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Biomedical subjects

B N Prichard

Publications and source records attributed to B N Prichard.

At least 19 recordsLinked to original sources
PubMed1997

In vitro adrenaline and collagen-induced mobilization of platelet calcium and its inhibition by naftopidil, doxazosin and nifedipine.

AIMS: The aim of the study was to obtain further information regarding the modes of action of doxazosin, naftopidil and nifedipine on platelet function. METHODS: We conducted an in vitro study of drug influences on adrenaline and collagen-induced mobilization of platelet calcium. RESULTS: In the presence of fibrinogen (300 micrograms ml-1) both collagen (5 micrograms ml-1) and adrenaline (16 microM) stimulated the aggregation of washed platelets. Collagen induced a transient rise (+4.97 +/- 0.63 microM) in platelet Ca2+ concentration, [Ca2+]i, as measured using the photoprotein aequorin, which coincided with the onset of aggregation. Adrenaline induced a smaller rise (+3.6 +/- 0.96 microM) which, however, occurred after the onset of aggregation. Naftopidil, an alpha 1-adrenoreceptor antagonist produced a concentration-dependent inhibition of collagen-induced Ca2+ mobilization, maximum inhibition (22.9 +/- 4%, P < 0.05) occurring with 40 microM naftopidil. The inhibition of Ca2+ mobilization was not reflected by a concentration-dependent inhibition of platelet aggregation, although 40 microM naftopidil produced statistically significant inhibition (23.3 +/- 11.7%, P < 0.05). The adrenaline-induced rise in [Ca2+]i was inhibited dose dependently by naftopidil (e.g. 40 microM naftopidil, 100 +/- 0%, P < 0.05), as was aggregation (40 microM naftopidil, 100 +/- 0%, P < 0.05). Doxazosin, another alpha 1-adrenoreceptor blocker, inhibited Ca2+ mobilization induced by collagen to similar extents as for naftopidil (30 microM doxazosin, 17.4 +/- 2.5%, P < 0.05), but did not inhibit platelet aggregation. It also inhibited the adrenaline-induced rise in [Ca2+]i in a concentration-dependent manner (30 microM doxazosin, 37.6 +/- 13.7%, P < 0.05), significant inhibitions of platelet aggregation also being produced (30 microM, 49.6 +/- 17.2%, P < 0.05). As expected, the calcium channel blocker nifedipine produced concentration-dependent inhibitions of both collagen-induced Ca2+ mobilization (e.g. 28 microM nifedipine, 47.8 +/- 2.7%, P < 0.05) and aggregation (28 microM, 55.1 +/- 9.2%, P < 0.05). CONCLUSIONS: These data indicate that the alpha 1-adrenoreceptor blockers, naftopidil and doxazosin, inhibit Ca2+ mobilization, this mechanism being possibly the means whereby these drugs inhibit platelet aggregation.

Adrenergic alpha-Antagonists↗
PubMed1997

The use of moxonidine in the treatment of hypertension.

BACKGROUND: Imidazoline I1-receptor agonism represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Adrenaline, noradrenaline and renin levels are reduced, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that moxonidine results in an acute decrease in blood pressure due to a fall in systemic vascular resistance, whereas the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months of treatment. PHARMACOKINETICS: Following oral administration, maximum concentration is reached at about 1 h, and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, and biotransformation is unimportant. The half-life of moxonidine is 2.5 h, which is prolonged by renal insufficiency. However, the antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the central nervous system. DRUG EFFECTS: Decreases of about 20-30 mmHg systolic and 10-20 mmHg diastolic blood pressure have been found in open studies with moxonidine. The dosage of 0.2-0.4 mg moxonidine daily controls hypertension in most patients. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and angiotensin converting enzyme inhibitors. Blood pressure control has been observed to be similar with moxonidine and these other agents. Generally, the overall incidence of side-effects has been found to be similar, although the incidence of side-effects with clonidine is greater than that seen with moxonidine. CONCLUSIONS: A meta-analysis of controlled studies with moxonidine found that moxonidine gave similar reductions in blood pressure in both men and women, in those aged below 50, 50-60 and over 60 years, and regardless of body weight. As often seen with some other drugs, higher systolic blood pressures are associated with larger reductions in systolic blood pressure and the same appears to be the case with diastolic blood pressure.

Antihypertensive Agents↗
PubMed1997

Pharmacology and clinical use of moxonidine, a new centrally acting sympatholytic antihypertensive agent.

