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Biomedical subjects

L G Howes

Publications and source records attributed to L G Howes.

At least 37 records · Page 2Linked to original sources
PubMed1998

Calcium antagonists and cancer. Is there really a link?

Recent publications have raised concerns about a possible link between calcium antagonist therapy and the development of cancer. Comparisons of the methodology and results of these studies with other studies where an association between calcium antagonist therapy and cancer has not been apparent suggests that the association is most likely to be due to selection bias or chance. Clinical and biochemical studies have not produced a consistent plausible mechanism for a causative link between calcium antagonists and the development of cancer. Further prospective data that will be available from long-term morbidity and mortality trials of the use of calcium antagonists in cardiovascular diseases will be of value in establishing the safety of these drugs.

Animals↗
PubMed1998

Angiotensin receptor antagonists and ACE inhibitors.

BACKGROUND: ACE inhibitors are valuable and effective drugs in the treatment of hypertension, heart failure, myocardial infarction and nephropathy. Angiotensin receptor antagonists, which have recently been introduced into clinical practice, have the potential to replace ACE inhibitor therapy in many patients. OBJECTIVE: To review the mechanisms of action, indications and side effects of ACE inhibitors and angiotensin receptor antagonists and to highlight similarities and differences between the two drug classes. DISCUSSION: Angiotensin receptor antagonists have the theoretical advantage of being more effective in blocking the effects of angiotensin II at angiotensin type I receptors. The potential disadvantage of not potentiating bradykinin may be compensated by the unopposed action of angiotensin II on vascular angiotensin type II receptors, which appear to mediate similar beneficial cardiovascular effects to bradykinin. Angiotensin II receptor antagonists have a lower incidence of adverse effects than ACE inhibitors as they do not produce cough and appear much less likely to produce angioedema. Although ACE inhibitors are the most commonly prescribed antihypertensive drug class in Australia, they are underused for the treatment of heart failure and left ventricular dysfunction following myocardial infarction. Angiotensin receptor antagonists may become alternative therapies to ACE inhibitors in these disorders. However, at present they are only indicated for the treatment of hypertension.

Angiotensin I↗
PubMed1997

Lipoproteins and cardiovascular reactivity.

The observation that relatively short periods of cholesterol lowering therapy can reduce the incidence of coronary artery disease events has prompted interest in the short term effects of lipoproteins on cardiovascular responsiveness. Numerous studies in animals and humans have demonstrated that oxidized LDL-cholesterol can impair endothelial dependent vasodilation in coronary arteries and peripheral resistance vessels. Reduction of plasma LDL-cholesterol levels in hypercholesterolaemic patients improves nitric oxide mediated vasodilator responses in the coronary and peripheral circulation. LDL-cholesterol also potentiates responses to vasoconstrictors such as noradrenaline and endothelin-1 in the absence of endothelium, possibly by enhancing calcium influx into vascular smooth muscle cells. Pharmacological reduction of plasma LDL-cholesterol levels has been shown to reduce blood pressure responses to intravenous infusions of pressor hormones and to stress. However, the relative contribution of changes in endothelial dependent vasodilation and vasoconstrictor or inotropic responses remains to be established. Short term changes in LDL-cholesterol produce changes in cardiovascular responsiveness that may influence the development of ischaemic events.

Animals↗
PubMed1997

Relationship between serum parathyroid hormone levels in the elderly and 24 h ambulatory blood pressures.

