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Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension
E G Bevan1, J M Connell, J Doyle
1University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, UK.
Insights
Candoxatril, a neutral endopeptidase inhibitor, did not significantly lower blood pressure in patients with essential hypertension. Despite increasing atrial natriuretic peptide levels, candoxatril showed limited efficacy for hypertension treatment.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
Background:
- Essential hypertension remains a significant global health concern.
- Neutral endopeptidase (NEP) inhibitors are being investigated for their potential antihypertensive effects.
- Candoxatril is an NEP inhibitor with potential therapeutic applications.
Purpose of the Study:
- To evaluate the efficacy and tolerability of candoxatril as a monotherapy for essential hypertension.
- To assess the impact of candoxatril on blood pressure and related biomarkers.
Main Methods:
- A 28-day, double-blind, placebo-controlled, parallel-group study was conducted.
- Forty patients with essential hypertension received either candoxatril (200 mg twice daily) or placebo.
- Blood pressure, atrial natriuretic peptide levels, and side effects were monitored.
Main Results:
- Candoxatril did not significantly reduce supine blood pressure compared to placebo.
- A significant reduction in erect systolic blood pressure was observed, but not in erect diastolic blood pressure.
- Candoxatril increased plasma atrial natriuretic peptide levels without stimulating the renin-aldosterone axis.
- The drug was well-tolerated, with no significant difference in adverse events compared to placebo.
Conclusions:
- Candoxatril (200 mg twice daily) did not achieve clinically relevant blood pressure reduction in essential hypertension.
- The study questions the role of neutral endopeptidase inhibition in treating unselected hypertensive patients.
- Further research may be needed to identify specific patient subgroups who could benefit from NEP inhibitors.
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 concentration of candoxatril at (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.