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J D Spence

Publications and source records attributed to J D Spence.

At least 73 records · Page 4Linked to original sources
PubMed1996

Cerebral consequences of hypertension: where do they lead?

BACKGROUND: Hypertension is a major risk factor for two distinct kinds of vascular problems: complications of atherosclerosis including myocardial and cerebral infarction, as well as complications of hypertensive small vessel disease, including renal failure, intracerebral hemorrhage and lacunar infarctions. If these consequences were solely due to elevation of blood pressure, they should be equally prevented by treatments that reduce blood pressure. OBSERVATION: The installation of a computed tomography (CT) scanner in our hospital before the initiation of a large study by the Department of Family Medicine markedly increased the detection and treatment of hypertension in our region. As a result, we found that treating high blood pressure prevented arteriolar but not atherosclerotic strokes. HYPOTHESIS: Our observation raises questions about the nature of hypertension, which can be regarded as a disorder of fluid energy, with arteriolar consequences being due to elevated pressure, and atherosclerotic consequences being related to kinetic energy, derived from pressure energy when flow patterns become disturbed. It is hypothesized that the remodelling of arteries to conform to flow patterns may be driven by increased nitric oxide at regions of high shear, leading the artery to 'grow away' from high shear, whereas endothelin released in regions of low shear may cause the artery to 'fill in' the low shear region. This may, in part, explain the protection that women enjoy until menopause, as estrogen increases nitric oxide release and probably reduces endothelin production in the endothelium. PREDICTORS OF ATHEROSCLEROSIS PROGRESSION: The pressure kinetic construct has led to studies on the effects of antihypertensive drugs on flow disturbances in arteries leading, in turn, to studies on the relationship between mental stress and atherosclerosis. We have shown that the rise in blood pressure during mental stress is a stronger predictor of atherosclerosis progression than any of the standard risk factors such as age, sex, blood pressure, smoking, lipids or diabetes. The regression model used to make explicit the effect of stress responses on atherosclerosis not only offers a powerful new way to identify new causes of atherosclerosis, but also leads to a new quantitative trait, the rate of progression of atherosclerosis not explained by the Framingham risk factors. This trait, "unexplained atherosclerosis progression', in combination with three-dimensional ultrasound measurement of atherosclerosis, may lead to the discovery of new genes for atherosclerosis and thus help to manage the genetic heterogeneity of this disease.

Adaptation, Physiological↗
PubMed1995

Combination therapy with colestipol and psyllium mucilloid in patients with hyperlipidemia.

OBJECTIVE: To test whether combining psyllium mucilloid with half the usual dose of colestipol reduces the adverse effects associated with colestipol and maintains or increases its efficacy in the treatment of hyperlipidemia. This strategy might make bile acid sequestrants, which are seldom used because they cause adverse effects such as bloating and constipation, more tolerable and less expensive. DESIGN: A randomized, parallel-group, double-blind, controlled trial. SETTING: An outpatient clinic in a tertiary care hospital. PATIENTS: 121 patients who had moderate primary hypercholesterolemia (total cholesterol level > 6 mmol/L and < 8 mmol/L; triglyceride level < 3 mmol/L) after following a low-fat diet for 1 year (National Cholesterol Education Program Step Two diet). INTERVENTION: 5 g of cellulose placebo; 5 g of colestipol; 2.5 g of colestipol plus 2.5 g of psyllium; or 5 g of psyllium three times daily before meals for 10 weeks. MAIN OUTCOME MEASURES: At baseline and at weeks 4 and 10, fasting blood lipid levels and apoprotein concentrations were measured and a quality-of-life instrument was completed. RESULTS: A combination of 2.5 g of psyllium and 2.5 g of colestipol was better tolerated than and as effective as either 5 g of colestipol alone or 5 g of psyllium alone. The combination therapy and colestipol alone did not differ significantly with respect to changes in individual lipid values. The ratio of total cholesterol to high-density lipoprotein cholesterol (HDL) was reduced by 18.2% (95% CI, 12.3% to 24%) with the combination therapy; by 10.6% (CI, 2.0% to 15.4%) with colestipol alone; by 6.1% (CI, 1.5% to 10.6%) with psyllium alone; and by 0.1% (CI, -4.8% to 7%) with placebo (P = 0.0002). Combination therapy reduced the ratio of total cholesterol to HDL significantly more than did colestipol alone or psyllium alone (P < 0.05). CONCLUSIONS: These findings suggest that adding psyllium to half the usual dose of bile acid sequestrant resins maintains the efficacy and improves the tolerability of these resins.

