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Biomedical subjects

J D Spence

Publications and source records attributed to J D Spence.

At least 91 records · Page 5Linked to original sources
PubMed1991

Tolerance to nicotinic acid flushing.

The mechanism of tolerance to nicotinic acid flushing was determined in subjects during a 5-day course of treatment. Objective measures of skin blood flow were used to confirm the development of tolerance. Plasma levels of nicotinic acid showed marked intraindividual variability but were not decreased with the development of tolerance. However plasma levels of 9-alpha 11-beta prostaglandin F2, a stable metabolite of prostaglandin D2, became undetectable in most subjects with the development of tolerance. Thus tolerance is not associated with decreased levels of nicotinic acid or development of tolerance to the prostaglandin mediator, but with decreased levels of the mediator.

Administration, Oral↗
PubMed1991

Prospective study of ambulatory monitoring and echocardiography in borderline hypertension.

This study was done to evaluate prospectively whether ambulatory blood pressure recordings (AMB) (Spacelabs) would more accurately predict increases in left ventricular mass (LVMI) than did blood pressures measured by a nurse in the absence of a physician, using a random zero sphygmomanometer (RZ) and an automated oscillometric digital device (BPI). One hundred patients being followed by their family physician with a diagnosis of borderline hypertension with at least two office diastolic readings of 90-100 mmHg were studied at baseline and every six months for two years with RZ, BPI, and AMB; echocardiography was repeated annually. Over sixty percent of the patients were normotensive in the research unit by AMB, BPI, and RZ at entry. At entry 24% of patients had increased LVMI greater than 110 g/m2 (left ventricular enlargement, LVE) and at 2 years 32% had LVE. Stepwise linear regression was used to determine which measurement was most predictive of LVE at two years. It showed that the most predictive were baseline echo LVMI and BPI systolic pressure. These two variables predicted 45% of the risk with no other variables contributing significantly. However, when BPI was removed, AMB systolic pressure contributed significantly, though the strength of prediction was reduced to 40%. In a subset of 40 patients who underwent mental stress with mental arithmetic and mirror tracing, the magnitude of systolic pressure elevation during mental stress correlated significantly with LVE over 2 years (R = 0.54, p less than 0.001).

Adolescent↗
PubMed1990

Hemodynamic and endocrine effects of mental stress in untreated borderline hypertension.

Mental arithmetic and mirror tracing were compared in 40 untreated patients with borderline hypertension, tested in random sequence in standardized protocols. Both tasks significantly increased systolic and diastolic blood pressure, heart rate, cardiac index, plasma renin, and decreased peripheral resistance. Mental arithmetic also increased cholesterol, triglycerides and HDL; plasma catecholamines were not changed significantly. Lipid changes were correlated with blood pressure changes. These methods will be useful in exploring the relationships between hemodynamic reactivity to stress, and the presence and progression of atherosclerosis, as well as testing the effects of antihypertensive drugs on stress-induced changes that may influence atherosclerotic complications of hypertension.

Adult↗
PubMed1989

Intramuscular administration of iron during long-term chelation therapy with 2,3-dimercaptosuccinic acid in a man with severe lead poisoning.

2,3-Dimercaptosuccinic acid (DMSA) an investigational chelant structurally similar to dimercaptopropanol (BAL), offers the advantage of not depleting iron stores on which basis it would not seem to form a toxic chelate with iron. We report the case of a man with a formidable body burden of lead (Pb) and depleted iron stores who was given iron intramuscularly during a defined period of long-term retreatment with DMSA. Initiation of retreatment with DMSA, 30 mg/kg/day given orally in three divided doses for the first 7 days markedly enhanced Pb diuresis, entailed a pronounced fall in blood Pb and abolished symptoms of Pb poisoning. Continuation of retreatment with two-thirds the initial DMSA dose for an added 15 days maintained blood Pb at sustained low levels. Iron sorbitol administered intramuscularly during this period in individual doses of 100 mg of elemental iron given 3 days apart to a conservative total of 400 mg produced no untoward effects, suggesting that a toxic chelate between iron and DMSA was not formed. Serum ferritin entered the normal range and there was virtually an immediate significant decrease in erythrocyte protoporphyrin. Together with discernible increases in haemoglobin, haematocrit and MCV, this pointed to enhanced iron utilization. Since iron utilization is curtailed by high concentrations of Pb, the immediacy and magnitude of the post-chelation rebound in blood Pb precluded iron administration at any other stage. From these data, DMSA emerges as a uniquely versatile new chelant. Suitable for long-term administration, it permits the simultaneous parenteral administration of iron during dose-related sustained decreases in blood Pb.

