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Biomedical subjects

J D Spence

Publications and source records attributed to J D Spence.

At least 37 records · Page 2Linked to original sources
PubMed2000

Angiotensin II antagonists for hypertension: are there differences in efficacy?

We compared the antihypertensive efficacy of available drugs in the new angiotensin-II-antagonist (AIIA) class. The antihypertensive efficacy of losartan, valsartan, irbesartan, and candesartan was evaluated from randomized controlled trials (RCT) by performing a metaanalysis of 43 published RCT. These trials involved AIIA compared with placebo, other antihypertensive classes, and direct comparisons between AIIA. A weighted-average for diastolic and systolic blood pressure reduction with AIIA monotherapy, dose titration, and with addition of low-dose hydrochlorothiazide (HCTZ) were calculated. Weighted-average responder rates were also determined. The metaanalysis assessed a total of 11,281 patients. The absolute weighted-average reductions in diastolic (8.2 to 8.9 mm Hg) and systolic (10.4 to 11.8 mm Hg) blood pressure reductions (not placebo-corrected) for AIIA monotherapy were comparable for all AIIA. Responder rates for AIIA monotherapy were 48% to 55%. Dose titration resulted in slightly greater blood pressure reduction and an increase in responder rates to 53% to 63%. AIIA/hydrochlorothiazide combinations produced substantially greater reduction in systolic (16.1 to 20.6 mm Hg) and diastolic (9.9 to 13.6 mm Hg) blood pressure reductions than AIIA monotherapy and responder rates for AIIA/HCTZ combinations were 56% to 70%. This comprehensive analysis shows comparable antihypertensive efficacy within the AIIA class, a near-flat AIIA-dose response when titrating from starting to maximum recommended dose, and substantial potentiation of the antihypertensive effect with addition of HCTZ.

Angiotensin II↗
PubMed2000

HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia.

BACKGROUND: Orange juice-a rich source of vitamin C, folate, and flavonoids such as hesperidin-induces hypocholesterolemic responses in animals. OBJECTIVE: We determined whether orange juice beneficially altered blood lipids in subjects with moderate hypercholesterolemia. DESIGN: The sample consisted of 16 healthy men and 9 healthy women with elevated plasma total and LDL-cholesterol and normal plasma triacylglycerol concentrations. Participants incorporated 1, 2, or 3 cups (250 mL each) of orange juice sequentially into their diets, each dose over a period of 4 wk. This was followed by a 5-wk washout period. Plasma lipid, folate, homocyst(e)ine, and vitamin C (a compliance marker) concentrations were measured at baseline, after each treatment, and after the washout period. RESULTS: Consumption of 750 mL but not of 250 or 500 mL orange juice daily increased HDL-cholesterol concentrations by 21% (P: < 0.001), triacylglycerol concentrations by 30% (from 1.56 +/- 0.72 to 2.03 +/- 0.91 mmol/L; P: < 0.02), and folate concentrations by 18% (P: < 0.01); decreased the LDL-HDL cholesterol ratio by 16% (P: < 0.005); and did not affect homocyst(e)ine concentrations. Plasma vitamin C concentrations increased significantly during each dietary period (2.1, 3.1, and 3.8 times, respectively). CONCLUSIONS: Orange juice (750 mL/d) improved blood lipid profiles in hypercholesterolemic subjects, confirming recommendations to consume >/=5-10 servings of fruit and vegetables daily.

Adult↗
PubMed2000

Nitrous oxide-induced increased homocysteine concentrations are associated with increased postoperative myocardial ischemia in patients undergoing carotid endarterectomy.

