Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0012833 (dizziness)
 9,689 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SPP301 is a competitive antagonist of ET-1 with a high selectivity for the ETA receptor. A double-blind, placebo-controlled study was performed to investigate the tolerability, pharmacokinetics, and pharmacodynamics of SPP301 after single oral doses in male healthy subjects; doses of 5, 20, 50, 100, and 200 mg were given to different groups of 4 or 8 subjects each. The effect of food on the pharmacokinetics of SPP301 was assessed for the 50-mg dose according to a sequential design in the same subjects. At regular intervals, blood pressure and pulse rate, plasma levels of ET-1 and of SPP301 and its hydroxymethyl metabolite, and urinary excretion of the parent drug and its metabolite were determined. SPP301 was generally well tolerated. At doses >20 mg, adverse events that are typical for vasodilating agents-namely, headache, nausea and vomiting, dizziness, and postural hypotension-were observed. Maximum plasma levels of SPP301 were reached within 4.5 hours. Cmax and AUC values increased linearly with doses up to 100 mg. The apparent terminal half-life was quite constant over the whole dose range and ranged from 7.5 to 15.2 hours. Urinary excretion of SPP301 was below 0.1% of any dose. Cmax and AUC of the metabolite amounted only to about 5% of the values for SPP301. Concomitant food intake had no effect on the overall exposure but increased average peak plasma concentrations of SPP301 by around 50%. Plasma ET-1 increased nearly twofold at the 5-mg SPP301 dose, with no further relevant increase at higher doses. In conclusion, SPP301 is an active ET-1 antagonist and is well tolerated. The pharmacokinetics of the drug and its metabolite are linear up to 100 mg. Food does not affect overall exposure of SPP301 but increases Cmax. Urinary excretion of SPP301 is below 0.1% of the dose administered.
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PMID:Pharmacokinetics and pharmacodynamics of the ETA-selective endothelin receptor antagonist SPP301 in healthy human subjects. 1468 42

Bosentan is a nonpeptide, specific, competitive, dual antagonist at both endothelin receptor subtypes (ET(A) and ET(B)). Orally administered bosentan effectively prevents endothelin 1-induced vasoconstriction in pulmonary vessels in patients with pulmonary arterial hypertension. Improvement in exercise capacity from baseline was significantly greater with bosentan than with placebo in two phase III trials in patients with WHO functional class III or IV pulmonary arterial hypertension (primary or associated with connective tissue disease) despite treatment with vasodilators, diuretics, anticoagulants, cardiac glycosides, or supplemental oxygen. The beneficial effects of bosentan on exercise capacity were maintained for at least 20 weeks. Compared with placebo, bosentan led to a significantly greater improvement from pretreatment values in secondary efficacy endpoints such as the Borg dyspnea index, WHO functional class, and cardiopulmonary hemodynamic parameters (cardiac index, pulmonary vascular resistance, pulmonary artery pressure, pulmonary capillary wedge pressure, mean right atrial pressure). Bosentan significantly reduced the incidence, and delayed the onset, of clinical worsening of pulmonary arterial hypertension compared with placebo. In published clinical trials, adverse events that occurred with similar or greater frequency with bosentan 125 mg twice daily than with placebo included headache, syncope, flushing and abnormal hepatic function. Those that occurred less frequently with bosentan 125 mg twice daily than with placebo included dizziness, worsening of symptoms of pulmonary arterial hypertension, cough and dyspnea.
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PMID:Bosentan. 1472 63