Long-term indoramin therapy in congestive heart failure: a double-blind, randomized, parallel placebo-controlled trial.

Twenty-one patients with moderately severe congestive heart failure participated in a double-blind, randomized, parallel placebo-controlled trial designed to evaluate the effects of long-term (2 months) indoramin therapy on rest and exercise hemodynamics, exercise capacity and clinical status of patients with this clinical syndrome. The long-term administration of indoramin in patients (mean dose 50 mg every 12 hours) caused a mild reduction from baseline values in supine rest mean systemic blood pressure and, after dosing, elicited a significant reduction in systemic and pulmonary vascular resistances, pulmonary capillary wedge pressure and heart rate as well as a mild increase in stroke volume. Long-term indoramin therapy caused a small decrease, as compared with baseline exercise responses, in systemic and pulmonary vascular resistance and pulmonary capillary wedge pressure at submaximal levels of exercise. It did not alter hemodynamic variables at maximal exercise, exercise capacity or overall clinical status, compared with findings at baseline or with placebo.

Effects of indoramin therapy on BP, renal function, and body fluid composition.

Indoramin hydrochloride is a new alpha 1-adrenoceptor antagonist. Eleven hypertensive men in whom the BP was normalized with indoramin underwent assessment of renal function, renal hemodynamics, and body fluid composition following short-term (three to six weeks), long-term (five to six months), and withdrawal (two weeks) therapy. Short-term indoramin therapy produced a 28% increase in glomerular filtration rate, a 24% increase in effective renal plasma flow, and a 31% decrease in renal vascular resistance. Although urine flow rate and free water clearance were unchanged, fractional sodium excretion decreased 38%. Long-term indoramin therapy was associated with qualitatively similar renal effects, but the changes did not achieve statistical significance. Plasma volume was increased only during short-term therapy; however, body weight was increased following both short- and long-term therapy. Indoramin effectively lowers BP without producing deleterious renal effects.

Indoramin in heart failure: possible adverse effects on hemodynamics and exercise capacity.

Indoramin is an alpha 1-adrenergic antagonist vasodilator of potential value in heart failure. We measured hemodynamics and exercise capacity in 12 patients with heart failure, before and after 1 week of indoramin dosing, 75 mg b.i.d. Maximal hemodynamic effects 2 hours after the first dose of indoramin consisted of reduced mean systemic arterial pressure from 96.0 +/- 15.3 to 87.9 +/- 15.3 mm Hg (P less than 0.05) and pulmonary wedge pressure from 23.6 +/- 7.8 to 16.9 +/- 6.6 mm Hg (P less than 0.001). Heart rate, cardiac index, and total systemic resistance did not change acutely after indoramin, but after 1 week mean systemic arterial pressure was still reduced whereas cardiac index fell from 2.69 +/- 0.38 to 2.32 +/- 0.44 L/min/m2 (P less than 0.05) and total systemic resistance rose from 20.4 +/- 2.8 to 21.9 +/- 4.0 U (P less than 0.1). After 1 week maximal exercise oxygen uptake fell from 16.8 +/- 5.6 to 12.5 +/- 3.5 ml/min/kg (P less than 0.02). This limited observation suggests that indoramin is a predominant venodilator acutely in patients with heart failure but that despite this effect it may worsen functional capacity and hemodynamics during continuous dosing in these patients.

Effect of indoramin and propranolol on cardiovascular response to cold in hypertensive patients.

Immersion of the hand into ice water (cold-pressor test) in nine hypertensive subjects induced elevation of mean blood pressure, increase of vascular resistance in the extremities, decrease of blood flow in the extremities, and increase in heart rate. The preejection phase of systole was not altered. Indoramin and propranolol, each alone and together, attenuated the pressor and other cardiovascular responses. Submaximal exercise increased heart rate during placebo treatment, a response only partially attenuated by indoramin, propranolol, and their combination, but it did not induce changes in mean blood pressure during any of the treatments.

Acute hemodynamic and hormonal response to indoramin in congestive heart failure.

Acute hemodynamic and hormonal responses to a single dose of indoramin, an alpha 1-antagonist, were evaluated in 11 subjects with severe chronic congestive heart failure. A hemodynamic effect began within 1 hr of indoramin and persisted during the 6 hr of hemodynamic monitoring. Decreased right and left ventricular filling pressures were associated with increased stroke index and decreased pulmonary and systemic vascular resistances. Heart rate did not increase despite a fall in systemic arterial pressure. Forearm blood flow, forearm venous capacitance, and plasma norepinephrine levels were unchanged, whereas plasma renin activity rose from 12.7 +/- 17.4 to 16.6 +/- 20.4 ng/ml/hr. The only side effect was drowsiness in five of the 11 subjects. Our data demonstrate the acute effectiveness of indoramin in reducing ventricular preload and systemic vascular resistance in heart failure.

Central and peripheral blockade of the sympathetic nervous system.