UNLABELLED: Nitrous oxide anesthesia causes increased postoperative plasma homocysteine levels. Acute increases in plasma homocysteine are associated with impaired endothelial function and procoagulant effects. This nitrous oxide-induced plasma homocysteine increase may therefore affect the risk of perioperative cardiovascular events. This prospective, randomized study was therefore designed to evaluate the effect of nitrous oxide anesthesia and postoperative plasma homocysteine levels on myocardial ischemia in patients undergoing carotid endarterectomy. After institutional review board approval and written informed consent, 90 ASA Class I-III patients presenting for elective carotid endarterectomy were randomized to receive general anesthesia with or without nitrous oxide. Prior to induction, on arrival in the postanesthesia care unit, and after 48 h, blood samples were obtained for homocysteine analysis. Three hours prior to induction and for 48 h postoperatively patients were monitored by a three-channel, seven-lead Holter monitor. Postoperatively in the postanesthesia care unit and at 48 h the nitrous oxide group had increased mean plasma homocysteine concentrations of 15.5 +/- 5.9 and 18.8 +/- 14.7 when compared with the nonnitrous group of 11.4 +/- 5.2 and 11.3 +/- 4.0 micromol/L, P: < 0.001. The nitrous oxide group had an increased incidence of ischemia (46% vs. 25%, P: < 0.05), significantly more ischemia (63 +/- 71 vs. 40 +/- 68 min, P: < 0.05), had more ischemic events (82 vs. 53, P: < 0.02), and had more ischemic events lasting 30 min (23 vs. 14, P: < 0.05) than the nonnitrous group. This study reconfirmed that intraoperative nitrous oxide is associated with postoperative increases in plasma homocysteine concentration. This was associated with an increase in postoperative myocardial ischemia. IMPLICATIONS: Use of nitrous oxide during carotid artery surgery induces increases in postoperative plasma homocysteine concentration and is associated with increases in postoperative myocardial ischemia.

Aged↗
PubMed2000

Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition.

Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein. Clinically important CYP3A4 inhibitors include itraconazole, ketoconazole, clarithromycin, erythromycin, nefazodone, ritonavir and grapefruit juice. Torsades de pointes, a life-threatening ventricular arrhythmia associated with QT prolongation, can occur when these inhibitors are coadministered with terfenadine, astemizole, cisapride or pimozide. Rhabdomyolysis has been associated with the coadministration of some 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ('statins') and CYP3A4 inhibitors. Symptomatic hypotension may occur when CYP3A4 inhibitors are given with some dihydropyridine calcium antagonists, as well with the phosphodiesterase inhibitor sildenafil. Excessive sedation can result from concomitant administration of benzodiazepine (midazolam, triazolam, alprazolam or diazepam) or nonbenzodiazepine (zopiclone and buspirone) hypnosedatives with CYP3A4 inhibitors. Ataxia can occur with carbamazepine, and ergotism with ergotamine, following the addition of a CYP3A4 inhibitor. Beneficial drug interactions can occur. Administration of a CYP3A4 inhibitor with cyclosporin may allow reduction of the dosage and cost of the immunosuppressant. Certain HIV protease inhibitors, e.g. saquinavir, have low oral bioavailability that can be profoundly increased by the addition of ritonavir. The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related. Generally, a doubling or more in plasma drug concentration has the potential for enhanced adverse or beneficial drug response. Less pronounced pharmacokinetic interactions may still be clinically important for drugs with a steep concentration-response relationship or narrow therapeutic index. In most cases, the extent of drug interaction varies markedly among individuals; this is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age. Interactions may occur under single dose conditions or only at steady state. The pharmacodynamic consequences may or may not closely follow pharmacokinetic changes. Drug interactions may be most apparent when patients are stabilised on the affected drug and the CYP3A4 inhibitor is then added to the regimen. Temporal relationships between the administration of the drug and CYP3A4 inhibitor may be important in determining the extent of the interaction.

Animals↗
PubMed2000

Effects of indapamide versus hydrochlorothiazide on plasma lipids and lipoproteins in hypertensive patients: a direct comparison.