Adult↗
PubMed1989

Measurement of atherosclerosis: development of an atherosclerosis severity index.

Treatment of hypertension has succeeded in preventing the complications attributable to pressure, including heart failure and the arteriolar complications such as brain hemorrhage and renal failure. Recent understanding that antihypertensive drugs have effects on lipoproteins and flow disturbances that may be important in atherosclerosis progression, and the recent development of drugs that are more effective in treating hyperlipidemia, have given impetus to the design of studies to test whether interventions are anti-atherosclerotic. Since studies depending on clinical endpoints by necessity consume vast resources, it is desirable to develop methods for measurement of atherosclerosis, in order to make it possible to conduct intervention studies efficiently. Because angiographic methods are costly and associated with risk, and many patients are unable or unwilling to undergo followup angiography at the end of a study, we are developing an atherosclerosis severity index based on clinical and noninvasive ultrasound assessment. This scale can be used as a surrogate outcome in place of, or complementary to angiographic measurement of atherosclerosis, to avoid costly loss of subjects in intervention studies. It has the additional advantage that it is suitable for repeated assessment over time, permitting the power of analyses such as life table analysis which look at time to development of endpoints.

Angiography↗
PubMed1989

Ethanol enhances the hemodynamic effects of felodipine.

The acute hemodynamic and pharmacokinetic interactions between the vasodilating/diuretic drugs ethanol and felodipine, a 1,4-dihydropyridine calcium entry blocker, were assessed in 10 patients with untreated borderline hypertension. A non-intoxicating dose of ethanol or placebo was administered in a randomized, crossover, double-blind manner followed by felodipine 5 mg. Maximum hemodynamic effects occurred at four hours. Felodipine plus ethanol decreased mean (+/- SE) supine total peripheral resistance (13 +/- 2 vs 17 +/- 2 mmHg/L/min, p = 0.05) and diastolic blood pressure (68 +/- 3 vs 75 +/- 2 mmHg, p less than 0.05) associated with increased heart rate (72 +/- 3 vs 67 +/- 2 bpm, p less than 0.05) and cardiac index (3.7 +/- 0.4 vs 3.0 +/- 0.3 L/min/m2, p less than 0.05) more than felodipine alone. Greater differences were apparent in standing blood pressure. Co-administration of ethanol decreased standing systolic (113 +/- 8 vs 126 +/- 5 mmHg, p less than 0.01) and diastolic (69 +/- 5 vs 82 +/- 3 mmHg, p less than 0.01) blood pressure to a greater degree, but heart rate was not altered (87 +/- 6 vs 84 +/- 3 bpm). Substantial four hour diuresis occurred with both treatments (807 +/- 126 vs 806 +/- 169 ml). Adverse effects were frequent but most often occurred with felodipine plus ethanol (17 vs 11) as a result of postural lightheadedness (5 vs 1) related to hypotension. Felodipine bioavailability was not influenced by ethanol. However felodipine plasma concentrations greatly exceeded the expected concentrations, possibly due to a pharmacokinetic interaction with the grapefruit juice vehicle. Ethanol can enhance felodipine hemodynamics to produce clinically relevant adverse effects.

Adult↗
PubMed1989

Quantitative spectral analysis of carotid Doppler signal: evaluation as a method for measurement of drug effects.

