Milrinone is a phosphodiesterase inhibitor that has been shown to improve hemodynamic parameters in patients with class III to IV heart failure when administered intravenously for less than or equal to 48 hours. This ...
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Milrinone is a phosphodiesterase inhibitor that has been shown to improve hemodynamic parameters in patients with class III to IV heart failure when administered intravenously for less than or equal to 48 hours. This study examines the tolerability of long-term intravenous milrinone therapy and assesses its utility in allowing upward titration of oral vasodilator agents. A retrospective review of hospital records identified 63 patients who underwent hemodynamic monitoring and received intravenous milrinone for >24 hours in a critical care setting. Hemodynamics and medications were recorded before and after 24 hours of milrinone therapy. Additional medications, as well as any adverse events, were recorded throughout milrinone therapy. The mean dose of milrinone was 0.43 +/- 0.10 mu g/kg/min, with a mean duration of 12 +/- 15 days (range 1 to 70). Therapy was continued for >48 hours in 89% of patients, After 24 hours of milrinone therapy, patients exhibited significant improvements in pulmonary artery pressures, pulmonary capillary wedge pressures, and cardiac index. When compared with baseline, significantly more patients received angiotensin-converting enzyme (ACE) inhibitors after 24 hours of:milrinone and at the end of milrinone therapy (67% vs 86%, p <0.01). Likewise, significantly more patients also received oral hydralazine and/or nitrates at the end of milrinone therapy (38% vs 65%, p <0.01) when compared with baseline. The mean doses of most oral medications at the 3 time periods were similar. The ACE inhibitor dose was significantly higher at the end of milrinone therapy when compared with baseline, and hydralazine dose was significantly higher at the end of therapy when compared with 24 hours. Few adverse effects were noted, with only 10% of patients experiencing symptomatic ventricular tachycardia and 2 patients with significant hypotension requiring discontinuation of the drug. The adverse events were similar in the group of patients who received milrinon
Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action...
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Sildenafil, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), is a well-tolerated and highly effective treatment for erectile dysfunction. The mechanism of action of sildenafil depends on activation of the nitric oxide (NO)cGMP pathway during sexual stimulation, which results In corpus cavernosal smooth muscle relaxation and penile erection. Endogenously derived NO is also involved in blood pressure regulation through its effect on basal vascular tone, which is mediated by cGMP levels. Organic nitrates and NO donors exert their therapeutic effects on blood pressure and vascular smooth muscle by the same mechanism as endogenous NO. Since both sildenafil and organic nitrates exert their pharmacologic effects via increases in cGMP concentrations, a double-blind, placebo-controlled, crossover study was undertaken to investigate the effects of sildenafil coadministered with glyceryl trinitrate on blood pressure and heart rate in healthy male subjects. The hemodynamic effects of sildenafil were also evaluated in a second placebo-controlled crossover study in men with hypertension who were taking the calcium antagonist amlodipine, which has a mechanism of action that does not involve the cGMP pathway. In the first crossover study, subjects were treated with oral sildenafil (25 mg, 3 times a day for 4 days) or placebo and then challenged on day 4 with a 40-minute, stepwise, intravenous infusion of glyceryl trinitrate (0.5 mg/mL in 5% dextrose at an initial infusion rate of 2.5 mu g/min and doubling every 5 minutes to a maximum rate of 40 mu g/min) 1 hour after taking sildenafil or placebo. On day 5, subjects received a sublingual glyceryl trinitrate tablet (500 mu g) 1 hour after taking 25 mg of sildenafil or placebo. During sildenafil treatment, the subjects were significantly less tolerant of intravenously administered glyceryl trinitrate than during placebo treatment based on the occurrence of a >25 mm Hg decrease in
Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovast...
