Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
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We compared the efficacy and safety of three doses of beraprost sodium, an epoprostenol analogue, with placebo in the treatment of intermittent claudication (Fontaine's stage II). One hundred sixty-four patients were randomized to receive either placebo, 20 micrograms beraprost sodium (BPS60 group), 40 micrograms beraprost sodium (BPS120 group), or 60 micrograms beraprost sodium (BPS180 group) three times daily administered orally in a double-blind manner for 12 weeks. Treadmill exercise tests were performed twice during an initial selection phase (D-28 and D0) at week 10 (at trough beraprost concentration) and week 12 (at peak beraprost concentration) of the treatment phase. At week 10, all groups showed an increase in pain-free walking distance, and this distance was greatest in the BPS60 and BPS120 groups (p = 0.055). At week 12, a similar pattern was observed, and the difference was significant between the groups (p = 0.023). The most frequent adverse events reported were gastrointestinal disorders, headaches, skin disorders, and flushes. Patients who received either 60 or 120 micrograms of beraprost sodium daily had an increased pain-free walking distance. Further studies are required to investigate why the highest dose used (180 micrograms daily) showed lower efficacy. Having both vasodilating and antiplatelet properties and being able to increase pain-free walking distance in the short term, beraprost sodium is a promising drug for the treatment of intermittent claudication.
J Cardiovasc Pharmacol 1996 Jun
PMID:A dose-effect study of beraprost sodium in intermittent claudication. 876 44

To evaluate the safety and pharmacologic activity of ITF 296 in humans, three groups of healthy male normotensive subjects were studied. The first two groups (six subjects each) received, in ascending order, three dose levels of ITF 296 by 30-min intravenous infusion (group I, 0.1, 0.5, 1.0 microgram/kg/min; group II, 2.0, 4.0, 6.0 micrograms/kg/min). The third group of eight subjects received, in ascending order, four dose levels of ITF 296 (10, 20, 40, 80 micrograms/kg) by 1-min i.v. injection. The study was double-blind, and placebo-controlled according to a within-patient, incomplete, unbalanced block design, such that each subject received the placebo once. Hemodynamics were assessed by means of Dynamap and BOMED. The following parameters were evaluated at different times before and after ITF 296 administration: systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), stroke volume index (SVI), cardiac index (CI), and systemic vascular resistance index (SVRI). Blood samples for kinetic assessment of ITF 296 were taken before and at different times after ITF 296 administration. The drug was well tolerated. Only a few mild (except for one, moderate) side effects (mainly headache and dizziness) were reported, usually at the higher dose levels. All safety clinical chemistry and hematologic parameters were unaffected. After i.v. infusion of ITF 296, blood pressure started to fall at the dose of 2 micrograms/kg/min, DBP being significantly reduced at doses above 1 microgram/kg/min. The effect lasted for up to 60 min after the end of the infusion. The increase in heart rate was only modest, although apparently dose-dependent. SVI was only slightly reduced, and the other hemodynamic parameters did not change. After bolus administration of ITF 296, SBP was significantly reduced starting at a dose of 20 micrograms/kg with higher doses producing a more marked effect (up to -15 mm Hg). DBP was significantly reduced only at the higher dose level of 80 micrograms/kg. The effect lasted for up to 60 min after bolus administration. HR was slightly increased after doses of 40 and 80 micrograms/kg. SVI was slightly reduced and a small transient decrease in CI was observed, whereas SVRI did not change. Satisfactory, linear kinetic correlation was found between total doses administered and AUCs measured. ITF 296 in healthy male normotensive volunteers was effective and well tolerated. The results of this study justify the planning of further studies in patients in order to test the anti-ischemic activity of the compound.
J Cardiovasc Pharmacol 1995
PMID:Safety and pharmacologic activity of a new nitrate ester, ITF 296, after intravenous administration in healthy volunteers. 883 30