Hemodynamic theories of atherogenesis suggest that the endothelial injury that initiates the process, as well as complications such as dissection and embolism, may be caused by arterial flow disturbances. Although treatment of high blood pressure prevents arteriolar complications such as brain haemorrhage and nephrosclerosis, little progress has been made in prevention of atherosclerotic events such as myocardial infarction. It is therefore desirable to develop methods for measuring the effects of antihypertensive drugs on the occurrence of such flow disturbances. We have evaluated quantitative spectral analysis of carotid Doppler signals in normals and in patients with carotid stenosis, in crossover studies of metoprolol vs placebo. Twenty healthy volunteers and 20 patients with carotid stenosis were treated in two double-blind placebo-controlled complete crossover studies, in which each subject took metoprolol 100 mg per os, and matching placebo, 1 hr before carotid scanning. In normals, peak frequency, mean frequency, and window index (WI) were measured at each of 2 sites in the left common, external and internal carotid arteries. Spectral broadening index (SBI), the ratio (peak-mean)/mean, was computed for comparison with window index (WI), the ratio of the area under the first 100 msec of the 25th percentile velocity curve to the area under the 75th percentile curve. Peak frequency, SBI and WI measure the extent of disturbance of arterial flow patterns, i.e. the extent to which flow has become non-laminar. Heart rate was reduced significantly by metoprolol, and in the external carotid artery, metoprolol significantly reduced both peak and mean frequency. Window index was not significantly changed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Pathogenesis of atherosclerosis and its complications: effects of antihypertensive drugs.

Since hypertension is an important risk factor for atherosclerosis, it is logical to assume that treatment to lower blood pressure will prevent atherosclerosis. However, the relationship between hypertension and atherosclerosis is indirect and complex. Drugs that lower pressure will prevent heart failure and arteriolar complications such as renal failure or strokes caused by lacunar infarction or brain haemorrhage due to rupture of microaneurysms. However, there is little evidence that atherosclerotic complications can be reduced by lowering pressure. It is important to understand the pathogenesis of atherosclerosis and its complications, which are related to lipoproteins and arterial flow disturbances, in order to develop an approach to selecting those antihypertensive drugs which may prevent atherosclerotic complications related not only to initiation and progression of atherosclerotic plaques, but to the embolisation of platelet clumps or atherosclerotic debris, or events such as intraplaque haemorrhages, that lead to myocardial or cerebral infarction. Antihypertensive drugs have different effects on lipoproteins and on arterial flow disturbances that may have important implications for prevention. Alpha-blockers and drugs with beta 2 agonist activity have beneficial effects on lipoprotein profiles, ACE inhibitors and calcium channel antagonists have some anti-atherosclerotic effects in animal models, while beta-blockers have beneficial effects on flow disturbances and are anti-atherosclerotic in animal models and man. Future studies to determine how to prevent atherosclerotic complications in hypertensive patients will require methods for noninvasive measurement of atherosclerosis.

Animals↗
PubMed1987

Hypertension and atherosclerosis: effects of antihypertensive drugs on arterial flow patterns.

High blood pressure (BP) is associated with increased risk of vascular disease, including myocardial infarction and stroke. Since drugs that lower BP will reduce the risk of those complications of hypertension that are due to high pressure (strokes due to small-vessel disease, including lacunar infarction and intracerebral hemorrhage due to rupture of microaneurysms, heart failure, and renal failure), it has been assumed that such drugs would also reduce the risk of myocardial infarction due to atherosclerosis. However, in addition to hypertension, many other factors are involved in the atherosclerotic process including blood lipids such as cholesterol, blood platelets, and arterial flow disturbances such as turbulence and vortex formation. Some drugs that lower BP have unwanted effects on blood lipids and arterial flow patterns, which are thought to offset the benefit of BP reduction, whereas other drugs have beneficial effects on such factors. Ames has calculated that the adverse effects of antihypertensive drugs on lipids are enough to completely offset the benefit of treating mild hypertension. We have shown that antihypertensive drugs have different effects on blood velocity, and that these effects are associated with differences in the effects of drugs on arterial flow disturbances at the site of carotid stenosis in man, such that propranolol reduced, and hydralazine increased, the occurrence of abnormal high-velocity flow patterns associated with turbulence and vortex formation. In cholesterol-fed hypertensive rabbits (one-kidney Goldblatt), propranolol was more effective than hydralazine in preventing the occurrence of aortic atherosclerosis, even though hydralazine lowered blood pressure more effectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗
PubMed1986

Effect of non-steroidal anti-inflammatory drugs on control of hypertension by beta-blockers and diuretics.

