Cadralazine (ISF 2469): Dose-related antihypertensive activity after single oral administration to patients

Catalano, M.; Parini, J.; Libretti, A

doi:10.1007/bf00613810

Cited by 17 publications

(2 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Dose-response curves and time courses of effects of cadralazine by single oral administrations were assessed by Catalan0 et al (8) in an early phase 2 singleblind, balanced, placebo-controlled, crossover study in 24 hypertensive patients. The drug, at 7.5 to 30.0 mg, effectively reduced supine and standing systolic and diastolic blood pressures (Fig.…”

Section: Monotherapy Studiesmentioning

confidence: 99%

Cadralazine

Dorigotti¹,

Ferni²

1987

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

Cadralazine is a new and potent antihypertensive vasodilator drug (22) that has slow onset and long duration of action. It is well tolerated after long-term administration. Cadralazine is almost completely absorbed orally, its biotransfonnation is limited, and its hypotensive response is consistent. The research program that led to the development of cadralazine started about 16 years ago. The aim was to find an antihypertensive drug that would reduce vascular smooth muscle tone directly and specifically and would normalize the increased peripheral vascular resistance. At that time the only direct vasodilator drug available for the therapy of hypertension was hydralazine, and various approaches were in progress to discover new derivatives that would be more potent and safer than hydralazine.In our laboratory several hundred hydrazinopyridazines have been synthesized and submitted to pharmacological screening. During the early stage of the research some interesting structure-activity relations were detected, and a potent antihypertensive vasodilator, pildralazine, was selected (15,23,25). Subsequent chemical efforts were devoted to optimization of the pharmacological profile of pildralazine; they led to the discovery of cadralazine in 1978 (7,24). CHEMISTRYThe chemical name of cadralazine (ISF 2469) is ethyl 2-[6-[ethyl-(2-hydroxypropyl)amino]-3-pyridazinyl]hydrazinecarboxylate. The structural formula is shown in Fig. 1. The empirical formula is C,2H21N,03, and the molecular weight is 283.33. The product is a pale yellow, crystalline powder with a melting point range of 161" to 164°C. It is slightly soluble in water but freely soluble in acid. Cadralazine is a 6-substituted derivative of 3-hydrazino-pyridazine, which shares with hydralazine the structural features required for antihypertensive activity (19). However, the highly reactive hydrazino moiety in cadralazine is masked by the ethoxycarbonyl group. This structure prevents the hydrazine group from reacting with carbonyl groups, which are ubiquitous in the body. Moreover, the ethoxycarbonyl group protects the hydrazino moiety from being acetylated, a reaction that is a capacity-limiting step in the first-pass metabolism of hydralazine (34). 15.5

show abstract

Section: Monotherapy Studiesmentioning

confidence: 99%

Cadralazine

Dorigotti¹,

Ferni²

1987

Cardiovascular Drug Reviews

View full text Add to dashboard Cite

show abstract

“…slow-onset, long-lasting antihypertensive activity (1)(2)(3)(4)(5)(6). The dose of cadralazine given orally judged to be adequately effective in a large enough proportion of hypertensive patients is 10-15 mg once daily (4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of cadralazine and its hydrazino-metabolite in patients with renal impairment after repeated administration of 5 mg once daily

Marichal

Brunel

Lecaillon³

et al. 1992

European Journal of Drug Metabolism and Pharmacokinetics

View full text Add to dashboard Cite

Since the hydrazino-pyridazine metabolite of cadralazine, CGP 22 639 is believed to contribute to the activity of the drug, its pharmacokinetics and that of cadralazine were investigated in 8 hypertensive patients with renal impairment. The creatinine clearance (CLcr) of patients ranged from 10 to 60 ml/min. The concentrations of cadralazine in plasma and urine, and of CGP 22 639 (plus its possible hydrazones) in plasma were measured after single and repeated administration of 5 mg of cadralazine once daily. A hypotension possibly linked to cadralazine treatment was recorded on day 3 for the patient with CLcr = 10 ml/min. Metabolite concentrations were found to be at least twice as high as in other patients indicating that in this patient, the daily dose of 5 mg was probably too high. The pharmacokinetics of cadralazine were not modified by repeated administration. The drug and its metabolite were eliminated more slowly in patients with low creatinine clearance. The t1/2 of CGP 22 639 was about twice the t1/2 of the unchanged drug. In patients whose CLcr ranged from 19-37 ml/min the mean accumulation factor of apparent CGP 22 639 was 1.7 times that of the unchanged drug. It shows that the apparent CGP 22 639 accumulated more than the unchanged drug. A starting daily dose of 2.5 mg of cadralazine in patients with CLcr < 40 ml/min appears to be suited to take into account the pharmacokinetics of CGP 22 639. This dose can be increased by 2.5 mg steps if the antihypertensive effect is not sufficient (maximum dose with CLcr < 40 ml/min: 10 mg).(ABSTRACT TRUNCATED AT 250 WORDS)

show abstract