Moxonidine is a centrally acting antihypertensive. Its action is mediated by imidazoline I1 receptors located in the rostral ventro-lateral medulla (RVLM). Animal experiments show much smaller amounts are required to reduce blood pressure (BP) when it is given intracisternally, or injected directly into the RVLM, compared to intravenous dose. The antihypertensive action of microinjection of moxonidine into the RVLM in the spontaneously hypertensive rat (SHR) is abolished by pretreatment with imidazoline I1 blockade from efaroxan, but alpha(2) blockade from SKF 86466 has much less effect. Similarly the fall of BP in the SHR from intravenous moxonidine is reversed by the microinjection of efaroxan into the RVLM. Receptor binding studies demonstrate that moxonidine binds with an affinity for the imidazoline I1 receptor that is thirty-three times more effective than is alpha(2) receptor binding, while for clonidine the difference is only four times. Moxonidine reduces adrenaline, noradrenaline and renin levels in man, a finding consistent with central inhibition of sympathetic tone. Acute haemodynamic studies indicate that moxonidine results in a fall of BP due to a decline in systemic vascular resistance, while the heart rate, cardiac output, stroke volume and pulmonary artery pressures are not affected. Left ventricular end systolic and diastolic volumes are reduced. Left ventricular hypertrophy has been found to regress after 6 months treatment with moxonidine. After oral administration Tmax is about 1 h, bioavailability approaches 90%. Moxonidine is mostly excreted unchanged, biotransformation is unimportant. The T1/2 is 2.5 h, which is prolonged by renal insufficiency. However, suggesting possible retention in the central nervous system (CNS), the antihypertensive effect lasts longer than would be expected from the half-life, as moxonidine is suitable for once daily administration. Moxonidine is an effective antihypertensive agent. It has been compared with representatives from each important class of antihypertensive drugs, with clonidine, diuretics, both alpha- and beta-blocking drugs, calcium antagonists and ACE inhibitors. BP control has been similar with moxonidine and these other agents. The side effect profile of moxonidine is favourable, its lack of effect on central alpha(2) receptors is important in this regard.

Animals↗
PubMed1996

Effective antihypertensive therapy: blood pressure control with moxonidine.

Stimulation of the imidazoline I1-receptor represents a new mode of antihypertensive action, inhibiting peripheral alpha-adrenergic tone by a central mechanism. Moxonidine is an imidazoline I1-receptor modulator. Acute hemodynamic studies indicate that moxonidine results in an acute fall of both blood pressure and systemic vascular resistance, whereas heart rate, cardiac output, stroke volume, and pulmonary artery pressures are not affected. The ejection fraction is not significantly affected. Left ventricular end-systolic and -diastolic volumes are reduced. There is regression of left ventricular hypertrophy after 6 months of treatment. Epinephrine, norepinephrine, and renin levels are all reduced, a finding consistent with central inhibition of sympathetic tone. After oral administration Tmax is about 1 h and bioavailability approaches 90%. Moxonidine is mostly excreted unchanged; biotransformation is unimportant. The T1/2 is 2.5 h, prolonged by renal insufficiency. The antihypertensive effect lasts longer than would be expected from the half-life, suggesting possible retention in the CNS. Open studies with moxonidine have revealed decreases on the order of 20-30 mm Hg systolic and 10-20 mm Hg diastolic blood pressure. Most patients are controlled by 0.2-0.4 mg daily. Moxonidine has been compared with representatives from each important class of antihypertensive drugs, with diuretics, clonidine, calcium antagonists, angiotensin-converting enzyme inhibitors, and both alpha- and beta- blocking drugs. Blood pressure control has been similar with moxonidine and these other agents. The overall incidence of side effects was similar, although moxonidine has a lower incidence of side effects than clonidine. Meta-analysis of controlled studies with moxonidine indicates that moxonidine causes similar decreases in blood pressure in both male and female subjects, in those below 50 years, those 50-60 years, and those over 60 years old, regardless of body weight. As with some other drugs, higher systolic blood pressure are associated with larger falls of systolic blood pressure, and the same is true for diastolic blood pressure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

The potentiation of adrenaline-induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.

