Time for a Time Window Extension: Insights from Late Presenters in the ESCAPE Trial.

BACKGROUND AND PURPOSE: The safety and efficacy of endovascular therapy for large-artery stroke in the extended time window is not yet well-established. We performed a subgroup analysis on subjects enrolled within an extended time window in the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial. MATERIALS AND METHODS: Fifty-nine of 315 subjects (33 in the intervention group and 26 in the control group) were randomized in the ESCAPE trial between 5.5 and 12 hours after last seen healthy (likely to have groin puncture administered 6 hours after that). Treatment effect sizes for all relevant outcomes (90-day mRS shift, mRS 0-2, mRS 0-1, and 24-hour NIHSS scores and intracerebral hemorrhage) were reported using unadjusted and adjusted analyses. RESULTS: There was no evidence of treatment heterogeneity between subjects in the early and late windows. Treatment effect favoring intervention was seen across all clinical outcomes in the extended time window (absolute risk difference of 19.3% for mRS 0-2 at 90 days). There were more asymptomatic intracerebral hemorrhage events within the intervention arm (48.5% versus 11.5%, P = .004) but no difference in symptomatic intracerebral hemorrhage. CONCLUSIONS: Patients with an extended time window could potentially benefit from endovascular treatment. Ongoing randomized controlled trials using imaging to identify late presenters with favorable brain physiology will help cement the paradigm of using time windows to select the population for acute imaging and imaging to select individual patients for therapy.

Beta-adrenergic blocking drugs in the treatment of hypertension.

The reduction in blood pressure seen with the use of beta-blocking drugs was an unexpected finding. Initially there was resistance to their use as the reduction of cardiac output and increase in peripheral resistance from beta-blockade was considered an undesirable pharmacological action for a drug in the treatment of hypertension. However, beta-blockers have now become established in the treatment of hypertension and have been recommended as a first line choice in various guidelines, although their exact mode of action remains a matter for debate. In broad terms beta-blocking drugs are at least of similar efficacy to the other major classes of antihypertensive drugs. They may be usefully combined with other anti-hypertensives, as is often required. There is some evidence that the beta-1 selective agents are more efficacious than the non-selective beta-blockers. Notwithstanding some observations to the contrary beta-blockers are often effective antihypertensive agents in the elderly and in black patients; the combination of being elderly and black, however, appears to result in a reduced fall in blood pressure. If they are given early in pregnancy they lead to a low birth weight. Co-existant disease may influence the choice of a beta-blocker to treat hypertension. Beta-blockers are valuable agents in ischaemic heart disease, notably the control of chronic angina pectoris and to improve prognosis post-myocardial infarction. While initial dose titration has to be extremely careful, heart failure is now a strong indication for the use of a beta-blocker, as prognosis is much improved. Diabetes should no longer be regarded as a contra-indication to the use of a beta-1 selective agent. Recent work confirms that beta-blockers should be given to patients undergoing surgery who have a high cardiac risk. Outcome studies suggest overall that in younger patients beta-blockers reduce the incidence of strokes and myocardial infarction. There is no convincing evidence of a difference between the ACE inhibitor captopril and the combination of diuretic and a beta-blocker. In high risk patients, i.e. those with diabetes, no difference was seen between captopril and atenolol. Diuretics may result in better outcome measurements in the elderly compared to beta-blockade but in combination, "conventional treatment" is as effective in terms of total mortality, strokes and myocardial infarction as ACE inhibitors or calcium antagonists. Co-existant asthma remains an important contraindication to beta-blockade, but not chronic obstructive airways disease where a beta-blocker should be used with caution if it is indicated, e.g. post-infarction. Quality of life measurements, at least with beta-1 selective agents compare favourably with other anti-hypertensive drugs. Beta-blockers, without partial agonist activity, should not be stopped abruptly, particularly in patients with, or at high risk of, co-existant ischaemic disease because of the danger of post-beta-blockade cardiac sympathetic hypersensitivity; alternatively bed rest should be instituted to reduce the risk of sympathetic stimulation.

I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly.

In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t(1/2)) of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t(1/2) values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.

New approaches to the uses of beta blocking drugs in hypertension.