A double-blind, randomized, three-way complete crossover study was carried out to compare pharmacodynamic effects and tolerability during a 24-h intravenous infusion of ITF 296, isosorbide dinitrate (ISDN), and placebo, in the supine position and during 70 degrees head-up tilt. Ten healthy men aged 21-34 years participated in the study to obtain complete data in nine. Dosing started at 1 microgram/kg/min and was titrated up during the first 30 min of infusion, to produce a 10% reduction in diastolic blood pressure (DBP). At least 6 days elapsed between consecutive treatments. Heart rate (HR) and blood pressure were measured at least half hourly throughout the infusion period and up to 2 h afterwards. Systolic time intervals were measured before and at 0.5, 1, 2, 3, and 24 h of infusion in the fasting state. Tilt tests (70 degrees head-up for 2 min) were performed at 1, 6, 12, and 24 h of infusion. From 60 min before tilt, during tilt, and up to 15 min after end of tilt, ECG was monitored and BP, HR, and b/a ratio were recorded by means of fingertip plethysmography. Plasma-renin activity and concentrations of epinephrine and norepinephrine were measured preinfusion, and before and after tilt tests. Subjects were questioned frequently about adverse events. General tolerability of ISDN in the nine subjects who completed the study was poor, with eight suffering from headache and four from symptoms suggesting postural hypotension during tilt tests. Tolerability of ITF 296 was better, with 5 of 10 subjects reporting headache and 2 of 10 symptoms of postural hypotension during the first tilt only. Both active treatments successfully reduced DBP by at least 10% in all subjects at similar dose levels (final infusion rates 2.8 and 2.3 micrograms/kg/min for ITF 296 and ISDN, respectively). Systolic blood pressure (SBP) was reduced by about 6-7 mm Hg by both treatments. HR was increased by about 5 beats/min by ISDN but not by ITF 296. Those changes in BP and HR persisted throughout the 24-h infusion and reversed when it was discontinued. Fingertip plethysmography showed a profound reduction of b/a ratio, which persisted throughout the 24-h infusion. ISDN had consistently greater effects than ITF 296, suggesting that ISDN has the greater effects on small arterial vessels. Both active treatments reduced QS2 index throughout the 24-h period. Both treatments also reduced left-ventricular ejection time (LVET) index up to 3 h of infusion, with ISDN having the greater effects on LVET index and ITF 296 being intermediate between ISDN and placebo. ISDN prolonged pre-ejection period (PEP) at 1 h, had no effect at 2 h, and shortened PEP at 3 and 24 h. ITF 296 decreased PEP consistently during the 24-h infusion. Plasma-renin activity, epinephrine, and norepinephrine were increased by ISDN substantially more than by ITF 296. These results show that both ITF 296 and ISDN had comparable effects on diastolic blood pressure at similar dose-levels. ISDN increased HR, whereas ITF 296 did not. b/a Ratio was reduced more by ISDN, suggesting a greater activity on small arterial vessels. Arterial effects were maintained throughout the 24-h infusion. ISDN had a greater effect on venous return than ITF 296. ITF 296 seemed to show more balanced effects on preload and afterload than ISDN. ISDN caused significantly greater neurohumoral counter-regulation than ITF 296. Hemodynamic response to tilt was attenuated, as judged by the fact that hypotension occurred only during the early hours of the infusion, but the variability in the response of BP to tilt does not allow any firm conclusions to be drawn about possible development of tolerance. Tolerability of ISDN was poor and that of ITF 296 was better.
J Cardiovasc Pharmacol 1995
PMID:Hemodynamic and humoral effects at rest and after head-up tilt tests during 24-hour infusion of a new nitrate ester, ITF 296, compared with ISDN and placebo in healthy volunteers: a double-blind, randomized, within-subject study. 883 31