Adult↗
PubMed1995

Pharmacokinetics of the combination of fluvastatin and gemfibrozil.

High-risk patients with dyslipidemias resistant to diet and single-agent pharmacotherapy may require combination therapy to achieve target levels of low density lipoprotein, triglycerides, and high density lipoprotein. Combinations of fibrates and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are effective, but because of safety concerns related to myopathy and rhabdomyolysis, it is important to consider the possibility of pharmacokinetic interactions when such combinations are used. In this study, the area under the curve, maximum plasma concentration, and time to maximum concentration for fluvastatin and gemfibrozil are compared, when used alone and in combination, in patients with hyperlipidemia and either coronary or carotid atherosclerosis, or a family history of coronary artery disease. A total of 17 patients were studied in a random sequence, open-label, crossover study of fluvastatin at 20 mg twice daily, gemfibrozil at 600 mg twice daily, and the combination of the 2 drugs. No significant difference was observed in area under the curve, maximum plasma concentration, and time to maximum concentration when comparing the combination with each drug alone. These pharmacokinetic data add support to the clinical observations that the combination of fluvastatin and gemfibrozil is both effective and safe.

Anticholesteremic Agents↗
PubMed1995

The acetylcholinesterase oxime reactivator HI-6 in man: pharmacokinetics and tolerability in combination with atropine.

In a double-blind, placebo-controlled, single-dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI-6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI-6 peak concentration (Cmax) and area under the concentration-time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI-6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean +/- SD time to maximum plasma HI-6 concentration (tmax = 0.69 +/- 0.21 h, n = 16), and absorption half-life (t/2a = 0.17 +/- 0.05 h) indicated rapid onset of effect. The volume of distribution (Vd = 0.25 +/- 0.04 L kg-1 TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 +/- 52 mL min-1) and short apparent elimination half-life (t/2e = 1.15 +/- 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance CLr = 137 +/- 33 mL min-1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 +/- 10%) indicated substantial non-renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine, and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI-6 suggest it may be a superior oxime antidote against nerve agent poisoning.

Adolescent↗
PubMed1995

Prognosis for patients following a transient ischemic attack with and without a cerebral infarction on brain CT. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Group.

BACKGROUND: Although cerebral infarctions are commonly observed on brain CTs of patients with TIAs, their prognostic importance is unknown. METHOD: The association between appropriately sited brain infarctions (ie, lesions located in the anterior circulation of the brain and ipsilateral to the symptomatic stenosed carotid artery) visualized on CT and the risk of subsequent stroke was assessed by Cox proportional hazards regression in 164 patients presenting with TIA (and no history of previous stroke) and severe angiographically defined carotid stenosis (70 to 99%) from the North American Symptomatic Carotid Endarterectomy Trial. RESULTS: Patients with a TIA and CT-verified brain lesions were older and were more likely to have higher degrees of carotid stenosis and carotid plaque ulceration, a longer duration of symptoms, and a history of hypertension. With regard to prognosis, after adjusting for all known risk factors (patient characteristics) in a regression analysis, the presence of ischemic lesions observed on CT was not associated with an increased risk of ipsilateral stroke at 2 years (adjusted hazard ratio = 1.00; 95% CI: 0.39 to 2.58; p value = 0.99). CONCLUSION: Considered in combination with other patient characteristics, the mere presence of an appropriately sited cerebral infarction on CT does not alter the prognosis (risk of ipsilateral strokes) of severely stenosed patients with TIA. Therefore, there is no clinical rationale in differentiating patients with TIA on the basis of CT findings alone.

Aged↗
PubMed1995

Advances in atherosclerosis.

In the past few years major advances have changed the way we think about atherosclerosis. Treatments for hyperlipidaemia not only regress angiographic stenosis and reduce coronary mortality; in meta-analysis, and in large trials of secondary prevention, they appear to reduce overall mortality. Reduction in events precedes regression of stenosis, partly through stabilization of plaque, and partly by reversal of the endothelial dysfunction caused by oxidized LDL. The study of lipid disorders has been advanced by new understanding of the role of apolipoproteins and lipoprotein (a). Significant advances have also been made in the understanding of effects of angiotensin, fibrinogen, homocysteinaemia, platelets, genetics of atherosclerosis, autoimmunity, flow disturbances and wall stress. Most importantly, because of a revolution in our understanding of the endothelium, we can now begin to make sense of some of the effects of risk factors such as lipids, menopause, flow disturbances, and pressure, to begin to understand atherosclerosis, arterial remodelling and the protective effect of oestrogen in a new light. These changes will profoundly affect the way we practise vascular medicine and neurology, and will give us powerful new ways to help our patients.

