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Biomedical subjects

B R Graham

Publications and source records attributed to B R Graham.

At least 19 recordsLinked to original sources
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↗
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↗
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↗
PubMed1990

Selective beta-adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects.

1. The effects of selective beta-adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1-selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2-adrenoceptors (pindolol) were each given for 3 weeks in a randomised double-blind crossover study in 10 subjects. Five additional subjects received only one drug. Plasma CK levels were monitored during a baseline placebo run-in phase, the active treatment period and a placebo washout phase which continued until CK levels returned to baseline. 3. The degree of beta-adrenoceptor antagonism was determined by the inhibition of exercise-induced tachycardia and was similar for the two drug doses used. 4. During pindolol administration plasma CK levels rose compared with pretreatment baseline levels and with levels during xamoterol administration which did not rise. After pindolol was withdrawn CK levels reached higher peaks in some subjects after 1-5 days. 5. Muscle cramps were reported by five subjects during pindolol administration and by one of these subjects but to a lesser extent during xamoterol administration. 6. Pindolol may produce this effect, which was not seen with xamoterol, because of its specific beta 2-adrenoceptor partial agonist activity. Elevations in plasma CK produced by this type of drug or its withdrawal may cause confusion in the diagnosis of muscle disease or myocardial infarction unless the myocardial isoenzyme is measured.

Adrenergic beta-Agonists↗
PubMed1990

Dilevalol: a dose-response study in normal volunteers.

Dilevalol, 100 mg, 200 mg and 400 mg, and placebo were given to eight normal volunteers and the effect on blood pressure and heart rate studied at rest and on exercise. There was a dose-dependent fall in exercising heart rate and in the increased heart rate on exercise with dilevalol, while exercising systolic blood pressure and the rise in systolic blood pressure on exercise fell dose-dependently up to 200 mg, but the effect of 400 mg was similar. Diastolic blood pressure was not affected. Supine heart rate and blood pressure changes were not different from placebo. Tilt heart rate fell most constantly from 200 mg. Some fall in tilt systolic blood pressure was seen but this was not dose-dependent, diastolic blood pressure was not affected. There was wide variation in plasma concentration of dilevalol, as might be expected from a liver metabolised drug, with a relatively larger amount absorbed of the 400 mg dose compared to the 100 or 200 mg doses.

Adult↗
PubMed1989

Effects of noradrenaline infusion on platelet catecholamine levels and platelet aggregation.

Noradrenaline infusions were administered to 10 normal subjects through stepped doses and continued at 60 ng/kg per min for 2 h. Plasma noradrenaline rose from 1.7 +/- 0.3 to 7.7 +/- 0.7 pmol/ml and platelet noradrenaline rose from 2.1 +/- 0.2 to 2.6 +/- 0.2 pmol/mg protein. There was no change in plasma or platelet adrenaline. Platelet aggregation studies using ADP, adrenaline, collagen and thrombin as aggregants showed no overall change during the course of the infusion. Blood was sampled from a heated hand vein (hot box at 60 degrees C) to test the degree of arterialization. Plasma noradrenaline and blood pO2 and pCO2 showed intermediate levels at this sampling site compared with venous and true arterial values. Changes in platelet noradrenaline content can occur over 2 h when plasma levels are considerably increased by noradrenaline infusion. No change in platelet sensitivity to aggregation was observed. The heated hand vein did not provide true arterial levels of noradrenaline.

Adult↗
PubMed1989

A log-dose-response study of xipamide and its effect on metabolic parameters.

An extended dose-response study with xipamide, using seven doublings of the dose, from 0.3125 to 40 mg/day at 4-week intervals, was carried out in 12 hypertensive patients. Blood pressure showed a progressive decline with doses from 5 to 20 mg, and 40 mg xipamide produced no greater fall. Some subjects showed a maximum fall in blood pressure with a single dose increase but most showed a declining blood pressure over two or more dose increases. Plasma urea increased with doses of 5-40 mg to a similar extent, but there was no fall in the mean potassium level except with the 40-mg dose. Urinary calcium was reduced (from 4.2 to 1.7 mmol/24 h) on the 40-mg dose and the corrected plasma calcium level rose from 2.28 to 2.32 mmol/l. Triglycerides, very-low-density lipoprotein cholesterol and plasma aldosterone increased at the maximum dose; the cholesterol ratio, however, was unchanged.

Blood Pressure↗
PubMed1988

Vasodilating mechanism and response to physiological pressor stimuli of acute doses of carvedilol compared with labetalol, propranolol and hydralazine.

There is conflicting evidence regarding the main mechanism of the vasodilating effect with carvedilol at therapeutic doses, and to examine this, single doses of carvedilol 50mg and 100mg were compared with labetalol 400mg, propranolol 160mg, propranolol 80mg plus hydralazine 50mg and placebo in healthy subjects. Dose-response studies (required to increase heart rate or systolic blood pressure by 25 beats/min and 20mm Hg, respectively) were performed with phenylephrine, angiotensin and isoprenaline after each drug, and placebo administration and the effects of physiological pressor stimuli were compared. Phenylephrine systolic pressure dose-response curves were shifted by labetalol (dose ratio 2.4) and both carvedilol doses (dose ratios 50mg 1.9, 100mg 20.2). The slight shift to the right of the angiotensin dose-response curves with hydralazine plus propranolol (dose ratio 1.4) and carvedilol 50mg (dose ratio 1.4) was not significant. beta-Blockade was greatest with propranolol 160mg, followed by carvedilol 100mg, propranolol 80mg plus hydralazine 50mg, carvedilol 50mg and was least with labetalol 400mg (isoprenaline dose ratios required to increase heart rate by 25 beats/min were 55.2, 27.2, 20.2, 14.2, 11.5, respectively). Blood pressure rise with cold pressor and isometric exercise was inhibited most by labetalol. At these acute doses carvedilol displayed some alpha-blockade, but the lower ratio of alpha-blockade to beta-blockade differed from that seen with labetalol, which may account for the different haemodynamic responses at rest and during physiological pressor stimuli with the 2 drugs. There was no definite evidence of direct vasodilator effect.