The effect of sulindac on renal function and blood pressure was compared with those of placebo, piroxicam, and naproxen in 20 patients with primary hypertension being treated with a diuretic and a beta-blocker. Although the three non-steroidal anti-inflammatory drugs (NSAIDs) did not differ in their effect on renal function (weight, glomerular filtration rate, creatinine clearance) or on serum thromboxane and plasma 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha), blood pressure was significantly lower with sulindac than with placebo, piroxicam, or naproxen. These differences were associated with less renal cyclooxygenase inhibition by sulindac (reflected by urinary thromboxane B2 and 6-keto PGF1 alpha) than by other NSAIDs. The findings suggest that the blood pressure differences reflect vasodilation due to differences in the balance between systemic and renal effects of the NSAIDs.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Evaluation of once daily endralazine in hypertension.

Endralazine, a novel vasodilator related to hydralazine, exhibits a longer half-life and is only minimally influenced by acetylator status. The antihypertensive action of once daily endralazine has been studied in 17 patients previously controlled with an antihypertensive regimen which included hydralazine and a beta-blocker. Hydralazine was discontinued but other medications were unchanged. Pre-study dosage of hydralazine ranged from 25 mg b.i.d. to 50 mg g.i.d., mean daily dose 126.5 mg. Endralazine was started at a dose of 10 mg o.d. and increased by 10 mg to a maximum of 40 mg o.d. until seated DBP was controlled below 95 mmHg. All 17 patients completed the study. Seated BP significantly decreased from 147.5/99.7 to 133.8/83.9 and standing BP from 145.8/99.2 to 133.6/87.3 mmHg. Ten patients (59%) were successfully controlled with endralazine once daily but 7 patients required twice daily dosage schedules because of lack of BP control at 24 h after dosing or excessive hypotension shortly after dosing. Other adverse effects were headache, palpitations and fatigue. There was a statistically insignificant average weight gain of 1 kg but pedal edema was not observed. Endralazine is an effective antihypertensive agent with adverse symptoms similar to those experienced with hydralazine.

Acetylation↗
PubMed1986

Differential glomerular filtration rate in diagnosis of renovascular hypertension and follow-up of balloon angioplasty.

Two hundred nine hypertensive patients with high stimulated plasma renin levels were screened for renovascular hypertension using Tc-99m DTPA renal scintigraphy. Differential glomerular filtration rate (Diff-GFR) was obtained by integrating the area under the background-subtracted renogram of each kidney between 1 and 3 minutes. 50 patients who also had undergone selective renal angiography were divided into four groups according to Diff-GFR contribution by one of the kidneys. If one kidney contributed 45-50% of total GFR, this was regarded as normal. A Diff-GFR of less than 45% was very considered to be very suggestive of renovascular hypertension in the appropriate clinical setting, while a Diff-GFR of less than 20% indicated that the renal artery might not be amenable to successful balloon angioplasty. Diff-GFR following balloon angioplasty closely reflected the early clinical response of the patients--and in some cases progressive Diff-GFR improvement was observed several months later. Diff-GFR as a scintigraphic criterion for renovascular hypertension has a sensitivity of 93%, specificity of 74%, and accuracy of 85%.

Adolescent↗
PubMed1986

The arthritic patient with hypertension: selection of an NSAID.