Traditional centrally acting antihypertensives have been associated with a high incidence of adverse effects and are no longer recommended as first-line therapy. The newer imidazoline receptor agonists must overcome this reputation if they are to gain recognition as potential first-line agents for hypertension. Methyldopa, a centrally acting alpha(2)-agonist, is characterized by a number of serious adverse reactions that limit its use. Although unpredictable idiosyncratic or hypersensitivity reactions are uncommon, these include hepatitis, myocarditis, and hemolytic anaemia. Less serious problems such as abnormal liver function tests, positive Coombs test, drug-induced fever, and pancreatitis also occur. Central side effects include drowsiness, fatigue, lethargy, sedation, depression, psychotic reactions, nasal stuffiness, impotence, and exacerbation of Parkinsonism. In hypertensive men, methyldopa is less well tolerated than either captopril or propranolol, and up to 20% of patients discontinue therapy because of adverse effects. Clonidine acts primarily as an alpha(2)-agonist but also acts as an agonist at imidazoline receptors in the rostroventrolateral medulla. It is equipotent to most other antihypertensives but is considerably less well-tolerated in comparative trials. The principal adverse effects of clonidine are drowsiness, sedation, lethargy and dry mouth. Reserpine acts primarily by depleting central catecholamine neurotransmitter stores. It was very extensively used in early hypertension trials, but its central side effects of sedation, nasal stuffiness, and severe depression are now considered so undesirable that the drug is seldom prescribed. The imidazoline (I1) agonists moxonidine and rilmenidine act selectively and have very little central alpha(2)-agonist activity. In comparative studies against placebo and other reference antihypertensives, the only adverse effect consistently associated with these drugs was dry mouth (approximate placebo-corrected incidence 10%). Sedation was not pronounced. Withdrawal syndromes are complex pathophysiologic processes and occur with a variety of antihypertensive drugs. Cessation of therapy with clonidine and, to a lesser extent, methyldopa may result in a severe withdrawal syndrome characterized by restlessness, sweating, anxiety, tremor, palpitations, and headache. There may be a rapid rise in blood pressure, often with a true "rebound" to higher than pretreatment levels. Plasma and urinary catecholamine levels are increased, and fatalities have been reported. It is important to stress that such a syndrome has not been recorded, in animal or human studies, with either moxonidine or rilmenidine.
J Cardiovasc Pharmacol 1996
PMID:Aspects of tolerability of centrally acting antihypertensive drugs. 887 99

Levosimendan belongs to a new group of heart failure drugs, the calcium sensitizers. Because these compounds are not yet available for clinical use, the adverse drug events (ADEs) during levosimendan treatment cannot be predicted in detail. To evaluate the tolerability of levosimendan in human subjects, ADEs, safety laboratory values before and after treatment, and ambulatory ECG findings have been collected from several phase I and phase II clinical studies. By June 1994, approximately 200 subjects had received levosimendan. The most common ADE seen in healthy volunteers is headache, reported by some 40% of subjects in oral dosing but only 10% in i.v. dosing. The incidence of headache does not correlate well with the total daily dose of the drug. However, the controlled release formulations tested appear to cause vasodilatory symptoms more frequently than i.v. or rapid release oral formulations. The other typical vasodilatory ADEs seen in healthy volunteers are nausea, palpitation, and dizziness. Symptomatic hypotension is rarely encountered. It appears that heart failure patients tolerate the vasodilatory actions of the drug better than healthy volunteers. Only individual cases of headache, vertigo, and flushing have been reported, and injection site irritation has been the most commonly reported ADE (with an incidence <5%). However, because the longest administration of the i.v. infusion has been only 24 h, the duration of exposure to the drug is too short to allow any definitive conclusions to be drawn. All patients who have received levosimendan have been monitored with an ambulatory ECG. Even though some increase in heart rate is seen with high doses of the drug, there are thus far no signs of an increased incidence of ventricular tachyarrhythmias, nor have there been any noteworthy changes in the clinical laboratory safety tests. The experience with levosimendan is limited thus far and long-term data are lacking. It can be concluded, however, that at least in i.v. dosing the drug is devoid of ADEs with significant medical seriousness.
J Cardiovasc Pharmacol 1995
PMID:Safety of levosimendan and other calcium sensitizers. 890 34