Adult↗
PubMed1995

Grapefruit juice-felodipine interaction: reproducibility and characterization with the extended release drug formulation.

1. Felodipine 10 mg extended release was administered with 250 ml regular-strength grapefruit juice or water in a randomized crossover manner followed by a second grapefruit juice treatment in 12 healthy men. The pharmacokinetics of felodipine and primary oxidative metabolite, dehydrofelodipine, were evaluated. 2. Initial grapefruit juice treatment increased felodipine AUC (mean +/- s.d.; 56.6 +/- 21.9 vs 28.1 +/- 11.5 ng ml-1 h; P < 0.001) and Cmax (8.1 +/- 2.5 vs 3.3 +/- 1.2 ng ml-1; P < 0.001) compared with water. Felodipine tmax (median; 2.8 vs 3.0 h) and t1/2 (7.3 +/- 3.7 vs 6.9 +/- 3.6 h) were not altered. 3. Readministration of felodipine with grapefruit juice produced mean felodipine AUC (61.5 +/- 32.2 ng ml-1 h) and Cmax (8.4 +/- 4.8 ng ml-1) which were similar to the initial grapefruit juice treatment 1-3 weeks previously. Felodipine AUC (r = 0.73, P < 0.01) and Cmax (r = 0.69, P < 0.02) correlated between grapefruit juice treatments among individuals. 4. The % increase in felodipine AUC with the initial grapefruit juice treatment compared with water correlated with the % increase in felodipine Cmax among individuals (r = 0.80, P < 0.01). Dehydrofelodipine AUC (74.7 +/- 28.7 vs 48.5 +/- 16.3 ng ml-1 h; P < 0.01) and Cmax (12.1 +/- 2.9 vs 7.9 +/- 2.6 ng ml-1; P < 0.01) were augmented with grapefruit juice compared with water.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Migrainous stroke.

Explore the source record for details and available documents.

Cerebrovascular Disorders↗
PubMed1994

Effects of antihypertensive drugs on flow disturbances: nifedipine, captopril, and metoprolol evaluated by quantitative spectral analysis of Doppler flow patterns in patients with carotid stenosis.

Hemodynamic theories of atherogenesis suggest that flow disturbances (departures from laminar flow including high and low shear) and increases in heart rate may be important in the initiation, progression, and complications of atherosclerosis such as dissection and embolism. It is therefore desirable to evaluate the effects of antihypertensive drugs on the occurrence of such flow disturbances. Effects of metoprolol, nifedipine, and captopril were studied, by quantitative spectral analysis, in 20 patients with carotid stenosis to evaluate 3 indices of disturbed flow: peak velocity, spectral broadening index and window index (WI). Heart rate (HR), and the product of WI by HR, were improved (reduced) significantly by metoprolol (p < 0.05), and worsened by nifedipine (p < 0.05), but most of the effect was due to effects on heart rate. These findings suggest that most of the benefit of antihypertensive drugs on flow disturbances can be identified by counting heart rate. Further developments will require improved methods for quantitation of flow disturbances.

Aged↗
PubMed1993

Report of the Canadian Hypertension Society Consensus Conference: 4. Hypertension in the elderly.

Several knowledge gaps, which made evidence-based guidelines impossible in 1985, have since been filled. There is now unequivocal evidence that treatment of isolated systolic hypertension benefits elderly patients, as does treatment beyond the age of 75 years. Pseudohypertension, although occasionally problematic, is not common and is not a reason to neglect the treatment of elderly patients, including those with isolated systolic hypertension. In general, long-term antihypertensive treatment of the elderly is well tolerated and does not cause important decreases in mental function. Comparative drug studies continue to accumulate; most show no clinically significant general differences between drugs, aside from the somewhat decreased efficacy and tolerability of beta-blockade in elderly patients. As in the young, certain drugs may be preferred in the presence of other conditions--e.g., congestive heart failure or diabetes.

Aged↗
PubMed1993

Effect of grapefruit juice and naringin on nisoldipine pharmacokinetics.