Vasodilator prostaglandins produced in the renal medulla have a role in blood pressure regulation, beyond modulation of sodium and water retention. Systemic vasodilation resulting from effects of renomedullary prostaglandins lowers systemic vascular resistance, and administration of NSAIDs elevates blood pressure in hypertensive patients treated with diuretics and/or beta blockers, in patients with myocardial infarction, and in patients taking sympathomimetic agents such as phenylpropanolamine. Aspirin, which appears in the urine as salicylic acid (which has no effect on cyclooxygenase) has not been implicated as a drug which attenuates blood pressure control. Similarly, sulindac, the active sulfide metabolite of which is not filtered, does not inhibit renal synthesis of prostaglandins, though given in doses sufficient to inhibit serum thromboxane and 6-keto PGF 1-alpha. In a double-blind complete crossover study of blood pressure and renal function in hypertensive patients controlled with timolol-hydrochlorothiazide, sulindac lowered blood pressure significantly, whereas naproxen and piroxicam significantly raised blood pressure, in the absence of any effect on GFR, plasma renin, weight, creatinine clearance, or urinary sodium. It is suggested that for arthritic patients with hypertension, the NSAIDs of choice are aspirin and sulindac.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Amiloride with or without salbutamol versus placebo: effects on lipoproteins in hypertensive patients treated with timolol-hydrochlorothiazide.

Because thiazides and beta-blockers have adverse effects on lipoproteins, while magnesium repletion (shown to occur with amiloride) and beta 2 agonists improve lipids, we studied the effects of 3 months each of amiloride with and without salbutamol with and without placebo in a 2 X 2 factorial crossover study in which all patients took timolol-hydrochlorothiazide twice daily for 1 year. A total of 118 subjects entered, and 97 patients completed all four crossovers of amiloride + salbutamol, amiloride + placebo, salbutamol + placebo and placebo + placebo. No significant differences were seen among the four study regimens with respect to blood pressure, total cholesterol, triglycerides or high-density lipoproteins (HDL). The study power was 99% for total cholesterol, 46% for triglycerides and 93% for HDL. Timolol-hydrochlorothiazide had no significant effect, suggesting that the use of such drugs to offset the adverse effects of antihypertensive drugs on lipoproteins is not effective; the selection of alternative antihypertensive agents appears to be a preferable strategy.

Albuterol↗
PubMed1985

Effects of triamterene and amiloride on urinary sediment in hypertensive patients taking hydrochlorothiazide.

In a crossover study of 26 hypertensive patients, the effects of triamterene (50 mg/day) and amiloride (5 mg/day) on urinary sediment were compared. Each drug was given for one month and all patients also received hydrochlorothiazide (50 mg/day). An abnormal urinary sediment--evident grossly as a reddish-brown precipitate after routine staining procedures and microscopically as characteristic reddish-brown crystals and casts, as previously described--was identified in 14 of 26 (54%) triamterene urine samples but in none of the amiloride samples. Results of renal function tests were similar for both drugs. In a clinic population of more than 1000 hypertensive patients over 4 years, interstitial nephritis was diagnosed in 4, all of whom were taking a triamterene-containing combination diuretic. It is possible that triamterene is a factor in the aetiology of interstitial nephritis.

Amiloride↗
PubMed1985

Spectrum of benign intracranial hypertension in children and adolescents.

A review of the most recent 23 cases of benign intracranial hypertension (BIH), admitted to the War Memorial Children's Hospital in London, Ontario, provided a compendium of the clinical manifestations of this disorder in children and adolescents. Although CT scanning lets one feel more secure in making such a diagnosis, pitfalls still exist. The sex ratio was 11 males to 12 females. Age groupings were: 0-6 years (2 patients); 7-12 years (10); 13-17 years (11). No postviral etiologies were encountered in patients more than 13 years of age. In only 6 cases could no definite etiology be established. Of great importance was the recognition of the condition in 12 patients who did not have papilledema. Elevated intracranial pressure was proven in 8 of these by lumbar CSF pressure monitoring, in 1 by lumbar punctures and in 1 infant with split cranial sutures. Absence of papilledema was confirmed by ophthalmological examination. Transient visual obscurations were very common in this group. In 6 patients, persistent signs and symptoms in spite of vigorous drug therapy prompted lumboperitoneal shunting, with immediate relief of symptoms in all. In only 1 case has the diagnosis of BIH proven to be in error. A warning leak from an aneurysm caused papilledema and headache, and a normal CT scan supported the diagnosis until the patient had a major hemorrhage weeks later. BIH has a variety of causes in children and adolescents, and papilledema is not a prerequisite for diagnosis.

Acetazolamide↗