To test the claim that indapamide causes fewer adverse metabolic effects than hydrochlorothiazide (HCTZ), six months of treatment with HCTZ 25 mg/day was compared with six months of treatment with indapamide 2.5 mg in a randomized double-blind study of 44 patients with mild to moderate hypertension. Both drugs significantly reduced blood pressure, with no significant differences in the reduction of potassium and chloride; neither drug was associated with a significant change in plasma total cholesterol, high density lipoprotein (HDL), apolipoprotein A1, apolipoprotein B or the ratio of total cholesterol to HDL levels. Triglyceride levels increased significantly more with indapamide than with HCTZ (P=0.02). The two drugs had similar effects on blood pressure and serum potassium; neither drug affected plasma glucose. Claims that indapamide is superior to HCTZ appear unwarranted; in view of the substantial cost difference, this finding, if confirmed in larger studies, has important policy implications.

Adolescent↗
PubMed2000

Infection-susceptibility alleles of mannose-binding lectin are associated with increased carotid plaque area.

The MBL gene, encoding mannose-binding lectin, determines interindividual variation in susceptibility to certain infectious agents, such as Chlamydia pneumoniae. We examined whether infection-susceptibility alleles of MBL, called "non-A alleles," would be associated with increased carotid plaque area (CPA), an intermediate phenotype of atherosclerosis. In 164 subjects, we measured CPA with 2-dimensional ultrasound. We also determined traditional atherosclerosis risk factors and genotyped all subjects for MBL codons 52, 54, and 57. We used ANOVA to determine sources of variation for CPA and tested the hypothesis that the presence of a single MBL non-A "infection-susceptibility" allele was associated with increased CPA; 45.7% of subjects had at least one non-A allele. ANOVA showed that CPA was significantly associated with MBL genotype, age, smoking, hypertension, and hyperlipidemia (P < 0.05). When MBL was used as the sole independent variable in the regression analysis, the association with CPA was even more significant (P = 0.009). Subjects with at least one MBL non-A allele had significantly higher CPA than subjects homozygous for the MBL A allele and were significantly more likely to have CPA in excess of the sample median. Thus, infection-susceptibility alleles of MBL were associated with increased CPA in this study sample; these alleles may be a determinant of interindividual differences in atherosclerosis risk.

Adult↗
PubMed2000

Validation of an enzyme immunoassay for the determination of total homocysteine in plasma.

In recent years, the determination of homocysteine (Hcy) has become increasingly important, since high levels of Hcy in plasma or serum represent an independent risk factor for occlusive vascular diseases. Nowadays, clinical laboratories use several analytical techniques to measure Hcy, of which high-performance liquid chromatography (HPLC) is the most popular. Recently, assays for Hcy quantification based on enzyme immunoassays (EIA) have become commercially available. Our group carried out the validation of the Axis method and compared results with those obtained by an established HPLC assay. Intra- and inter-assay coefficients of variation were < or = 8.5%. Compared with HPLC, linear regression analysis showed r=0.984, slope=0.952, intercept = 1.24 /mol/l; Bland-Altman procedure, the mean of the difference EIA-HPLC results = 0.5 micromol/l. Our results suggest that Hcy determinations by both methods are equivalent, and that the Axis assay provides reproducible and reliable data.

Homocysteine↗
PubMed1999

Low-dose and high-dose acetylsalicylic acid for patients undergoing carotid endarterectomy: a randomised controlled trial. ASA and Carotid Endarterectomy (ACE) Trial Collaborators.