The bioavailability of some dihydropyridine calcium antagonists can be markedly augmented by grapefruit juice and may involve the bioflavonoid naringin. The pharmacokinetics of nisoldipine coat-core tablet were studied in a Latin square-designed trial in which 12 healthy men were administered the drug with water, grapefruit juice, or encapsulated naringin powder at the same amount as that assayed in the juice. Compared with water, grapefruit juice increased the maximum concentration of nisoldipine to 406% +/- 73% (mean +/- SEM; range, 107% to 836%; p < 0.001), increased the area under the plasma concentration-time curve to 198% +/- 46% (range, 81% to 682%; p < 0.001), and reduced time to reach maximum nisoldipine concentration to 58% +/- 9% (range, 13% to 100%; p < 0.01), probably by inhibition of presystemic metabolism and possibly by enhancement of drug dissolution. The interaction could not be predicted from baseline pharmacokinetics with water and resulted in greater interindividual variability. The naringin capsule did not change nisoldipine pharmacokinetics. All treatments produced minor effects on supine blood pressure and heart rate, probably because subjects were normotensive. Current information supports the cautioning of patients about concomitant ingestion of grapefruit juice and nisoldipine.

Adolescent↗
PubMed1993

Grapefruit juice--felodipine interaction: mechanism, predictability, and effect of naringin.

Grapefruit juice produces a marked and variable increase in felodipine bioavailability. The pharmacokinetics of felodipine and its single primary oxidative metabolite, dehydrofelodipine, were studied after drug administration with 200 ml water, grapefruit juice, or naringin in water at the same concentration as the juice in a randomized crossover trial of nine healthy men. With grapefruit juice, mean +/- SEM felodipine area under the plasma concentration-time curve (AUC) and peak plasma concentration (Cmax) were 206% +/- 23% (range, 123% to 330%, p < 0.01) and 170% +/- 24% (range, 127% to 310%, p < 0.02), respectively, compared with water. Dehydrofelodipine/felodipine ratios for AUC (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) and felodipine Cmax (1.5 +/- 0.2 versus 2.2 +/- 0.2, p < 0.001) were reduced, consistent with inhibition of presystemic felodipine metabolism. Intersubject changes in felodipine and dehydrofelodipine AUC supported inhibition of both primary and secondary metabolic steps as a mechanism. The interaction could not be predicted from baseline pharmacokinetics with water and did not result in more consistent bioavailability among individuals. Naringin solution produced much less of an interaction, showing that other factors were important.

Adult↗
PubMed1992

Differences in metabolism of time-release and unmodified nicotinic acid: explanation of the differences in hypolipidemic action?

The possibility that differences in metabolism might underly the differences in efficacy and toxicity between time-release and unmodified formulations of nicotinic acid was investigated by measuring 24-hour urinary excretion of metabolites in 10 subjects who received both forms. Nicotinic acid has two metabolic fates: formation of nicotinamide adenine dinucleotide (NAD) and formation of nicotinuric acid, the glycine conjugate of nicotinic acid. Catabolism of NAD releases nicotinamide, which is subsequently methylated and/or oxidized to form a number of metabolites, with 2-pyridone predominating. Excretion of nicotinuric acid was more than four times greater when subjects took unmodified nicotinic acid than when they took time-release nicotinic acid (78.2 and 18.8 mg, respectively). In contrast, excretion of 2-pyridone with unmodified nicotinic acid was only 30% more than with time-release nicotinic acid (171.0 and 129.9 mg, respectively). These results demonstrate a marked difference in the metabolism of unmodified and time-release nicotinic acid. It is proposed that nicotinyl coenzyme A (CoA), the metabolic intermediate in the formation of nicotinuric acid, mediates some of the hypolipidemic actions of nicotinic acid, as the acyl-CoA esters of xenobiotics, including clofibrate, have been shown to interfere with lipid metabolism.

Adult↗
PubMed1991

Interaction of citrus juices with felodipine and nifedipine.

Six men with borderline hypertension took felodipine 5 mg with water, grapefruit juice, or orange juice. The mean felodipine bioavailability with grapefruit juice was 284 (range 164-469)% of that with water. The dehydrofelodipine/felodipine AUC ratio was lower, diastolic blood pressure lower, and heart rate higher with grapefruit juice than with water. Vasodilatation-related side-effects were more frequent. Orange juice had no such effects. Six healthy men took nifedipine 10 mg with water or grapefruit juice; the bioavailability with grapefruit juice was 134 (108-169)% of that with water.

Biological Availability↗