Pharmacokinetics of cadralazine in hypertensive patients

Leonetti, Gastone; Parini, J.; Visconti, M.; Gradnik, R.

doi:10.1007/bf03190093

Cited by 5 publications

(2 citation statements)

References 8 publications

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“…This finding indicates that cadralazine could be a prodrug and that its antihypertensive effect is mainly attributable to the pharmacological activity of ISF-2405. Similar pharmacokinetic data [tmax 1.3 ± 0.3h (mean ± SE); t'l2 3.1 ± OAh] were reported in patients with hypertension (Leonetti et al 1988). Cadralazine was rapidly absorbed, with a time to Cmax (tmax) of 0.6 to 0.8h.…”

Section: Mechanism Of Actionsupporting

confidence: 81%

Metabolites of Antihypertensive Drugs

Ebihara

Fujimura

1991

Clinical Pharmacokinetics

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Many antihypertensive drugs are extensively metabolised in humans. Since some metabolites are active and may therefore contribute to the pharmacological activity of the parent drugs, knowledge of the pharmacokinetic properties of active metabolites is important for understanding the overall effects of drugs. Four categories of antihypertensive drugs with active metabolites are dealt with, with selected examples described in some detail. First, drugs with effects relying totally on active metabolites include agents such as methyldopa, cadralazine and many angiotensin converting enzyme (ACE) inhibitors. Secondly, those with effects primarily due to active metabolites include drugs such as triamterene and spironolactone. Thirdly, agents with effects primarily due to the parent drug, but with active metabolites providing significant contributions to the overall pharmacological effect, include drugs such as indoramin, alprenolol, acebutolol, diltiazem and verapamil. Lastly, agents with pharmacological effects with only minor (if any) contributions from active metabolites include drugs such as propranolol, metoprolol, carteolol and others.

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Section: Mechanism Of Actionsupporting

confidence: 81%

Metabolites of Antihypertensive Drugs

Ebihara

Fujimura

1991

Clinical Pharmacokinetics

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“…Currently, the gold-standard model for preclinical assessment of in vivo anti-relapse efficacy is rhesus macaques infected with Plasmodium cynomolgi, a zoonotic, relapsing species closely related to P. vivax 46 . Because we found cadralazine substantially more potent against hypnozoites than hydralazine, it was selected for a rhesus macaque pharmacokinetic study in which plasma levels were measured over 24 h following an oral dose of 1 mg/kg, which was calculated to be well-tolerated, and 30 mg/kg, which was calculated to likely cause drug-induced hypotension [47][48][49] . The 30 mg/kg dose resulted in maximum plasma concentration of 13.7 μg/mL (or 48.2 μM) and half-life of 2.19 ± 0.24 h, which was sufficient to cover the in vitro EC 90 for several hours without noticeable side effects.…”

Section: Reframe Library Screening Cascade Hit Identification and Con...mentioning

confidence: 99%

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

Maher

Bakowski

Vantaux

et al. 2023

Preprint

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Radical cure of Plasmodium vivax malaria must include elimination of quiescent "hypnozoite" forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets, we screened the Repurposing, Focused Rescue, and Accelerated Medchem library against P. vivax liver stages and identified the DNA methyltransferase inhibitors hydralazine and cadralazine as active against hypnozoites. We then used bisulfite sequencing and immunostaining to identify cytosine modifications in the infectious stage (sporozoites) and liver stages, respectively. A subsequent screen of epigenetic inhibitors revealed hypnozoites are broadly sensitive to histone acetyltransferase and methyltransferase inhibitors, indicating that several epigenetic mechanisms are likely modulating hypnozoite persistence. Our data present an avenue for the discovery and development of improved radical cure antimalarials.

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Cadralazine

McTavish

Young²,

Clissold³

1990

Drugs

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Cadralazine is a peripheral arteriolar vasodilator which, unlike hydralazine or dihydralazine, has a protected hydrazino group. In hypertensive patients the optimal effect, based on the antihypertensive efficacy to tolerability ratio, is seen after a 15 mg dose when the drug is administered as monotherapy. When administered in combination with other antihypertensive agents, a 10 mg daily dosage seems appropriate. Noncomparative trials have shown that, in patients who had failed to respond adequately to a beta-blocker and/or diuretic, the addition of cadralazine 10 to 30 mg once daily reduced systolic/diastolic blood pressure by 11 to 19%/13 to 22%. This antihypertensive effect becomes evident over a 2- to 6-week period of therapy and persists during longer term administration. Comparative studies have shown that cadralazine is superior to placebo, and has a similar blood pressure lowering effect to hydralazine, dihydralazine and prazosin in patients not controlled by beta-blocker and/or diuretic but who continued to receive these treatments. Similarly, cadralazine and chlorthalidone were equally effective in reducing blood pressure in resting hypertensive patients but cadralazine shows an advantage in reducing the pressor response in exercising patients. Cadralazine is well tolerated when administered with a beta-blocker or diuretic. Most adverse effects become less frequent and severe with continued use, occur more frequently at dosages of 20 mg/day or more, and do not generally require withdrawal of therapy. Manifestations of the drug's vasodilating properties such as headache, asthenia, dizziness, palpitations and flushing are the most commonly reported symptoms during cadralazine monotherapy, but these may be reduced during combination therapy. The drug does not appear to induce a systemic lupus-like erythematosus syndrome, as may occur with hydralazine, but additional clinical experience is required to completely exclude this possibility. In conclusion, because of its efficacy as a second- or third-line antihypertensive agent, its simple once daily dosage regimen and favourable risk: benefit ratio, cadralazine may have a useful role, particularly in those hypertensive patients who do not respond adequately to established antihypertensive treatments. However, the therapeutic potential of cadralazine cannot be clearly established until the present limited clinical base is expanded to include comparisons with other classes of vasodilating drugs (ACE inhibitors and calcium antagonists), and its utility in the management of other indications such as severe hypertension during pregnancy has been adequately explored.

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Pharmacokinetics of cadralazine in hypertensive patients

Cited by 5 publications

References 8 publications

Metabolites of Antihypertensive Drugs

Metabolites of Antihypertensive Drugs

A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways inPlasmodium vivaxHypnozoites

Cadralazine

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