BACKGROUND: An association between serum parathyroid hormone (PTH) levels in normotensive elderly subjects and blood pressure values had been reported. OBJECTIVE: To examine the relationship between PTH levels and other biochemical markers of calcium metabolism in elderly subjects and 24 h ambulatory blood pressures. METHODS: We performed 24 h ambulatory blood pressure recordings for 123 independent elderly subjects aged 63-88 years using a SpaceLabs 90207 recorder. Mean night-time blood pressures were calculated from the average of readings during sleep; mean daytime blood pressures were calculated from the remaining recordings. Demographic data and details concerning the alcohol consumption and medication usage of the subjects were recorded. Serum PTH, 25-hydroxy-vitamin D, albumin, renin, aldosterone, noradrenaline, creatinine and calcium levels were measured. RESULTS: Fifty-five patients were being administered antihypertensive therapy. Serum PTH levels correlated to the nocturnal systolic blood pressure (SBP; beta = 0.29, P = 0.002), nocturnal diastolic blood pressure (DBP), daytime SBP and mean 24 h SBP on univariate and multivariate analysis. Aldosterone levels were related to nocturnal SBP in univariate analysis (beta = 0.21, P = 0.02) but the relationship was weakened when PTH levels were included in the analysis (beta = 0.16, P = 0.09). Nocturnal, daytime and mean 24 h blood pressures were not significantly related to serum calcium, 25-hydroxy-vitamin D, age, body mass index and alcohol consumption. Sex was a significant predictor of the DBP, men having higher levels than did women (daytime DBP beta = 0.29, P = 0.001). CONCLUSIONS: Serum PTH levels are related strongly to the blood pressure, particularly the nocturnal blood pressure in the elderly. It is not known whether PTH levels are a consequence or a cause of the elevation in blood pressure.

Age Factors↗
PubMed1997

Acute effects of oral glibenclamide on blood pressure and forearm vascular resistance in diabetics.

1. To determine the effects of an acute oral dose of glibenclamide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K+ATP channel activating vasodilator diazoxide, a placebo-controlled, double-blind cross-over study was performed in eight male volunteers with non-insulin-dependent diabetes mellitus. 2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75-30 mg/kg per min) and noradrenaline (25-100 ng/kg per min) were measured by venous occlusion plethysmography. 3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01). 4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra-arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K+ATP channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.

Adenosine Triphosphate↗
PubMed1997

Blood pressure changes in acute cerebral infarction and hemorrhage.

BACKGROUND AND PURPOSE: We sought to investigate the changes in blood pressure (BP) that occur after hospitalization of patients with different types of acute stroke. METHODS: Twenty-four-hour ambulatory BP monitoring was performed on days 1 and 7 after admission to the hospital in 72 patients with acute stroke (44 thromboembolic strokes, 18 lacunar infarcts, and 10 intracerebral hemorrhages) and in 22 control patients. Stroke was categorized clinically into the above stroke subtypes with radiological confirmation. The controls were patients admitted with a range of acute medical problems other than stroke who were not severely ill or in significant pain. Left ventricular hypertrophy was assessed with echocardiography. Multiple linear regression was used to determine the effect of stroke category on BP after adjustment for the effects of potential confounders. RESULTS: Patients with thromboembolic and lacunar strokes had significantly higher systolic BP (SBP) on day 1 than control subjects (mean, 8.6% and 13.2%, respectively). Diastolic BP (DBP) was also significantly higher for patients with thromboembolic and lacunar strokes on day 1 (mean, 11.7% and 14.6%, respectively). Patients with intracerebral hemorrhage had SBP 9.7% and DBP 6.3% higher than control subjects on day 1, but the results did not achieve statistical significance. By day 7 there was no significant difference in SBP or DBP between the stroke subgroups and control subjects. CONCLUSIONS: BP is elevated after stroke but resolves spontaneously after 7 days. This transient elevation in BP does not appear to result solely from the stress of hospitalization.

Acute Disease↗
PubMed1997

Comparative effects of glibenclamide and metformin on ambulatory blood pressure and cardiovascular reactivity in NIDDM.