Agents that work primarily by inhibiting effects of the sympathetic nervous system continue to be widely used for the therapy of hypertension. There are two principal types of drugs: those that work in the central nervous system, and those that act primarily at peripheral neuromuscular sites. Both types of drugs are often effective as single-agent therapy although they also work well in combination with diuretics and other antihypertensive agents. Recently, there has been interest in a new transdermal method for administering the centrally-acting drug clonidine; the consistency of the plasma drug concentrations achieved by this form of treatment appears to minimize adverse effects while providing continuous therapeutic efficacy. Interest is also focusing on the ability of sympathoinhibitory agents such as alpha-methyldopa to produce regression of left ventricular hypertrophy, possibly by mechanisms independent of their antihypertensive action.

Selective alpha 1-adrenergic antagonists: therapeutically relevant antihypertensive agents.

Alpha-adrenergic antagonists were the first substances to receive serious consideration as antihypertensive agents. However, their therapeutic potential in the management of essential hypertension was not realized until prazosin, a highly selective alpha 1-adrenergic antagonist, became available. A number of analogs of prazosin have now been synthesized, as have several structurally distinct alpha 1-adrenergic antagonists. Preliminary investigations suggest that these agents may also be clinically useful antihypertensive drugs. The alpha 1 receptor of arteriolar smooth muscle is the predominant adrenergic subtype determining sympathetically mediated vascular tone. Therefore, its selective blockade by an agent such as prazosin is a relevant approach to the major pathophysiologic defect in hypertension: an elevation of peripheral vascular resistance. Because prazosin has little selectivity for the alpha 2 receptor, the negative feedback control of norepinephrine release from sympathetic nerve terminals remains intact. This unique action of prazosin may explain why it effectively lowers arterial pressure without markedly increasing cardiac output, heart rate and plasma renin activity. An additional factor in the favorable therapeutic effects of this agent is its ability to induce a balanced reduction in both arteriolar and venous tone, with little change or even improvement in renal hemodynamics. The antihypertensive effects of prazosin, when used as a single agent, may be modest. However, it may be useful as initial as well as adjunctive therapy for the management of hypertension because of its high toxic to therapeutic ratio, coupled with a sustained reduction in arterial blood pressure, a low incidence of side effects, and a potentially favorable metabolic profile.

Indoramin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and related vascular, cardiovascular and airway diseases.

Indoramin is a postsynaptic selective alpha 1-adrenoceptor antagonist used in the treatment of hypertension. In contrast to some other alpha-blockers, animal studies suggest that its blood pressure lowering effect results from relaxation of peripheral arterioles as a consequence of blockade of postsynaptic alpha 1-adrenoceptors. Furthermore, unlike some other alpha-blockers, this lowering of blood pressure is rarely associated with reflex tachycardia or postural hypotension. Therapeutic trials have shown indoramin to be effective in lowering blood pressure in all grades of hypertension: mild and moderate hypertension when used alone, but generally in combination with a thiazide diuretic, and in moderate to moderately severe hypertension when used in combination with a beta-blocker and diuretic. In a few small comparative studies, no significant difference was found in the blood pressure lowering effects between indoramin and methyldopa, propranolol and prazosin. Side effects were similar for indoramin, propranolol and methyldopa; however in the 1 comparative study with prazosin, prazosin produced a lower incidence of sedation. Indeed, the most common side effect with indoramin therapy has been sedation of a mild to moderate and/or transient nature, reported in about 19% of cases. Other side effects which have sometimes led to a withdrawal of indoramin treatment have been dry mouth, dizziness, and in males, failure of ejaculation; however, side effects may be reduced by starting therapy with smaller doses and titrating more gradually.

Indoramin in the treatment of hypertension: a placebo controlled trial.

The effect of the alpha-blocker indoramin was studied in a 4-week double-blind comparative trial with placebo in 39 patients with mild to moderate essential hypertension. Dosage of indoramin was individually adjusted and ranged from 125 mg to 200 mg daily. Indoramin produced a significantly greater reduction in diastolic blood pressure than placebo, and 9 (56%) out of 16 patients attained diastolic pressures of 90 mmHg or less. Heart rate, haematology and blood biochemistry were unaffected by treatment with indoramin, and there were no E.C.G. changes. Nine out of 19 patients on indoramin complained of side-effects. These were generally not troublesome, although 3 patients withdrew because of severe tiredness or weight gain.

A double-blind comparison of indoramin and propranolol in the treatment of moderate to severe essential hypertension.

