Antihypertensive effects of a novel peripheral vasodilator, Ro 12-4713

Abstract

The effects of Ro 12-4713, a vasodilator, on blood pressure and heart rate, were tested in 13 ambulant patients with mild to severe hypertension. The patients received Ro 12-4713 in total oral doses ranging from 1.5 to 4 mg/kg over a 3-5 day period. Standard laboratory tests were done 24 h before and after the study. Standing and supine blood pressure and heart rate were determined before, and every hour for 6-8 h after drug administration. ECGs were recorded before, during and at the end of each study day. Ro 12-4713 reduced the pretreatment standing and supine-blood pressure from 213 +/- 34/126 +/- 21 mmHg and 218 +/- 31/130 +/- 20 mmHg to 156 +/- 33/85 +/- 9 mmHg and 158 +/- 25/88 +/- 11 mmHg at the end of Day 5. Heart rate was only transiently increased in patients with pretreatment values of less than 90 beats/min. Although abnormal ECGs tended towards normalization, there were 2 cases of T-wave inversion (the patients remained asymptomatic). Raised BUN levels tended to decrease towards normal. Side effects reported spontaneously by patients (headaches, palpitations, dizziness, nausea and one case of water retention) appeared to be transient in nature. Ro 12-4713 appeared to be a very potent and long lasting antihypertensive agent, whose inherent side effects were only transient in nature.

Vasodilator Treatment for Mild to Moderate Heart Failure

“…As shown by the study of segmental motion, with all the limitations of this procedure, Ro 12-4713 did not induce detectable dyskinesia. The changes in EF and ER reflect a decreased 'af terload', as expected from other studies [1,2]. The resting EDV did not change significantly, but the exercise EDV decreased by 25.6% (p < 0.005).…”

“…6 patients (33.3%) presented with side effects: ankle edema and periorbital swelling, 4 patients presented also an increase of myocardial ischemia (S-T changes). We observed similar side effects in patients treated with Ro 12-4713 for arterial hypertension [2]. Similar side effects are reported with minoxidil [7], Furthermore, in another study we have treated 102 hypertensive patients with Ro 12-4713 for 6-18 months (mean duration 9.3 months): severe hypertrichosis (70% of pa tients), myocardial ischemia (20% of pa tients) and diuretic-resistant water retention (45% of patients) were observed after the 10th week of therapy; they were severe enough to require withdrawal of the therapy in most of the cases, and forced us to stop the treatment in spite of good antihypertensive efficacy [9], Lastly, a few months ago, the drug was been totally withdrawn from clinics because of toxicity in the long-term cancerogenetic studies in animals [1].…”

“…On the other hand, these patients were normotensive; systemic vaso dilators rarely decrease blood pressure in normotensive subjects [5], The absence of tachycardia might seem puzzling in a minoxidil-like vasodilator. However, Ro 12-4713 induces less tachycardia than one would ex pect from a potent vasodilator [1,2], Fur thermore, all patients were digitalized. The improved cardiac function may have con tributed to the lack of tachycardia.…”

“…In recent years, how ever, the clinical use of vasodilators in the treatment of heart failure has become an accepted approach. Ro 12-4713, mcthyl-5-3.6-dihydro-1 (2H)-pyridil [-2-oxo-2H-l,] 4-oxadiazolo-2,3-a-pyrimidine-7 carbamate, belongs to the class of oxadiazolo-pyrimidines [1], Its pharmacologic effects are char acterized by a slow onset and long duration of action, the drug having a minoxidil-like pro file but with less tachycardia [1,2]. In this study we investigated the possibility that chronic treatment with Ro 12-4713 would increase cardiac output and stroke volume in patients with mild to moderate heart failure who were treated with digitalis and diuret ics.…”