1. Aggregation in platelet-rich plasma from normotensive men was induced by adrenaline (0.25-16 microM), ADP (0.25-16 microM), collagen (0.25-8 micrograms ml-1) or serotonin (10 microM) alone, or by previously sub-threshold concentrations of adrenaline (0.03-1 microM) in combination with sub-threshold concentrations of serotonin (2.5 microM), ADP (0.5 microM) or collagen (0.125 micrograms ml-1). The effects of the alpha 1-adrenoceptor blockers naftopidil and doxazosin on platelet aggregation were investigated. 2. The dose-response curves for collagen and ADP were unaffected by either drug. However, naftopidil (40 microM) inhibited serotonin-induced platelet aggregation (23.9%, 95% confidence interval (CI) 10.7 to 37.1%; P < 0.01) and caused a slight shift to the right of the adrenaline dose-response curve with a mean increase in the EC50 value of 0.5 microM (95% CI 0.07 to 0.93 microM; P < 0.05). Doxazosin had no effect on serotonin or adrenaline-induced aggregation. 3. A marked potentiation of the aggregation induced by subthreshold concentrations of adrenaline resulted from the prior addition of low concentrations of ADP, collagen or serotonin. 4. These potentiated responses were inhibited in a dose-dependent manner by naftopidil and to a lesser extent doxazosin. The maximum inhibitions (%) produced by naftopidil (40 microM) on the responses of adrenaline potentiated by ADP were 58.3% (95% CI 36.8 to 79.8%; P < 0.001), serotonin 58.9% (95% CI 40.0 to 77.8%; P < 0.001), and collagen 70.9% (95% CI 52.5 to 89.3%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

Clinical experience with moxonidine.

Moxonidine is an imidazoline receptor modulator, specific for the I1-imidazoline receptor. The stimulation of imidazoline receptors represents a new mode of antihypertensive action to inhibit peripheral alpha-adrenergic tone by a central mechanism. Acute hemodynamic studies reveal moxonidine produces an acute fall of blood pressure and systemic vascular resistance. Heart rate, cardiac output, stroke volume, and pulmonary artery pressures are not affected. Left ventricular end-systolic and diastolic volumes are reduced. Ejection fraction is not significantly affected but 6-month studies showed a regression of left ventricular hypertrophy. After oral administration the maximum concentration of moxonidine is reached in about 1 hour, and elimination half-life is 2.5 hours, prolonged by renal insufficiency. The antihypertensive effect lasts longer than would be expected from the half-life. Open studies with moxonidine have revealed falls between 20 and 29 mmHg systolic, and between 10 and 19 mmHg diastolic blood pressure. In the largest study, over 12 months in 141 patients, most patients were controlled by 0.2 mg daily (58%) or 0.2 mg b.i.d. (38%). Moxonidine has been compared with representatives from each important class of antihypertensive drugs. In a crossover trial of clonidine in 20 patients, blood pressure control was similar, but the incidence of tiredness and dry mouth was less on moxonidine, as was the total number of patients experiencing side effects, 85% versus 30% (p < 0.01). In a larger parallel group study of moxonidine (n = 122) and clonidine (n = 30), blood pressure control was similar, but the overall incidence of side effects was less on moxonidine. In comparative studies of moxonidine with atenolol, ACE inhibitors, dihydropyridine calcium antagonists, hydrochlorothiazide, and alpha 1 blockade, the blood pressure control with representatives of these various classes of drugs was similar to moxonidine.

Administration, Oral↗
PubMed1994

Platelet function in patients with hypercholesterolaemia.

Platelets and plasma lipoproteins, particularly low density lipoprotein, have important roles in atherogenesis. Evidence from several sources suggests that important interactions occur between these individual components of the atherogeneic process. Here we review work from our own laboratory on platelet function in normal individuals and patients heterozygous for familial hypercholesterolaemia (FH). Data is presented on the role of platelet noradrenaline and also on altered cellular signalling in platelets from FH individuals who have plasma low density lipoprotein concentrations which are approximately double those seen in normal subjects.

Blood Platelets↗
PubMed1993

Carvedilol in ischaemic heart disease.

beta-adrenoceptor-blocking drugs, first introduced for the treatment of symptomatic angina pectoris, have been found effective across the whole spectrum of ischaemic disease. Labetalol was the first combined-action beta-blocking drug to be described and was shown to be capable of increasing exercise tolerance in patients with angina pectoris. Carvedilol also possesses a peripheral vasodilating action mainly due to an alpha 1-adrenoceptor blockade. Haemodynamic studies with carvedilol in patients with ischaemic heart disease have shown a reduction in peripheral vascular resistance in contrast to propranolol which increases systemic resistance and reduces cardiac output. Additionally, in ischaemic heart failure there is evidence of improved myocardial function, as shown by an increase in ejection fraction, after the administration of carvedilol. Carvedilol has been shown to improve exercise tolerance in patients with angina pectoris and reduce the occurrence of episodes of silent myocardial ischaemia. Carvedilol, unlike many beta-blocking drugs, does not adversely affect the plasma lipid profile qualitatively or quantitatively. In contrast to many non-selective beta-blocking drugs, carvedilol has a more favourable haemodynamic profile, and its lack of adverse influence on the plasma lipid profile may be important in its long-term use.