OBJECTIVE: To compare the effects of chronic glibenclamide and metformin therapy on blood pressure (BP) and cardiovascular responsiveness in patients with NIDDM. RESEARCH DESIGN AND METHODS: Fourteen patients with NIDDM received metformin or glibenclamide for 1 month in a double-blind, randomized crossover study. At the end of each treatment period, patients were tested for forearm vascular responsiveness to intrabrachial arterial infusion of diazoxide (an ATP-sensitive potassium channel opener), acetylcholine, sodium nitroprusside, and norepinephrine, BP responses to intravenous infusions of NE and angiotensin II, BP responses to cold pressor testing and isometric exercise, and 24-h ambulatory BP monitoring. RESULTS: Metformin and glibenclamide produced similar glycemic control. Mean 24-h BPs did not differ between the two groups, but mean 24-h heart rates were significantly lower (75 +/- 6 bpm vs. 80 +/- 6 bpm) on glibenclamide therapy than on metformin. Plasma norepinephrine levels were significantly higher on glibenclamide (6.41 +/- 1.77 vs. 4.26 +/- 1.54 mmol/l, P < 0.01), and systolic BP responses to intravenous norepinephrine and angiotensin II were significantly higher on glibenclamide than on metformin (P < 0.02 and P < 0.05, respectively). Systolic BP responses to cold pressor testing appeared higher on glibenclamide than on metformin, but the difference did not quite achieve statistical significance (P = 0.052). Baseline forearm vascular resistance did not differ between the two drugs, nor did forearm vascular resistance responses to diazoxide, acetylcholine, sodium nitroprusside, and norepinephrine differ. CONCLUSIONS: Glibenclamide therapy is accompanied by greater systolic BP responses to norepinephrine and angiotensin II and higher plasma norepinephrine levels than those that occur on metformin therapy. Lower heart rates on glibenclamide therapy despite evidence of greater sympathetic activity suggests that glibenclamide may have negative chronotropic effects.

Acetylcholine↗
PubMed1997

Effects of dietary lipid modification on adrenoceptor-mediated cardiovascular responsiveness and baroreflex sensitivity in normotensive subjects.

To examine the effects of short-term dietary lipid modification on alpha- and beta-adrenoceptor-mediated cardiovascular responsiveness, 19 normal volunteers consumed either a high-fat or a low-fat diet for 2 weeks in an open, randomized, crossover study of 6 weeks' duration. Diets were balanced for sodium and potassium content. Adrenoceptor-mediated cardiovascular responsiveness was assessed by measuring blood pressure and heart rate responses to incremental infusions of phenylephrine and isoprenaline. Baroreflexes were studied by examining heart rate responses to phenylephrine and to the Valsalva manoeuvre. Total plasma cholesterol and low-density lipoprotein cholesterol levels both fell significantly (by 22% and 26%, respectively), on the low-fat compared with the high-fat diet, as did resting supine blood pressures and heart rate (by 6 mmHg systolic and 3 mmHg diastolic, and 5 beats/min). These changes were accompanied by a significant reduction in the systolic blood pressure response to isoprenaline. Blood pressure responses to phenylephrine and baroreflex sensitivity did not change. These results suggest that dietary fat intake alters cardiac beta-adrenergic reactivity without significant effects on vascular alpha-adrenoceptor mediated responses or baroreflexes.

Adult↗
PubMed1997

Alcohol consumption and blood pressure in recently hospitalised patients.

One-thousand-four-hundred-and-fifty-three patients admitted to a teaching hospital, haemodynamically stable and not severely ill nor in significant pain, were interviewed within 48 h of admission and demographic data and a detailed drinking history were obtained. Supine blood pressures (BP) were recorded on the day following admission. The mean age of the population was 60.5 +/- 19.9 years (range 16-99 years) and the mean reported alcohol consumption was 67.8 +/- 273 g/week (range 0-6125 g/ week). Thirty-six percent of patients were currently receiving antihypertensive drug therapy. On multivariant analysis, reported alcohol intake was not significantly related to systolic BP (beta = 0.000, p = 0.902) or diastolic BP (beta = 0.028, p = 0.281). Age (beta = 0.331, p = 0.0001) and body weight (beta = 0.121, p = 0.0002) were significant independent predictors of systolic BP, and body weight was a significant independent predictor of diastolic blood pressure (beta = 0.207, p < 0.0001). A relationship between alcohol consumption and blood pressure was not apparent in this population of patients following admission to hospital. A positive association between alcohol consumption and blood pressure may not be a universal finding and may be contributed to by a "white coat" effect.

Adolescent↗
PubMed1997

Nocturnal fall in blood pressure in the elderly is related to presence of hypertension and not age.

