Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Dose Regimens of BIA 5-453

Exclusion Criteria

• •Criteria associated with hypertension, associated risk factors, and target organ damage:
• •1. Severe hypertension (SBP≥180 mm Hg and/or DBP≥110 mm Hg) at any time during the study from screening period to end of study visit or in the medical history, malignant hypertension
• •2. Secondary hypertension (including known renovascular hypertension, pheochromocytoma)
• •3. Any recent history of coronary artery disease (in the previous 6 months) and including myocardial infarction, or precordial pain suggesting angina pectoris and coronary revascularisation
• •4. Any recent history of cardiac failure (in the previous 6 months)
• •5. Any recent history of cerebrovascular stroke or transient ischemia (in the previous 6 months)
• •6. Any known aortic or mitral valve stenosis or hypertrophic obstructive myocardiopathy
• •7. Any known severe ocular complication of hypertension (stage III or IV retinopathy),
• •8. Any history of ventricular rhythm disorders (torsades de pointes, ventricular tachycardia, polymorphic ventricular extra-systoles except isolated extra-systoles), auricular disorders (fibrillation or flutter).
• •9. Any surgical or medical condition that might significantly alter the absorption, distribution, metabolism, or excretion of Etamicastat (BIA 5-453)
• •10. Presence or history of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, haematological, neurological or psychiatric disease.
• •11. Frequent headaches and/or migraine, recurrent nausea and/or vomiting (more than twice a month).
• •Criteria associated with patient characteristic:
• •12. History or presence of drug dependence.
• •13. Patients smoking more than 10 cigarettes per day
• •14. History of alcoholism within 1 year before day 1. Consumption of more than 50 g of ethanol per day (12.5 cL glass of 10° \[10%\] wine = 12 g; 4 cL of aperitif, 42° \[42%\] whiskey = 17 g; 25 cL glass of 3° \[3%\] beer = 7.5 g; 25 cL glass of 6° \[6%\] beer = 15 g
• •15. Participation in a drug trial within 3 months preceding the selection visit.
• •16. Positive result from the hepatitis serology for hepatitis B (HBs Ag) and/or hepatitis C (HCV Ab).
• •17. Positive result for HIV1+2 serology.
• •18. Positive Urine Drug Screen (UDS) (amphetamines, benzodiazepines, ecstasy, cocaine, opiates).
• •19. Loss of greater than 400 mL or blood donation within the last 3 months.
• •Criteria associated with concomitant diseases:
• •20. Patients taking one of the following treatments: aldosterone antagonists, nitrite derivatives.
• •21. Presence or history of any allergic or unusual reaction to drugs.
• •22. Excessive consumption of beverages containing xanthine bases (more than six cups or glasses per day) or inability to stop consumption during the hospitalization.