Adrenergic beta-Antagonists↗
PubMed1992

Clinical pharmacology of carvedilol.

Animal work has shown that carvedilol is a nonselective beta-blocking drug. It has a vasodilator action from alpha-receptor blockade, but there is evidence that it has further action to relax smooth muscle, possibly from calcium channel antagonism. Carvedilol is lipid soluble and 25% bioavailable, and it has a half-life of about 7 h. It lowers blood pressure at rest and reduces the tachycardia and the rise of blood pressure on exercise. It reduces the level of blood pressure reached during isometric exercise or the cold pressor test. Cardiac output at rest is maintained, and the haemodynamics in the compromised heart is improved. It has an important peripheral vasodilator action, peripheral flow being maintained to important organs, e.g. kidneys, despite the fall in blood pressure. Exercising renin and noradrenaline levels are increased, as are the latter at rest. Carvedilol is lipid neutral. Carvedilol shifts the dose-response curve to isoprenaline to the right, as well as to alpha-stimulants such as phenylephrine. Responses to angiotensin are little affected. The ratio of beta- to alpha-blockade has been found to be 7.6 for 50 mg and 12.5 for 100 mg of carvedilol. There is no evidence of a decline in alpha-blockade after 1 week of continuous administration.

Adrenergic beta-Antagonists↗
PubMed1992

Plasma and platelet free catecholamine concentrations in patients with familial hypercholesterolaemia.

1. Plasma and platelet free catecholamine concentrations were measured in 22 normal subjects and in 10 treated and 11 untreated patients with heterozygous familial hypercholesterolaemia. 2. Plasma noradrenaline concentrations were significantly higher in both treated and untreated hypercholesterolaemic patients than in normal subjects. Adrenaline concentrations did not differ. 3. Platelet noradrenaline levels were higher in untreated hypercholesterolaemic patients than in normal subjects. 4. Positive correlations between the plasma noradrenaline concentration and the platelet noradrenaline concentration were observed in both normal subjects and hypercholesterolaemic patients. 5. Combining the data for normal subjects and hypercholesterolaemic patients revealed that the plasma noradrenaline concentration correlated positively with the plasma cholesterol concentration. The platelet noradrenaline concentration was also found to correlate with the plasma cholesterol concentration. 6. Our results suggest that an increased plasma cholesterol concentration may be associated with increased sympathetic nervous system activity as indicated by elevated plasma and platelet noradrenaline levels. Increases in circulating catecholamines may contribute to the platelet hyperaggregability seen in familial hypercholesterolaemia.

Adult↗
PubMed1992

Adverse reactions to diuretics.

Diuretics can result in various undesired biochemical changes, such as impotence, skin rashes, nausea, dizziness and lethargy as well as subjective side effects. The side effects are mostly predictable, their effects depending on both the circulatory blood volume and on the transport of water and solute in the renal tubules. Two of the commonest side effects are mild hypovolaemia, when any diuretic is used, and mild hypokalaemia when the non-potassium-sparing diuretics, such as thiazides and frusemide are used. Its occurrence is dose dependent and can be corrected by potassium supplements, but potassium-retaining diuretics, which also correct the often associated fall in serum magnesium, are preferable. Many reports link hypokalaemia with cardiac arrhythmias, but some dispute this association in the absence of the concomitant use of digoxin. Hyponatraemia rarely occurs, but can be life threatening. Calcium excretion is markedly reduced, but unlike other electrolyte disturbances from diuretics, this may be valuable: some suggest diuretics have an anti-osteoporotic action. Diuretics increase glucose and insulin resistance and should be used sparingly in diabetics. They rarely cause a non-ketotic hyperosmolar coma. Urate is raised, but clinical gout is not common. Cholesterol elevation has been reported in some studies, but long-term studies indicate that lipid changes are minor. Other rare side effects are not predictable from their pharmacological actions and these include the occurrence of skin rashes, thrombocytopenia, pancreatitis and interstitial nephritis; and ototoxicity from frusemide.