AIMS: To determine whether the reduced nocturnal fall in blood pressure (BP) reported in elderly hypertensives is due to ageing or to the presence of hypertension. METHODS: Twenty-four hour ambulatory BP recordings of 68 normotensive elderly were compared with those of 55 elderly treated hypertensives, aged 63-88 years. Mean night-time BPs were calculated from the average of readings during sleep and mean daytime BPs from the remaining recordings. The maximum day-night BP differences were calculated. Plasma renin, aldosterone and noradrenaline were measured. RESULTS: Normotensive subjects were aged 72.0 +/- 4.7 years and treated hypertensives 73.7 +/- 4.9 years (p = 0.049). Normotensives had lower systolic BP (SBP) than hypertensives (125 +/- 12 mmHg versus 135 +/- 14 mmHg, p < 0.01). The fall in SPB at night was greater in normotensives than in hypertensives (18 +/- 9 versus 14 +/- 9 mmHg, p < 0.02). Non-dipping occurred in 24% of all subjects, with 59% of these being hypertensives. The nocturnal fall in SBP was not related to age (beta = -0.04, p < 0.62) but was inversely related to a history of hypertension (chi (2) = 5.82, p = 0.02). Serum noradrenaline was significantly related to nocturnal SBP fall (beta = 0.28, p = 0.01). CONCLUSIONS: Elderly normotensives have a greater decline in nocturnal SBP than treated elderly hypertensives. The failure of SBP to fall at night appears to be more a feature of hypertension than of ageing. Early morning noradrenaline estimations are higher in patients with a greater nocturnal blood pressure fall.

Aged↗
PubMed1996

Benzodiazepine prescribing in a Sydney teaching hospital.

OBJECTIVES: To determine the pattern of benzodiazepine prescribing in hospital and at discharge in relation to prior benzodiazepine therapy. DESIGN: Patient interview within 48 hours of admission to determine benzodiazepine, alcohol and other psychotropic drug use before admission and review of medical records after discharge to document drugs prescribed in hospital and at discharge. SETTING: Tertiary teaching hospital, January to August 1995. RESULTS: 1453 patients (mean age, 60 [SD, 19] years; 52.7% female) were interviewed; 277 patients (19.1%) were taking benzodiazepines regularly (one or more doses per week) before admission. Of these, 28.5% did not have benzodiazepine therapy continued while in hospital and 63.9% did not receive benzodiazepines at the time of discharge. Of the remaining 1176 patients (those not previously taking benzodiazepines), 277 (23.6%) were prescribed them for the first time in hospital and 5.3% received benzodiazepines at the time of discharge. Older age, female sex, marital status (single, divorced or widowed) and the use of antidepressants and Schedule 8 narcotic analgesics were all statistically significant predictors of benzodiazepine use before admission, but alcohol consumption was not. CONCLUSIONS: A substantial number of patients do not have their benzodiazepine therapy continued in hospital and at the time of discharge, and are thus at risk of developing benzodiazepine withdrawal syndromes, including delirium. A small but clinically significant number of patients who do not usually take benzodiazepines receive them at the time of discharge and may be at risk of becoming long term users.

Anti-Anxiety Agents↗
PubMed1996

Cardiovascular effects of oral hypoglycaemic drugs.

1. There is increasing evidence that sulfonylurea and biguanide oral hypoglycaemic drugs have cardiovascular effects and influence risk factors for cardiovascular disease in patients with non-insulin-dependent diabetes because of actions that are unrelated to alterations in glycaemic control. 2. While sulfonylureas may have anti-arrhythmic effects following myocardial ischaemia, there is concern that their action on vascular ATP-sensitive potassium channels may contribute to elevated blood pressure and enhanced vascular responsiveness. 3. In contrast to sulfonylureas, metformin (a biguanide) appears to reduce blood pressure and have beneficial effects on plasma lipoproteins by reducing low-density lipoprotein cholesterol and possibly increasing high-density lipoprotein cholesterol levels. 4. The pharmacological basis and clinical significance of these effects of sulfonylureas and biguanides require further investigation.

Biguanides↗
PubMed1996

Dose dependent in vivo inhibition of human colorectal cancer (LoVo) by the gastrin receptor antagonist, CI-988.