Moexipril is a new, long-acting angiotensin-converting enzyme (ACE) inhibitor. In contrast to captopril, it is a prodrug of the pharmacologically active agent moexiprilat and will be administered once daily. The objective of this study was to compare the efficacy, safety, and tolerability of moexipril with that of captopril during a 12-week treatment of patients with mild to moderate hypertension. Patients with a sitting diastolic blood pressure (SDBP) of 95-114 mm Hg, inclusive, were randomized in a 2:1 ratio to receive moexipril, 7.5 mg, once daily or captopril, 25 mg, twice daily. After 6 weeks of treatment, the dose of moexipril and captopril was increased to 15 mg once daily and 50 mg twice daily, respectively, if the patient's SDBP remained > or = 90 mm Hg. Blood pressure was measured at biweekly visits. At study endpoint, adjusted mean reductions in SDBP were comparable between the moexipril and captopril groups (-9.8 vs. -8.7 mm Hg), and moexipril was more effective than captopril in reducing sitting systolic blood pressure. Adverse experiences (headache, dizziness, and upper respiratory infection) occurred at similar frequencies in the moexipril and in the captopril groups. The data indicate that moexipril at dosages of 7.5 and 15 mg once daily is as efficacious as twice daily captopril in reducing blood pressure in patients with mild to moderate hypertension.
J Cardiovasc Pharmacol 1996 Dec
PMID:Moexipril versus captopril in patients with mild to moderate hypertension. 896 Oct 74

Irreversible, nonselective monoamine oxidase (MAO) inhibitors have been reported adversely to interact with indirectly acting sympathomimetic amines present in many cough and cold medicines. This study investigated the safety and tolerability of concomitant administration to 12 healthy subjects of both genders (aged 19-36 years) of ephedrine and moclobemide, a reversible MAO-A inhibitor. A 2-day, randomized, crossover administration of placebo or ephedrine (two doses of 50 mg with a 4-h interval) was followed by 9 days open-label dosing with moclobemide, 300 mg b.i.d.. On the last 2 days of moclobemide dosing, the randomized crossover treatment of ephedrine and placebo was repeated. No subject was withdrawn from the study for tolerability reasons. Moclobemide treatment, however, increased the incidence of adverse events elicited by ephedrine, particularly palpitations and headache. The pharmacodynamic interaction between the two drugs was quantified by calculation of the area under the effect-time course (AUE) for systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR). The difference in AUE between monotreatment with ephedrine and placebo was statistically significant for all three vital signs. Moclobemide potentiated the effect of ephedrine by a median factor of 3.2 for SBP, 3.8 for DBP, and 0.6 for HR. Ephedrine had no significant influence on the plasma concentrations of moclobemide or its metabolites. In conclusion, the combined use of moclobemide and high doses of sympathomimetic drugs should be approached with caution.
J Cardiovasc Pharmacol 1996 Dec
PMID:Modification of the cardiovascular effects of ephedrine by the reversible monoamine oxidase A-inhibitor moclobemide. 896 Oct 85