Adrenergic beta-Antagonists↗
PubMed1987

Haemodynamics of carvedilol in normal subjects compared with propranolol, pindolol, and labetalol.

Single doses, in log steps, of carvedilol from 12.5 to 200 mg, propranolol 40 to 320 mg, pindolol 2.5 to 20 mg, labetalol 50 to 400 mg, and placebo control were given randomised double blind to six healthy volunteers. Noninvasive measurements of blood pressure and heart rate were made supine, standing, and during cycle exercise 1 and 2 h postdose. All drugs produced a dose-dependent reduction in exercise heart rate, but this was greater for propranolol and pindolol than for carvedilol and labetalol at the dose studied. Exercise systolic blood pressure was similarly reduced but there was less separation in the dose response curves between the various drugs. Supine and standing heart rate was reduced only by propranolol, but supine systolic blood pressure was reduced by carvedilol (50, 100, and 200 mg), propranolol (40, 160, and 320 mg), pindolol (5, 10, and 20 mg), and labetalol (400 mg). Standing systolic blood pressure was reduced by carvedilol (50, 100, and 200 mg) and pindolol (2.5 and 20 mg). The effects of carvedilol on resting blood pressure suggest additional blood pressure lowering properties other than the pure beta-antagonism of propranolol. Effects on exercise heart rate and systolic blood pressure were similar to carvedilol (12.5-200 mg) with labetalol (50-400 mg), but changes in resting systolic blood pressure were less consistent with labetalol.

Adrenergic alpha-Antagonists↗
PubMed1982

The effect of intrinsic sympathomimetic activity on beta-receptor responsiveness after beta-adrenoceptor blockade withdrawal.

1 Heart rate (HR) and blood pressure (BP) changes supine, at 60 degrees tilt and in response to increasing exercise loads, and HR responses to Valsalva's manoeuvre and to isoprenaline bolus injections were studied in 19 healthy volunteers to assess the response to abrupt withdrawal of atenolol n = 6, propranolol n = 6 and pindolol n = 7. 2 The dosage of each drug administered double-blind was gradually increased over a period of 2 weeks and the dose to produce maximum inhibition of exercise-induced tachycardia was continued for one further week. 3 Plasma renin activity, plasma noradrenaline and serum free thyroid hormones were measured during control periods, maximum dosage and withdrawal periods. 4 An increased sensitivity to isoprenaline injections was seen on Day 5 after withdrawal in the atenolol treated group whereas the pindolol treated group showed decreasing hyposensitivity to isoprenaline for the 13 days of observation after withdrawal and propranolol showed an intermediate effect. 5 There was no overshoot in HR or BP measurements at rest or in response to tilting, Valsalva's manoeuvre or exercise with atenolol or propranolol and with pindolol the HR response to tilt only was significantly higher on the third day post-drug. 6 Plasma noradrenaline and serum free T3 were reduced on drug treatment and further reduced in the early withdrawal period but there were no consistent changes in plasma renin activity.

Adrenergic beta-Antagonists↗
PubMed1981

Effect of food on the absorption of hydralazine in man.

Single oral doses of hydralazine (Apresoline) 50 mg were administered on two occasions to eight healthy volunteers when fed and fasting. Blood and saliva samples were taken at intervals after dosing and analysed for drug. Heart rate and blood pressure were measured before and at intervals after dosing, at rest, after tilt and exercise. Plasma hydralazine levels showed wide inter-individual variation. The areas under the plasma concentration-time curve (0-8 h), the height of the peak plasma levels and the time to peak were not significantly different between the fed and fasting state. Salivary hydralazine levels were readily measurable but showed little correlation with plasma levels. The heart rate and pulse pressure were increased after drug both at rest, supine and erect, and after exercise for between 6 and 8 h.

Adult↗
PubMed1976

A modification of the Johnson-Neyman technique comparing two regressions, applied to treatment effects dependent on baseline levels.

Treatment effects can often depend on baseline (pre-treatment) variables. This is ignored in many studies, or else the relationship is removed statistically by analysis of covariance. The latter method, however, assumes that slopes are equal and also loses information on the base-line contribution. Instead, the Johnson-Neyman technique does not assume that slopes are equal and furthermore permits examination of the baseline contribution. The method was devised for education research and is here extended to biological studies. However, the method assumes that variances are equal for the regressions, which might not be always so. The mmodification proposed accommodates inequalities of variance, whether intrinsic to the regressions or resulting from differences in group size. The Johnson--Neyman technique is discussed in relation to alternative analyses and, in appropriate situations, is considered to yield more information. Furthermore, with the refinement described, it involves even fewer assumptions and becomes more powerful.

Biology↗
PubMed1976

A within-patient comparison of bethanidine, methyldopa and propranolol in the treatment of hypertension.

1. A within-patient comparison showed that bethanidine, methyldopa and propranolol produced similar control of the blood pressure. 2. Unlike bethanidine, propranolol did not produce postural and exercise hypotension; methyldopa was intermediate in effect. 3. Overall side effects were of a similar incidence though there were differences in incidence of particular side effects.

Bethanidine↗