1. The dose-response relationship of a new, potent and selective cholecystokinin B receptor antagonist, CI-988, on the growth of LoVo, a human colon cancer cell line, was studied in vivo. 2. We have previously shown the growth of LoVo to be inhibited both in vitro and in vivo by CI-988. 3. LoVo was grown for 10 days in nude mice that were then treated with CI-988 at 1, 5, 10, 25 and 50 mg/kg per day orally for 20 days. 4. CI-988 significantly inhibited the growth of xenografts at all concentrations except the highest concentration of 50 mg/kg per day (P < 0.00001; ANOVA). The largest inhibitory activity was caused by the 10 mg/kg per day dose, causing a 47% inhibition at day 29 (P = 0.00003: Newman-Keul's test). 5. CI-988 may be of use in inhibiting the growth of colorectal cancer.

Animals↗
PubMed1996

Gastrin receptor antagonist CI-988 inhibits growth of human colon cancer in vivo and in vitro.

BACKGROUND: Whilst gastrin has been found to be trophic for some colorectal cancer cell lines, and gastrin receptor antagonists are able to block this phenomenon, their potency has been modest. METHODS: The effect of a new, potent and selective CCK B receptor antagonist, CI-988 on the growth of LoVo, a human colon cancer cell line both in vitro and in vivo was instigated. RESULTS: Basal growth of LoVo in vitro was inhibited by up to 58.93 +/- 7.30% with concentrations of CI-988 as low as 1 X 10(-11) mol/L whereas the addition of gastrin (G17) at 0.5 nmol/L had no effect. LoVo was also grown in vivo for 10 days in nude mice subsequently treated with CI-988 at 10 mg/kg per day orally for 20 days. CI-988 inhibited the growth of xenografts by 53%. CONCLUSION: This was the first study in cancer with this potent gastrin receptor antagonist, CI-988. The results suggest that CI-988 may be of use in inhibiting the growth of colorectal cancer.

Administration, Oral↗
PubMed1995

Effects of pravastatin on cardiovascular reactivity to norepinephrine and angiotensin II in patients with hypercholesterolemia and systemic hypertension.

This study was conducted to examine the effects of short-term cholesterol reduction on cardiovascular reactivity in mildly hypertensive patients. Seven male and 7 female patients, aged 34 to 68 years, received pravastatin (40 mg/day) or matched placebo for 3 weeks in a randomized, double-blind, crossover study. Cardiovascular reactivity was assessed by measurement of blood pressure (BP) responses to incremental infusions of angiotensin II and norepinephrine, by cold pressor testing and isometric exercise. Compared with placebo, pravastatin caused significant reductions in plasma total and low-density lipoprotein cholesterol levels, which averaged 20% and 31%, respectively (both p < 0.0001), and in diastolic BP responses (expressed as the infusion rate required to raise BP by 20 mm Hg) to both angiotensin II (7.3 +/- 3.0 vs 9.7 +/- 4.7 ng/kg/min, p = 0.05) and norepinephrine (0.15 +/- 0.13 vs 0.38 +/- 0.33 micrograms/kg/min, p = 0.03). Systolic BP responses were similar with both treatments. Body weight, resting BP, and maximal BP responses to physical stressors were similar with each treatment.

Adult↗
PubMed1995

Efficacy of pravastatin in combination with captopril in hypertensive patients.

OBJECTIVE: To determine the efficacy of pravastatin in the treatment of primary hypercholesterolaemia in patients being treated with captopril for hypertension. DESIGN: A double-blind parallel group study comparing 12 weeks of pravastatin therapy (20-40 mg/day) with placebo. PARTICIPANTS: 25 patients (age, 37-73 years) with mild-to-moderate hypertension and hypercholesterolaemia (total cholesterol level, 5.5-8.8 mmol/L). RESULTS: Pravastatin reduced total cholesterol levels by 22% (from 7.1 +/- 0.29 [SEM] to 5.5 +/- 0.25 mmol/L; P < 0.001) and low-density-lipoprotein cholesterol levels by 32% (from 5.0 +/- 0.32 to 3.4 +/- 0.28 mmol/L; P < 0.001) in four weeks and these levels were maintained for the 12 weeks of therapy. Pre-pravastatin values returned three weeks after stopping therapy. Levels of total cholesterol, cholesterol fractions and triglycerides remained constant or deteriorated in the placebo group. Pravastatin therapy was well tolerated. An integrated coronary risk score showed a 40% reduction in risk. CONCLUSION: This study indicates that pravastatin (combined with captopril) is an effective cholesterol-lowering drug, but that treatment needs to be maintained.

Adult↗