BACKGROUND: Endarterectomy benefits certain patients with carotid stenosis, but benefits are lessened by perioperative surgical risk. Acetylsalicylic acid lowers the risk of stroke in patients who have experienced transient ischaemic attack and stroke. We investigated appropriate doses and the role of acetylsalicylic acid in patients undergoing carotid endarterectomy. METHODS: In a randomised, double-blind, controlled trial, 2849 patients scheduled for endarterectomy were randomly assigned 81 mg (n=709), 325 mg (n=708), 650 mg (n=715), or 1300 mg (n=717) acetylsalicylic acid daily, started before surgery and continued for 3 months. We recorded occurrences of stroke, myocardial infarction, and death. We compared patients on the two higher doses of acetylsalicylic acid with patients on the two lower doses. FINDINGS: Surgery was cancelled in 45 patients, none were lost to follow-up by 30 days, and two were lost by 3 months. The combined rate of stroke, myocardial infarction, and death was lower in the low-dose groups than in the high-dose groups at 30 days (5.4 vs 7.0%, p=0.07) and at 3 months (6.2 vs 8.4%, p=0.03). In an efficacy analysis, which excluded patients taking 650 mg or more acetylsalicylic acid before randomisation, and patients randomised within 1 day of surgery, combined rates were 3.7% and 8.2%, respectively, at 30 days (p=0.002) and 4.2% and 10.0% at 3 months (p=0.0002). INTERPRETATION: The risk of stroke, myocardial infarction, and death within 30 days and 3 months of endarterectomy is lower for patients taking 81 mg or 325 mg acetylsalicylic acid daily than for those taking 650 mg or 1300 mg.

Aged↗
PubMed1999

Lifestyle modifications to prevent and control hypertension. 7. Recommendations on stress management. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada.

OBJECTIVE: To provide updated evidence-based recommendations for health care professionals concerning the effects of stress management on the prevention and control of hypertension in otherwise healthy adults (except pregnant women). OPTIONS: Alternatives to stress management include other nonpharmacologic interventions and medical therapy; these options are not mutually exclusive. OUTCOMES: The health outcome considered was reduction of blood pressure. There is little evidence to date that stress management prevents death or vascular events. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: A systematic search of the literature (which yielded, among other sources, 3 meta-analyses) was conducted for the period 1966-1997 with the terms essential hypertension, treatment, psychological, behavioural, cognitive, relaxation, mediation, biofeedback and stress management. Other relevant evidence was obtained from the reference lists of the articles identified, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design and graded according to level of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by uncontrolled hypertension. BENEFITS, HARMS AND COSTS: The magnitude of the reduction in blood pressure obtained with multicomponent, individualized cognitive behavioural intervention for stress management was comparable in some studies to that obtained with weight loss or drugs; single-component interventions such as biofeedback or relaxation were less effective. The adverse effects of stress-management techniques are minimal, but the cost for effective interventions is substantial, similar initially to drug costs; continuing costs are probably minimal. RECOMMENDATIONS: (1) In patients with hypertension, the contribution of stress should be considered. (2) For hypertensive patients in whom stress appears to be an important issue, stress management should be considered as an intervention. Individualized cognitive behavioural interventions are more likely to be effective than single-component interventions. VALIDATION: These recommendations were reviewed by all of the sponsoring organizations and by participants in a satellite symposium of the fourth International Conference on Preventive Cardiology. They have not been clinically tested. SPONSORS: The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada.

Adult↗
PubMed1999

An approach to ascertain probands with a non-traditional risk factor for carotid atherosclerosis.

In our previous studies of the determinants of carotid plaque area (CPA), we used a linear multiple regression model, which permitted us to control for the presence of known risk factors in order to reveal the contribution of putative new risk factors. We recognized that this approach could identify patients whose observed CPA was excessive when considering traditional risk factors. Subjects whose observed CPA markedly exceeded the expected CPA were easily identified because of their deviation from the regression line that was derived using all members of the study sample. We classified such subjects as having 'unexplained atherosclerosis' relative to the overall study sample when traditional risk factors were included as independent variables. We then examined the plasma homocyst(e)ine concentration in members of the subgroup with 'unexplained atherosclerosis'. We found a significantly higher mean plasma concentration of homocyst(e)ine in the subgroup with 'unexplained atherosclerosis', compared to rest of the study sample (20.4 +/- 4.3 vs. 13.2 +/- 3.2 mumol/l, P < 0.005). We also found that significantly more subjects with 'unexplained atherosclerosis' had plasma homocyst(e)ine concentrations in excess of 14 mumol/l compared to the rest of the study sample (52 vs. 33%, P < 0.002). We thus propose that systematic identification of subjects with 'unexplained atherosclerosis' relative to the rest of a well-characterized study sample might be a useful approach to identify subjects in whom there are newer, non-traditional determinants of predisposition to atherosclerosis.