After a slow start, beta-blockers have become widely used as first-line agents in the treatment of hypertension, and recommended as such in recently published guidelines. There is evidence that the beta1-selective agents are more efficacious than non-selective blockers that inhibit both beta1 and beta2 receptors. Notwithstanding some earlier evidence to the contrary, it appears that beta1-selective drugs are equi-effective in young and elderly whites, younger, ie, under mid 60s, blacks. It is with the combination of age and being black that beta-blockers are usually less useful than some other groups of antihypertensive drugs, most notably calcium antagonists and diuretics. Primary prevention studies indicate beta-blockers reduce the incidence of cerebro-vascular disease and coronary heart disease in younger patients but they appear less effective than diuretics in the elderly. Beta-blockers are particularly indicated in patients who have experienced a myocardial infarction where they are often under used. There is some evidence that even in post-infarction patients with co-existent chronic obstructive airways disease, usually regarded as a contra-indication, experience an improved 2-year survival with the use of beta-blockers. Recently they have also been demonstrated to improve prognosis in heart failure patients, previously regarded as a contra-indication. Likewise, recent studies have shown that atenolol was at least as effective as captopril in improving the outlook in hypertensive patients with non-insulin dependent diabetes. While earlier comparisons with the non-selective lipid soluble propranolol indicated otherwise, comparisons with beta1-selective agents have indicated a similar effect on quality of life assessments with angiotensin-converting enzyme inhibitors.

Moxonidine: a new antiadrenergic 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 that 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. Pretreatment with imidazoline I1 blockade from efaroxan abolishes the antihypertensive action of microinjection of moxonidine into the RVLM in the spontaneously hypertensive rat (SHR), while alpha2 blockade from SKF 86466 is much less effective. Microinjection of efaroxan into the RVLM prevents the fall of BP in the SHR from intravenous moxonidine. Moxonidine binds with an affinity for the imidazoline I1 receptor that is 33 times more effective than is alpha2-receptor binding. There is only a few fold preference for binding at the imidazoline I1-receptor for clonidine. Moxonidine results in a fall in adrenaline, noradrenaline and renin levels in humans, as might be expected from central inhibition of sympathetic tone. Moxonidine gives 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. There is a reduction in left-ventricular end systolic and diastolic volumes. There is a regression of left-ventricular hypertrophy after moxonidine was given for 6 months. Following oral administration the half-life (Tmax) is about 1 h. Moxonidine is highly bioavailable, approaching 90%. Moxonidine is largely excreted unchanged, biotransformation is unimportant. It has a T(1/2) of 2.5 h, renal insufficiency prolongs the T(1/2). However, suggesting possible retention in the central nervous system (CNS) the antihypertensive effect lasts longer than would be expected from the half-life. Moxonidine has been shown to be suitable for administration once daily. Moxonidine is an effective antihypertensive drug. In the course of its evaluation it has been compared with representatives from each important class of antihypertensive drugs, with diuretics, both alpha- and beta-blocking drugs, clonidine, calcium antagonists and angiotensin-converting enzyme (ACE) inhibitors. These studies have shown that BP control is overall similar with moxonidine and these other agents. Moxonidine has a favourable side-effect profile, at least in part due to its lack of effect on central alpha2 receptors.

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.

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.

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.

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)

An Examination of Some Factors which Influence the Stability of in Vitro Platelet Responses.

Platelet sensitivity to ADP and adrenaline was determined after storage of platelet-rich plasma (PRP) under various conditions to establish those yielding optimal platelet stability. The effects of the exclusion of air from the storage syringes, temperature, PRP dilution and duration of storage were tested. Storage at room temperature (22° C) in the absence of air stabilised PRP pH over 24 h and stabilised platelet sensitivity to ADP up to 4 h. Storage at 4°C and 13 C caused platelet activation and eventually spontaneous aggregation, as evidenced by significant reductions in platelet counts. Samples stored at 37° C were less responsive to ADP and adrenaline than samples maintained at 22 C. Platelet count adjustment to 200 × 10(9)/L reduced platelet sensitivity as reflected by increased agonist EC(50) values and threshold concentrations. Positive correlations between agonist EC(50) values (and between threshold concentrations) for diluted and undiluted samples were obtained, indicating that platelet count adjustment did not affect the ranking order of platelet sensitivity within the subject group. No correlations between platelet count and indices of platelet sensitivity were seen suggesting that differences in platelet aggregation arise from intrinsic differences in platelet sensitivity rather than differences in platelet count. With time of storage the responses to ADP (EC(50) and threshold concentration) and adrenaline (EC(50)) declined to a greater extent for undiluted PRP than for diluted PRP. No changes in the platelet-poor plasma concentrations of the dense granular component, serotonin, occurred in diluted or undiluted samples over 24 h. We conclude that in order to ensure optimal stability of platelets, PRP should be stored at room temperature (22°C) in the absence of air and tested within 4 h of preparation. A decision on platelet count adjustment is also required dependent upon the experimental objectives.

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.

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.

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.

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.

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.

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.

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.

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.

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.