Blood Volume↗
PubMed1992

Beta-blocking agents with vasodilating action.

beta-Adrenoceptor-blocking drugs in current use can be separated into two main groups: those nonselective and those selective for beta 1-receptors. Members of each group reduce cardiac output and lead to an increase in peripheral resistance with a concomitant reduction in blood flow. beta-Blocking drugs not only may occupy the receptor preventing stimulation but also may have intrinsic sympathomimetic activity. Those with marked partial agonist activity at the beta 2-receptor giving some beta 2-mediated vasodilation can be regarded as the first multiple-action beta-blocking drugs. Subsequently, drugs have been developed that in addition to blocking the beta-receptor have an important peripheral vasodilator activity. Labetalol was the first drug of this group to be developed; prizidolol followed but has been withdrawn because of toxicity. Several other agents have been described, including bucindolol, carvedilol, celiprolol, dilevalol (one of the isomers of labetalol), and medroxolol. Three mechanisms have been reported to be responsible for peripheral vasodilation: alpha-receptor blockade, beta 2-agonism, and a dilator action independent of either the alpha- or beta-receptors. Evidence for these various mechanisms is more readily obtainable from animal experiments, but some confirmatory evidence has been obtained in humans. Inhibition of alpha-stimulation had been found with labetalol, medroxalol, and carvedilol and suggested with celiprolol. beta 2-Mediated vasodilation has been demonstrated by, for example, celiprolol and dilevalol; evidence of a vasodilation independent of alpha-blockade or beta 2-stimulation has been reported with celiprolol and carvedilol.

Adrenergic alpha-Antagonists↗
PubMed1992

Hypertension and insulin resistance.

Insulin resistance and hyperinsulinemia is now recognized in non-insulin-dependent diabetes, essential hypertension, obesity, atherosclerotic heart disease, dyslipidemia, heart failure, and in heavy smokers. Several mechanisms have been proposed to explain hyperinsulinemia, insulin resistance and its relationship to hypertension; reduced sodium excretion, activation of the sympathetic nervous system, increased activity of the sodium/hydrogen pump, and stimulation of cellular growth. Some of the nonpharmacological methods to control hyperinsulinemia are of benefit in the management of hypertension, most notably weight loss, exercise program, and reduced salt intake. High-fiber and reduced-protein diets also reduce hyperinsulinemia. Thiazide diuretics can result in insulin resistance, and insulin secretion may be inhibited, possibly associated with concomitant hypokalemia. beta-Blockers result in some reduction of glucose tolerance and mask some of the features of hypoglycemia. Angiotensin-converting enzyme (ACE) inhibitors and alpha-receptor blockers do not effect insulin resistance; probably the same is true for calcium antagonists. Although the effect on risk factors should not be discounted, it is the effect of treatment on hard end points, cerebrovascular accidents, myocardial infarction, or death that is most important. Evidence in hypertension is at present restricted to diuretics and beta-blocking drugs.

Animals↗
PubMed1991

The effect of urapidil on responses to phenylephrine, angiotensin and isoprenaline in man.

Intravenous urapidil, 40 mg bolus followed by an infusion of 18 mg.h-1 for 2 h was administered to 6 female non-patient volunteers. Randomised cumulative dose response curves to angiotensin, phenylephrine and isoprenaline were performed before and commencing 30 min after the start of the infusion of urapidil. Urapidil significantly reduced supine systolic blood pressure, 118.5 mm Hg to 105.3. The diastolic blood pressure was not significantly reduced, heart rate was not affected. Urapidil did not affect the responses to angiotensin or isoprenaline. Urapidil inhibited the pressor response to phenylephrine. The dose required to increase systolic blood pressure by 20 mm Hg increased from 156.9 micrograms.min-1 before to 685 micrograms.min-1 during urapidil; Dose ratio from individual values of 4.58. Urapidil concentrations were not significantly different before and after each agonist infusion. It is concluded that urapidil has alpha 1-adrenoceptor blocking activity in man without any non specific vasodilator action and that it is devoid of beta adrenoceptor blocking action.

Adrenergic alpha-Antagonists↗
PubMed1991

Trace element and vitamin deficiency in alcoholic and control subjects.

A wide range of trace elements and vitamins was studied in alcoholic patients admitted for detoxification and in healthy controls. Alcoholic subjects were found to be deficient relative to controls in magnesium and vitamin E, while a relative excess of serum iron and copper, and sweat nickel, was noted. A surprisingly wide range of deficiencies, as compared with standard laboratory ranges, was seen in the control group. This finding emphasizes the need for adequate control groups in nutritional studies of alcoholism, the insufficiency of an adequate diet alone to guarantee adequate nutrition, and the likely high prevalence of undetected nutritional deficiency in the general population. Further research is required on the clinical benefits of nutritional supplementation as part of the treatment of alcoholism, and the value of conventional supplements as a routine treatment is questioned.

Adult↗