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Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension

Bevan Elizabeth G.; Connell, John M.C.; Doyle, Jacqueline; Carmichael, Hugh A.; Davies, David L; Lorimer, A Ross; Mclnnes, Gordon T.
Journal of Hypertension: July 1992
RAPID PUBLICATION: PDF Only

Objective:

To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension.

Design:

Double-blind, placebo-controlled, parallel-group study of 28 days' duration.

Setting:

Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK).

Patients:

Forty patients with essential hypertension with diastolic blood pressure 95–114 mmHg after a 2–4 week placebo run-in period.

Interventions:

Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules.

Main outcome measures:

Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment.

Results:

When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin—aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentrations of candoxatrilat (UK 73,967 — the active metabolite of candoxatril) reached a peak of 1010±437 ng/ml after acute dosing, and 1328±405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo.

Conclusions:

Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.

© Lippincott-Raven Publishers.