Pharmacological advancements in the treatment of chronic anal fissure.

Chronic anal fissure is a tear in the lining of the anal canal that, if not treated appropriately at an early stage, causes considerable anal pain during defaecation. Surgery is no longer considered the first-line treatment of this common condition, as recent advancements in medical treatment has produced promising results in the healing of fissures, thus avoiding the unwanted complications that frequently occur following operative treatment. This review looks at those pharmacological agents used commonly in the treatment of chronic anal fissures and explores alternative therapies that may be of benefit in the future.

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.

Alpha-1 adrenoceptor blockade: potential new treatment for anal fissures.

PURPOSE: Patients with chronic anal fissures are known to have high resting anal pressures that return to normal after successful surgical treatment. Internal anal sphincter activity is increased by sympathetic excitatory innervation via alpha adrenoceptors. The objective of this study was to determine the effect of alpha-1 adrenoceptor blockade on anal sphincter pressure in patients with and without chronic anal fissures. METHODS: The effect on the anal canal pressure profile of a single oral 20 mg dose of indoramin, an alpha-1 adrenoceptor antagonist, on seven patients with chronic anal fissure and six healthy patients without a fissure was investigated. RESULTS: Indoramin reduced anal resting pressures in those with anal fissure by a mean of 35.8 percent, from 106.9 +/- 22.15 cm H2O to 68.6 +/- 20.35 cm H2O, and in those without anal fissure by a mean of 39.9 percent, from 84.17 +/- 27.46 cm H2O to 52.17 +/- 24.78 cm H2O, after one hour. This pressure reduction persisted at three hours, and its magnitude is comparable to that obtained after internal sphincterotomy. The pressure reduction occurred over the whole length of the anal canal. CONCLUSION: It is proposed that alpha-1 adrenoceptor antagonists could be a suitable treatment for chronic anal fissure and other painful conditions where reduction in anal pressure is warranted.

Medical therapy for benign prostatic hyperplasia: a review of the literature.

OBJECTIVE: To review the existing evidence regarding the efficacy and safety of medical therapy for lower urinary tract symptoms (LUTS) indicative of benign prostatic hyperplasia (BPH). To assess randomised controlled trials investigating the six alpha-adrenergic receptor antagonists (alpha-blockers), prazosin, alfuzosin, indoramin, terazosin, doxazosin, and tamsulosin, that benefit patients by relaxing prostatic smooth muscle, and the anti-androgen, finasteride, that mediates its more long-term benefits by reducing prostate size. RESULTS: This review suggests that both classes of drug offer significant improvement in criteria used to evaluate symptomatic BPH and can be effective whilst being acceptably safe. Furthermore, the therapeutic efficacy of all contemporary alpha-blockers appear similar, both in terms of symptom relief and urodynamic improvements. Randomised controlled trials have additionally demonstrated that finasteride therapy can provide improvement in terms of quality of life indices, prostate volume, and risks of progressing to acute urinary retention or prostatic surgery. While alpha-blockers have a rapid onset of action, likely to produce a therapeutic result within weeks, regardless of whether prostatic enlargement or bladder outlet obstruction is present, finasteride appears to be effective for more long-term therapy for up to 4 years, but only in alleviating symptoms when they are associated with a significantly large prostate. Neither finasteride nor the alpha(1a)-receptor-selective blocker, tamsulosin, are associated with the lowering of blood pressure and incidence of cardiovascular side effects that are apparent with other less selective alpha-blocker therapies such as dizziness and postural hypertension. They are, however, both associated with an increased risk of sexual dysfunction, albeit less than those associated with surgical intervention. Whereas tamsulosin is associated only with ejaculatory dysfunction, finasteride is additionally linked to decreased libido and impotence.

A prospective placebo controlled double blind randomised study to investigate the use of indoramin to prevent post-operative voiding disorders after surgical treatment for genuine stress incontinence.

A prospective placebo controlled double blind randomised study was undertaken to investigate the use of indoramin an alpha blocker to prevent post-operative voiding disorders after surgical treatment for genuine stress incontinence. Fifty-six patients were randomised to receive indoramin 20 mg orally twice a day or identical placebo from the first post-operative day until discharge from hospital. After seven exclusions, 49 patients were included in the study. There was no significant difference between the treatment (indoramin) group and placebo group for any of the outcomes measured. The routine use of indoramin to prevent post-operative voiding problems cannot be justified on the basis of these data.

Do alpha-blockers have a role in lower urinary tract dysfunction in multiple sclerosis?

Lower urinary tract dysfunction is a major cause of morbidity in patients with multiple sclerosis. alpha 1-Adrenergic receptors are present at the bladder neck, where increased tone may be responsible for urinary retention and diminished flow rates. A randomized placebo controlled study was designed to test the hypothesis that blockade of these receptors using the selective alpha 1-adrenergic receptor antagonist indoramin would improve bladder emptying in patients with multiple sclerosis. Peak and mean urinary flow rates, residual volume and symptom score were evaluated at trial entry and again after 4 weeks in 18 men with multiple sclerosis. There was a mean 41% improvement in peak flow rate in the actively treated group compared with a 7.4% deterioration in the placebo group (p < 0.05). Residual volume improved in both groups. Patients taking indoramin reported a greater improvement in urinary symptoms. Modulation of the alpha 1-receptor may have a role in the management of lower urinary tract dysfunction in multiple sclerosis.