In a double-blind study, patients with moderate to severe essential hypertension were treated randomly with either indoramin or propranolol orally. The dose of both drugs was increased as necessary, to a predetermined level, in order to reduce the diastolic (Phase V) blood pressure to 100 mmHg or less. Patients were followed up for 12 weeks. There were 23 patients on propranolol and 27 on indoramin. The blood pressure in 22 patients on propranolol and 25 patients on indoramin was satisfactorily controlled in both the supine and standing positions. Mean supine blood pressure decreased from 181.3 +/- 14.2/116.2 +/- 6.8 mmHg to 140.6 +/- 7.1/95.7 +/- 3.6 mmHg after 12 weeks of treatment in patients receiving propranolol and from 188.3 +/- 18.9/118.4 +/- 8.7 mmHg to 144.7 +/- 7.3/95.7 +/- 2.5 mmHg in those treated with indoramin. There were no significant differences between the effects on supine and standing blood pressures and blood pressure control was maintained throughout the 12-week period in patients receiving indoramin and those receiving propranolol. Propranolol reduced the mean heart rate by approximately 16 beats/min in both the supine and standing positions. The maximum effect was seen 4 weeks after starting treatment and was maintained throughout the study. Sinus bradycardia (heart rate less than 60/min) occurred in 9 (39%) patients receiving propranolol. Indoramin caused a small but significant reduction in mean heart rate of approximately 4 beats/min in both the supine and standing positions. The maximum effect was seen after 2 weeks of treatment and was maintained for the rest of the duration of treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in myocardial ischaemia during isosorbide dinitrate or indoramin therapy in patients with stable angina using relations between the ST segment and heart rate.

The effect of isosorbide dinitrate or indoramin on myocardial ischaemia was examined in patients with stable angina pectoris. In a prospective trial, randomization resulted in 8 and 9 patients, respectively, given isosorbide dinitrate in a dose of 30-90 mg daily, and indoramin in a dose of 75-225 mg daily; 2 of these patients were serially examined during the two types of therapy. Changes in myocardial ischaemia were assessed by exercise testing using 12 standard electrocardiographic leads and a bipolar lead CM5. Individual and group comparisons showed that isosorbide dinitrate resulted in an increase in ST segment depression, the maximal ST/heart rate slope and the ratio of net ST segment depression to increases in heart rate (at least P less than 0.01). In contrast, with indoramin therapy there were no significant changes in these indices. The results in these patients suggest that isosorbide dinitrate leads more consistently to increases in the severity of myocardial ischaemia than indoramin, although this effect on ischaemia is apparently less than the benefit of these agents on exercise performance.

Current treatment options for fissure-in-ano.

BACKGROUND: Fissure-in-ano is a painful condition that affects a sizable majority of the population. Selecting a method of treating the condition that could achieve optimal clinical results and the least pain and inconvenience to the patient has always posed a challenge to the surgeons. This led to the innovation of a number of surgical and pharmacological methods that relax the anal muscle. While acute fissures could be managed with medical therapy alone, chronic fissures do need some form of manipulation to relieve internal sphincter spasm. MATERIALS AND METHODS: The present study discusses various techniques advocated for the treatment of acute and chronic fissure-in-ano. It also elaborates on the advantages and deficiencies of each. DISCUSSION: Despite the initial success with pharmacological agents in the treatment of patients with chronic anal fissures, a growing concern is developing about their use. Increasing incidence of adverse effects and decreasing long-term efficacy have been the major drawbacks. CONCLUSION: Surgery still remains the preferred option which should be offered to patients with relapse or therapeutic failure with prior pharmacological treatment. Nevertheless, the patient should be informed about the pros and cons of each mode of treatment with details of cure rates and possible complications.

The medical and surgical management of chronic anal fissure.

Major advances in our understanding of the mechanisms involved in chronic anal fissure have allowed the introduction of many new medical therapies for this condition. The literature about current treatment modalities licensed for anal fissure and those novel therapies still under evaluation has been reviewed. These new treatments are examined in the context of traditional surgical management of the disease and a future treatment algorithm suggested.

The usefulness of alpha-adrenoceptor blockade in the treatment of hypertension.

The development of selective peripheral alpha 1-adrenoceptor antagonists such as prazosin has produced a valuable class of antihypertensive agents. Side effects of fluid retention and reflex sympathetic stimulation usually limit these agents to third-line therapy but their combination with a beta-receptor antagonist and a diuretic provides a powerful regimen. Alpha-adrenoceptor antagonists are useful in patients with conditions such as gout, diabetes or bronchospasm which preclude the use of other agents. Although many new drugs are being developed, little information is available yet on the long-term outcome of therapy with this class of drugs for patients with hypertension.

The effect of placebo on indirect and direct blood pressure measurements.

We have conducted a series of experiments which clearly show that intra-arterial ambulatory blood pressure is not altered by the administration of placebo. This finding is in contrast to the apparent fall in pressure that appears when the indirect (Korotkoff) method is used. The evidence suggests that the apparent fall in indirect pressure is due to abolition of the orienting reflex with time. Therefore, clinical trials of antihypertensive drugs using the intra-arterial method do not need a placebo control, whereas a placebo control is essential in all trials using the indirect technique for measuring blood pressure.