Adult↗
PubMed1999

Effect of usual doses of folate supplementation on elevated plasma homocyst(e)ine in hemodialysis patients: no difference between 1 and 5 mg daily.

Hyperhomocyst(e)inemia is a probable contributor to the excess atherosclerosis of patients with chronic renal failure on dialysis. Although treatment with folate 2 mg daily is usually effective in normalizing plasma homocyst(e)ine (H(e)) in patients with normal renal function, higher doses of folate or other approaches to treatment may be necessary in renal failure. There is no agreement among dialysis units regarding the 'correct' dose of folate supplementation; routine doses range from 1 to 5 mg daily. To determine whether one of these doses is more effective, we compared H(e) in 55 hemodialysis taking 1 mg folate versus 73 patients taking 5 mg folate daily at two dialysis units. In the group as a whole, mean H(e) was 28.23 +/- 17.49, significantly higher than in a group of 290 volunteers with normal renal function 12.31 +/- 6.17 (p = 0. 0001). H(e) levels were 28.93 +/- 16.79 micromol/l on 5 mg folate and 27.31 +/- 18.49 on 1 mg; p = 0.61. There was no significant relationship between adequacy of dialysis (Kt/V) and H(e). In a small group of peritoneal dialysis patients, H(e) was significantly lower at 18.8 +/- 7.89 (p = 0.026), but further study is required in a larger sample to confirm that observation. It appears that routine doses of folate in use in dialysis units are not sufficient to reduce H(e) to levels associated with average cardiovascular risk; new approaches to treatment of hyperhomocyst(e)inemia in dialysis patients are required.

Aged↗
PubMed1999

Plasma homocyst(e)ine concentration, but not MTHFR genotype, is associated with variation in carotid plaque area.

BACKGROUND AND PURPOSE: Elevated plasma homocyst(e)ine [H(e)] concentration is associated with premature atherosclerosis. A common cause of elevated plasma H(e) concentration is a thermolabile mutation (677T) in the gene encoding methylenetetrahydrofolate reductase (MTHFR). We sought to determine whether plasma H(e) concentration or MTHFR genotype would be more strongly associated with carotid plaque area (CPA), a potential intermediate phenotype of atherosclerosis. METHODS: In 307 subjects who were ascertained through a premature atherosclerosis clinic, we measured CPA with 2-dimensional ultrasound and also determined traditional atherosclerosis risk factors, in addition to plasma H(e) concentration and MTHFR genotypes. RESULTS: We found that the frequency of the MTHFR 677T allele was 0.363 in this sample. Mean plasma H(e) concentration was significantly higher in 677T/T homozygotes than in 677T/C heterozygotes and 677C/C homozygotes (17. 1+/-13.7 versus 13.5+/-6.1 versus 12.6+/-5.9 micromol/L, respectively, P<0.001). Analysis of variance showed that CPA was significantly associated with age, sex, smoking, diabetes, hypertension, and hyperlipidemia (each P<0.05). When plasma H(e) concentration was included in the model, it was significantly associated with CPA (P<0.05). However, when the MTHFR genotype was included in the model, it was not associated with CPA (P=0.50). Furthermore, there was a significant correlation of CPA with plasma H(e) (r=0.23, P<0.0001). However, the mean CPA did not differ between subjects according to genotype. CONCLUISONS: Thus, plasma H(e), but not MTHFR genotype, is significantly associated with carotid atherosclerosis, suggesting that the biochemical test may be sufficient to identify patients who may be at increased risk of atherosclerosis through this mechanism.

Adult↗
PubMed1999

Efficacy of angiotensin II antagonists in hypertension.