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Objective: To assess the effects of cilostazol on lovastatin pharmacokinetics. Design: This was a single-centre, open-label, multiple dose, sequential treatment study. Participants received single oral doses of lovastatin 80mg on days 1, 7 and 9, as well as oral cilostazol 100mg twice daily on days 2 to 8, followed by a single oral 150mg cilostazol dose on day 9. Study Participants: 15 healthy, nonsmoking male or female volunteers (aged 18 to 60 years) were enrolled, and 12 completed the study. Main Outcome Measures: Pharmacokinetic parameters were calculated using plasma concentrations of lovastatin and its beta-hydroxy metabolite and of cilostazol and its metabolites. Differences in the pharmacokinetics of each drug when given alone or in combination were assessed by analysis of variance. Results: The maximum observed plasma concentration (C-max) of lovastatin or its metabolite did not differ significantly when lovastatin was given alone and when it was given with 100mg of cilostazol. The mean ratios of the area under the plasma concentration-time curve from zero to the time of the last measurable concentration (AUC(t)) for lovastatin coadministered with 100mg of cilostazol to that with lovastatin given alone were 1.6 for lovastatin and 1.7 for its metabolite. With 150mg of cilostazol, lovastatin Cmax did not change, whereas Cmax of the metabolite increased 2.2-fold. The mean AUC(t) ratios for lovastatin given with 150mg cilostazol/lovastatin given alone were 1.6 and 2.0 for lovastatin and its metabolite, respectively. All increases in lovastatin and metabolite AUC were statistically significant, except for the 1.6-fold increase in lovastatin AUC with 150mg of cilostazol. Maximum steady-state plasma drug concentration (C(ss)max) and AUC during a dosage interval (AUC(tau)) for cilostazol 100mg twice daily decreased 14 and 15%, respectively, upon lovastatin coadministration. Conclusions: Lovastatin and metabolite exposure is increased only by up to 2-fold when cilos
The objectives of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (phase 2) were (1) to compare the efficacy, safety, and feasibility of recombinant hirudin versus unfractionated hepar...
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The objectives of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (phase 2) were (1) to compare the efficacy, safety, and feasibility of recombinant hirudin versus unfractionated heparin as short-term therapy in patients with acute coronary syndromes without ST elevation and (2) to compare the efficacy and safety of long-term therapy with warfarin and aspirin versus standard therapy with aspirin alone in the same patient population, Investigators at 31 Canadian centers randomized 909 patients to receive either medium-dose hirudin, low-dose hirudin, or unfractionated heparin, The incidence of the 7-day primary composite outcome of cardiovascular death, new myocardial infarction (MI), or refractory angina was significantly tower among patients who received hirudin than among those assigned to unfractionated heparin, A subset of these patients was subsequently randomized to long-term, low-intensity (international normalized ratio [INR] <1.5) or moderate-intensity (INR 2-2.5) anticoagulant treatment with warfarin or to standard therapy. In this substudy, promising results were observed in favor of moderate-intensity warfarin. These findings provided the rationale for the design and conduct of the large-scale, phase III OASIS-2 trial. (C) 1999 by Excerpta Medico, Inc.
A retrospective study has been carried out to assess the effectiveness of indomethacin in preventing heterotopic ossification after total hip arthroplasty, and the effect of using it for different periods of time. One...
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A retrospective study has been carried out to assess the effectiveness of indomethacin in preventing heterotopic ossification after total hip arthroplasty, and the effect of using it for different periods of time. One hundred and sixty-eight hips operated on in 1983 were not given indomethacin and acted as a control. One hundred and fifty hips operated on in 1988 were given indomethacin and divided into 3 groups: 42 received indomethacin for 5 days, 49 for 11 days and 59 for 45 days. The results indicate that ossification is significantly reduced in those patients receiving indomethacin for 5 and 11 days, but there was no additional reduction when it was given for 45 days. Treatment should begin on the night of operation and continued for 11 days while the patient remains in hospital.
OBJECTIVE Hormone replacement therapy (HRT) is usually prescribed as medium- to high-dose formulations. Little is known, however, about dose-dependency of oestrogen effects on plasma hormone levels, markers of cardiov...
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OBJECTIVE Hormone replacement therapy (HRT) is usually prescribed as medium- to high-dose formulations. Little is known, however, about dose-dependency of oestrogen effects on plasma hormone levels, markers of cardiovascular risk in lipid metabolism and the haemostatic system, or markers of bone turnover. SUBJECTS AND DESIGN In an open trial, three groups of 12 or 13 healthy, non-obese postmenopausal women received conjugated equine oestrogens (CEE) for 6 months at doses of 0.3 mg/day (group 1), 0.6 mg/day (group 2) or 1.25 mg/day (group 3). From day 1 to day 10, CEE was administered alone, and from day ii to day 21, in combination with 5 mg of medrogestone. Each treatment cycle was followed by a pause of 7 days. Fasting blood samples were obtained before treatment as well as on days in, 21 and 28 of the first, third and sixth months on treatment. All results obtained on day 10 were grouped together as phase A, on day 21 as phase B, and on day 28 as phase C. MEASUREMENTS Plasma concentrations of oestradiol (E), dehydroepiandrosterone sulphate (DHEA-S), total testosterone (T), FSH, PRL, sex hormone binding globulin (SHBG), type 1 procollagen propeptide (PICP) and the cross-linked carboxyterminal telopeptide of type I collagen (ICTP), total cholesterol, HDL-cholesterol, triglycerides (TG), apolipoprotein (apo) A-1, apo B, lipoprotein(a)[Lp (a)], fibrinogen, factor VIIe and plasminogen activator inhibitor 1 (PAI-1) were evaluated with commercially available kits. RESULTS Dose-dependently, the three regimens increased E, SHBG and factor Vile activity and decreased FSH, DHEAS, cholesterol, LDL-cholesterol and apoB. HDL-cholesterol and apoA-1 were slightly decreased in group 1 but increased in groups 2 and 3. The high CEE dosage in group 3 resulted in a significant increase of TG and decrease of Lp(a) and PAI-1. Markers of bone turnover were not significantly changed by any CEE dosage. CONCLUSIONS Six months of treatment with 0.3 mg/day of conjugated equine oestrogen sign
Objective: The pharmacokinetics of cilostazol were studied in patients with mild, moderate and severe renal impairment and in healthy volunteers after administration of 50mg single and multiple doses of cilostazol. De...