Nisoldipine is a second-generation dihydropyridine calcium channel blocker (CCB). It is the most vascular selective of the currently available CCBs, and thus has the capacity to lower blood pressure without affecting the functioning of the myocardium and skeletal muscle, and without producing any negative inotropic effects. Nisoldipine coat core (CC) is an extended-release formulation that allows nisoldipine to be released gradually over 24 hours, minimizing fluctuations in plasma concentration and providing a good trough/peak ratio. It has a slow onset and long duration of action, and ambulatory blood pressure monitoring has demonstrated that its antihypertensive effect is maintained over 24 hours with no evidence of reflex tachycardia, hypotension, or sympathetic neurohormonal activation and no effects on circadian variation. Studies in patients with hypertension have shown that nisoldipine CC provides reductions in blood pressure that are at least equivalent to those seen with diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and other CCBs, without deleterious effects on metabolic parameters. In particular, it has been found to be effective in elderly patients and in black patients with severe hypertension. The DEFIANT studies have demonstrated that nisoldipine CC improves cardiac function and exercise tolerance in patients recovering from acute myocardial infarction, without increasing the risk of mortality compared with placebo. It also improves exercise performance in patients with stable angina pectoris. Nisoldipine CC is well tolerated in all groups of patients, with the most frequently reported side effects being headache and peripheral edema, which are usually mild and transient.
Cardiovasc Drugs Ther 1997 Jan
PMID:Nisoldipine CC: efficacy and tolerability in hypertension and ischemic heart disease. 912 76

Openers of adenosine triphosphate (ATP)-sensitive potassium channels relax vascular smooth muscle and protect ischemic myocardium. Cromakalim and BMS-180448 are examples of this class of compounds. They are equipotent in their cardioprotective activity, but cromakalim and related compounds are extremely hypotensive, an activity that limits their use. The effects of cumulative i.v. doses of BMS-180448 or cromakalim on hemodynamics and regional blood flow (radiolabeled microspheres) were evaluated in pentobarbital-anesthetized dogs and ferrets. Both compounds significantly reduced mean arterial blood pressure, cromakalim after 0.03-0.04 mg/kg in both species, and BMS-180448 only after 10 mg/kg in dogs and 30 mg/kg in ferrets. Neither drug affected cardiac output. BMS-180448, like cromakalim, increased blood flow in the heart, with augmented regional left ventricular blood flow occurring more in the subepicardium than in the subendocardium. The effect of BMS-180448 on myocardial blood flow, in both the dog and ferret, occurred at doses that were less hypotensive than those of cromakalim. The most striking difference between the actions of these agents was seen in the brain where cromakalim, but not BMS-180448, increased blood flow in all regions. The results of these studies further demonstrate the myocardium-specific vasodilator activity of BMS-180448. Moreover, the cerebral vasodilator effect of K(ATP) openers, which has been thought responsible for the occurrence of headache in clinical trials, has been found lacking in BMS-180448; this difference may represent a clear advantage in the pharmacologic profile of the agent.
J Cardiovasc Pharmacol 1997 Jul
PMID:Selectivity of BMS-180448 on myocardial versus brain blood flow in dogs and ferrets. 926 22

The efficacy and safety of nisoldipine CC and lisinopril were compared in 278 patients with mild to moderate systemic hypertension in a double-blind, placebo run-in trial. Patients were randomized to nisoldipine CC or lisinopril for 8 weeks to achieve a trough sitting diastolic blood pressure (BP) < or = 90 mmHg. Responders were maintained on their optimal dose for a further 8 weeks. Nonresponders were switched to combination therapy and treated for 8 weeks. Twenty-four-hour ambulatory BP monitoring (ABPM) was carried out during placebo and monotherapy. The responder rate of 73.8% with nisoldipine CC after 8 weeks was greater than 56.1% with lisinopril (p = 0.007). The responder rate with combination therapy was 61%. ABPM showed that both nisoldipine CC and lisinopril produced constant blood pressure lowering effects over the 24-hour period and maintained circadian rhythm. Adverse effects were more frequent with nisoldipine CC (headache and peripheral edema) than with lisinopril (cough) monotherapy. Nisoldipine CC monotherapy was at least as effective as lisinopril monotherapy in the management of mild to moderate hypertension. Both agents were well tolerated. Combination therapy with nisoldipine CC and lisinopril was effective and well tolerated in patients with blood pressure not controlled by monotherapy alone.
Cardiovasc Drugs Ther 1997 Sep
PMID:Nisoldipine CC and lisinopril alone or in combination for treatment of mild to moderate systemic hypertension. Canadian Nisoldipine CC Hypertension Trial Group. 935 63


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