Advertising claims of superior antihypertensive efficacy of one angiotensin antagonist over another are not substantiated by a review of available evidence from 43 randomized, controlled clinical trials, in which 11,281 patients were included. There were no clinically important differences among the drugs. At initial doses, the mean reduction of diastolic pressure was 8.5 mmHg and of systolic pressure was 10.7 mmHg; 50% were responders. Doubling the dose of these agents produced only small additional blood pressure reduction. Diastolic blood pressure fell by an additional 1.5 mmHg, and systolic blood pressure by 2.5 mmHg; there were only 7% more responders. In contrast, the addition of hydrochlorothiazide 12.5 mg daily to the initial doses provided 40% to 60% more reduction of blood pressure and 40% more responders. The author concludes that adding hydrochlorothiazide to any angiotensin II antagonist results in much greater efficacy than switching or increasing doses of the angiotensin II antagonist.

Angiotensin Receptor Antagonists↗
PubMed1999

Physiologic tailoring of therapy for resistant hypertension: 20 years' experience with stimulated renin profiling.

Renin profiling to assist in management of hypertension was first proposed about 27 years ago. However, it is still not widely used, perhaps because it was initially emphasized for management of primary hypertension, which is usually relatively easy to manage. Our experience in more than 4000 patients with referral hypertension screened since 1977 suggests that this approach, which I call "Physiologic Tailoring" of management, is particularly helpful in resistant hypertension, especially in cases of adrenocortical hypertension. Three cases of resistant hypertension spanning the 20 years of the clinic's existence, are presented to illustrate the contribution of renin profiling to the diagnosis and management of adrenocortical hypertension. It is suggested that adrenocortical hypertension is virtually always due to bilateral hyperplasia and that true curable solitary nodules may not exist if patients are followed long enough; and that adrenocortical hyperplasia is much more common in blacks and patients of African origin. A study to test the cost-utility of a renin-based algorithm for management of resistant hypertension is recommended.

Adrenal Cortex Diseases↗
PubMed1999

1999 Canadian recommendations for the management of hypertension. Task Force for the Development of the 1999 Canadian Recommendations for the Management of Hypertension.

OBJECTIVE: To provide updated, evidence-based recommendations for health care professionals on the management of hypertension in adults. OPTIONS: For patients with hypertension, there are both lifestyle options and pharmacological therapy options that may control blood pressure. For those patients who are using pharmacological therapy, a range of antihypertensive drugs is available. The choice of a specific antihypertensive drug is dependent upon the severity of the hypertension and the presence of other cardiovascular risk factors and concurrent diseases. OUTCOMES: The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. EVIDENCE: MEDLINE searches were conducted from the period of the last revision of the Canadian Recommendations for the Management of Hypertension (January 1993 to May 1998). Reference lists were scanned, experts were polled and the personal files of the authors were used to identify other studies. All relevant articles were reviewed, classified according to study design and graded according to levels of evidence. VALUES: A high value was placed on the avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. BENEFITS: Harms and costs: The diagnosis and treatment of hypertension with pharmacological therapy will reduce the blood pressure of patients with sustained hypertension. In certain settings, and for specific drugs, blood pressure lowering has been associated with reduced cardiovascular morbidity and mortality. RECOMMENDATIONS: This document contains detailed recommendations pertaining to all aspects of the diagnosis and pharmacological therapy of hypertensive patients. With respect to diagnosis, the recommendations endorse the greater use of non-office-based measures of blood pressure control (i.e., using home blood pressure and automatic ambulatory blood pressure monitoring equipment) and greater emphasis on the identification of other cardiovascular risk factors, both in the assessment of prognosis in hypertension and in the choice of therapy. On the treatment side, lower targets for blood pressure control are advocated for some subgroups of hypertensive patients, in particular, those with diabetes and renal disease. Implicit in the recommendations for therapy is the principle that for the vast majority of hypertensive patients treated pharmacologically, practitioners should not follow a stepped-care approach. Instead, therapy should be individualized, based on consideration of concurrent diseases, both cardiovascular and noncardiovascular. VALIDATION: All recommendations were graded according to the strength of the evidence and the consensus of all relevant stakeholders. SPONSORS: The Canadian Hypertension Society and the Canadian Coalition for High Blood Pressure Prevention and Control.

Adult↗