Is indoramin an effective alternative to prostatectomy?

Alpha-1-adrenergic antagonists are recommended for symptomatic treatment of patients awaiting prostatic surgery. Their efficacy has been confirmed in placebo controlled clinical trials, but to date no comparison of their effects with the results of subsequent prostatectomy has been made. Fifty-five patients awaiting prostatectomy were assessed (by symptom scores and peak urinary flow rates) prior to treatment, on indoramin 20 mg bd, and 2 months following prostatectomy. Side effects while taking indoramin were experienced by 36% of patients. Despite an overall improvement in mean symptom scores, 26% of patients with obstructive and 30% of those with irritative symptoms who were assessed while taking indoramin failed to experience any improvement. Of the 31 patients assessed while on indoramin and again following surgery, prostatectomy produced a greater symptomatic relief than indoramin. The increase in peak flow rate following prostatectomy was 11.7 ml/s compared with 3.2 ml/s on indoramin. However, 5 patients preferred to continue taking indoramin rather than proceeding to surgery. Indoramin is no substitute for prostatectomy. Although some patients might benefit from treatment while awaiting surgery, significant side effects may severely restrict its use for this purpose. The response to indoramin cannot be used as an accurate predictor of response to prostatectomy.

Anti-arrhythmic properties of the alpha-adrenoceptor blocking drug indoramin.

1. The anti-arrhythmic properties of the alpha-adrenoceptor blocking drug indoramin were compared with the effect of disopyramide and placebo in a randomised, single-blind, cross-over study. Two doses of indoramin were tested, 25 mg and 50 mg and the dose of disopyramide was 150 mg. All treatments were administered three times daily. 2. Forty patients with benign ventricular arrhythmia were studied. 3. Assessment was by 24 h ambulatory electrocardiography at entry and at the end of each 2 week treatment period. 4. Indoramin was found to have a significant anti-arrhythmic effect compared with placebo, but only at the higher dose tested. 5. The anti-arrhythmic effect was less than that achieved with disopyramide. 6. The mechanism for this anti-arrhythmic effect is unknown but these results suggest that alpha-adrenoceptor blockade may merit further attention as an anti-arrhythmic treatment.

Indoramin in the treatment of prostatic bladder outflow obstruction.

A series of 40 patients took part in a double-blind, placebo-controlled trial of indoramin in prostatic bladder outflow obstruction. Patients were assessed clinically and urodynamically before and after 4 weeks' treatment. Significant improvement was seen in nocturia, volume voided, flow rates and residual urine. The drug was well tolerated, although 7 patients on treatment and 7 on placebo noted side effects. These results suggest that indoramin may be a useful agent in the symptomatic management of bladder outflow obstruction.

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.

Indoramin in the treatment of pregnancy hypertension. A placebo-controlled trial comparing the efficacy of indoramin with alpha-methyldopa.

A placebo-controlled trial was used to assess the antihypertensive efficacy of indoramin in the management of pregnancy hypertension. Sixty patients were recruited into the study and only 17 attained satisfactory blood pressure control. In the doses of drugs administered indoramin was not shown to be more effective than alpha-methyldopa.

Multicentre controlled trial of indoramin in the symptomatic relief of benign prostatic hypertrophy.

A group of 139 patients with symptoms of bladder outflow obstruction due to benign prostatic hypertrophy were entered into a double-blind, parallel group, multicentre study of 2 doses of indoramin versus placebo. There were 18 withdrawals or exclusions, leaving 121 patients for analysis. After 8 weeks, mean peak flow rates increased more in patients treated with indoramin 20 mg bd than in those with placebo. The difference between indoramin 20 mg nocte and placebo was not significant. The change in mean peak flow rate for the higher dose of indoramin represented an increase of 50%. Both patients and investigators reported that the patients' symptoms had improved significantly on both indoramin 20 mg bd and 20 mg nocte; 9 patients were withdrawn because of adverse events, 5 taking placebo and 2 in each of the treatment groups. It was concluded that indoramin 20 mg bd was both effective and well tolerated in the management of symptomatic benign prostatic hypertrophy.

Double-blind study comparing indoramin and propranolol in the treatment of black patients with hypertension.

A 20-week double-blind randomised study of 50 black hypertensive patients was designed to compare the efficacy and safety of indoramin (Baratol; Wyeth/Ayerst) and propranolol in patients who did not respond to diuretic therapy alone. Indoramin (initial dose 50 mg/d) or propranolol (initial dose 80 mg/d) was added to the regimen of patients whose supine diastolic blood pressure (SDBP) remained elevated at 100- 200 mmHg after 2 weeks' treatment with a combination diuretic tablet (hydrochlorothiazide 50 mg plus amiloride HCl 5 mg). Supine systolic blood pressure (SSBP) and SDBP of all patients was successfully controlled (SDBP lowered to less than 95 mmHg) by daily doses that did not exceed 100 mg of indoramin or 160 mg of propranolol; over 90% of patients in each group achieved control with lower doses, i.e. 50-75 mg of indoramin or 80-120 mg of propranolol. Although heart rate decreased from baseline values by approximately 9/min with both agents, the decreases were not significantly different between the treatment groups, and neither agent caused orthostatic hypotension. There were no statistically significant differences between the groups in the types or frequency of side-effects. Indoramin is well tolerated and is as effective as propranolol in black patients with essential hypertension who are not controlled by a thiazide diuretic alone.

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.

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.