's syndrome. Accentuation and subsequent correction of the unconjugated hyperbilirubinaemia with rifampicin produced reciprocal changes in PROTO oxidase activity indicating that bilirubin may be inhibiting the activity of this enzyme.

5-Aminolevulinate Synthetase↗
PubMed1987

Enhanced oral bioavailability of meptazinol in cirrhosis.

Kinetic analysis was carried out after single intravenous (25 mg) and oral (200 mg) doses of the novel partial opioid agonist meptazinol (Meptid) in patients with non-cirrhotic liver disease (NCLD) and biopsy proven cirrhosis. Comparison was made with a group of patients with normal hepatic function. Elimination half-lives after the intravenous dose were slightly prolonged in the cirrhotics (n = 10; 4.2 +/- 0.6 h) compared with the control (n = 8; 2.7 +/- 0.2 h: p less than 0.05) and NCLD (n = 8; 3.2 +/- 0.5 h) groups. There was no significant difference in meptazinol plasma clearance between the groups (cirrhotics = 72 +/- 8 l/h; NCLD = 89 +/- 9 l/h; control = 83 +/- 10 l/h). After the oral dose, seven of 15 cirrhotic patients vomited but only one patient in each of the other groups was unable to tolerate the drug (p = 0.06). This may be explained by very much higher peak meptazinol concentrations in the cirrhotic (n = 8; 184 +/- 37 ng/ml, p less than 0.01) and NCLD (n = 8; 131 +/- 38 ng/ml, p less than 0.05) patients than those of the controls (n = 7; 53 +/- 12 ng/ml) reflecting a mean four-fold and two-fold increase in oral bioavailability respectively (cirrhotics: n = 8; 27.9 +/- 5.3%: p less than 0.001; NCLD: n = 7; 13.7 +/- 3.9% p less than 0.05; controls: n = 7; 6.5 +/- 1.3%). There was no evidence of accumulation after chronic dosing with 200 mg meptazinol four times daily for 13 doses in seven control, seven NCLD and six cirrhotic patients. There were no detectable differences in psychomotor function measured objectively using the Leeds Psychomotor Tester of subjectively by linear analogue scoring between the groups in all three parts of the study. The oral use of meptazinol in patients with chronic liver disease is associated more with the development of nausea and vomiting rather than excessive sedation. These data suggest that dosage reduction in cirrhotic patients is advisable particularly if the drug is taken by mouth.

Administration, Oral↗
PubMed1987

Who still prefers aggressive surgery for breast cancer? Implications for the clinical applications of clinical trials.

Conservative breast surgery and modified radical mastectomy may, according to recent reports, yield equivalent survival. Analysis of a 1985 Canada-wide study (N = 228) compared surgeons and oncologists still recommending modified radical mastectomy (30%) with those recommending less aggressive surgery (69%) for a hypothetical stage I patient. The groups did not differ significantly in most physician characteristics, estimated survival and cure probabilities, importance of most treatment goals, uncertainty about treatment choice, or most attitudinal responses. Although equally involved with and cognizant of the value of clinical trials, the modified radical group expressed more skepticism about the ability of trial results to be transferred to practice and to take sufficient account of patient uniqueness, indicating greater focus on variation than mean results. Trial results might be more readily adopted if they are reported in accessible data-bases, incorporating patient characteristics potentially relevant to treatment choice. This would allow clinicians to individualize treatment by analyzing patient subsets of their own choosing.

Attitude of Health Personnel↗