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Objective: The pharmacokinetics of cilostazol were studied in patients with mild, moderate and severe renal impairment and in healthy volunteers after administration of 50mg single and multiple doses of cilostazol. Design: This was an open-label, single and multiple dose study administering 50mg cilostazol every 12 hours to healthy volunteers and patients with varying degrees of renal impairment. Participants: 6 normal volunteers [creatinine clearance (CLCR) greater than or equal to 90 ml/min];6 patients with mild (CLCR 50 to 89 ml/min), 5 with moderate (CLCR 26 to 49 ml/min) and 6 with severe (CLCR 5 to 25 ml/min) renal impairment. Outcome Measures: Noncompartmental pharmacokinetic parameters were determined for each study participant. Results: At steady state, in the severe renal disease group, cilostazol and OPC-13015 peak concentrations (C-max) were 24 and 41% lower and the areas under the concentration-time curve over the dosage interval (AUC(tau)) 39 and 47% lower than in the healthy volunteers. C-max and AUC(tau) of OPC-13213 were significantly higher, 173 and 209%, respectively, than those in the healthy volunteers. The accumulation ratios were not significantly different between the various renal function groups for cilostazol and its metabolites. The estimated pharmacological activity of cilostazol and its metabolites was similar between the normal volunteers and those with severe renal impairment. Conclusions: A dosage reduction in renally impaired patients is not supported by the pharmacokinetics of cilostazol and its metabolites in this patient group.
OBJECTIVES We sought to study the effect of early infusion of abciximab on coronary patency before primary angioplasty in patients with acute myocardial infarction. BACKGROUND Glycoprotein IIb/IIIa antagonists have pr...
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OBJECTIVES We sought to study the effect of early infusion of abciximab on coronary patency before primary angioplasty in patients with acute myocardial infarction. BACKGROUND Glycoprotein IIb/IIIa antagonists have proved to be effective in reducing ischemic events associated with coronary angioplasty. The present study explores whether abciximab alone, without administration of thrombolytic therapy, may induct reperfusion in patients with acute myocardial infarction. METHODS In the Glycoprotein Receptor Antagonist Patency Evaluation pilot study 60 patients with less than 6 h signs and symptoms of acute myocardial infarction eligible for primary angioplasty received in the emergency room a bolus of abciximab 250 mu g/kg followed by a 12-h infusion of 10 mu g/min. All patients were also treated with an oral dose of 160 mg aspirin and 5,000 IU of heparin intravenously, As soon as possible a diagnostic angiography was performed to evaluate the patency of the infarct-related artery. RESULTS The median time between onset of symptoms and the administration of the abciximab bolus was 150 min (range 45 to 345), and the median time between abciximab bolus and first contrast injection in the infarct-related artery was 45 min (range 10 to 150). In 24 patients (40%, 95% confidence interval 28% to 52%) Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 was observed at a median time of 45 min (range 10 to 150) after abciximab bolus;TIMI flow grade 3 was observed in 11 patients (18%, 95% confidence interval 9% to 28%). There was no difference fn percentage of TIMI flow grade 2 or 3 between patients who received abciximab within 2.5 h after onset of symptoms or thereafter. CONCLUSIONS Abciximab therapy given in the emergency room in patients awaiting primary angioplasty is associated with full reperfusion (TIMI flow grade 3) in about 20% and with TIMI flow grade 2 of 3 in about 40% of the patients at a median time of 45 min. These figures are higher than those in primar
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