Moxonidine treatment of hypertensive patients with advanced renal failure.

OBJECTIVES: To compare safety and tolerability of moxonidine versus nitrendipine in hypertensive patients with renal failure. A secondary endpoint was to test whether the sympatholytic drug moxonidine slows decline of renal function when added to standard therapy with an angiotensin-converting enzyme inhibitor or AT(1) receptor antagonist plus loop diuretic. DESIGN: This prospective, randomized, double-blind, multicenter study recruited 177 patients with advanced renal failure receiving antihypertensive standard therapy at outpatient clinics in Germany and Hungary. Following a 2 week run-in, patients were randomized to 24 weeks of add-on treatment with 0.3 mg/day moxonidine or 20 mg/day nitrendipine. RESULTS: The incidence of pre-defined specific adverse events was 42% in the moxonidine (37/89 patients) and 46% in the nitrendipine group (38/82 patients) in intention-to-treat analysis. Intensity and multiplicity were comparable. The dropout rate due to adverse events was 12.4% in the moxonidine and 9.8% in the nitrendipine group. Creatinine clearance according to Cockcroft and Gault decreased by 0.5 +/- 4.3 ml/min (mean +/- standard deviation) in the moxonidine group and 2.3 +/- 4.0 ml/min in the nitrendipine group. Serum creatinine increased by 12.7 +/- 49.2 micromol/l in the moxonidine group and by 43.4 +/- 71.3 micromol/l in the nitrendipine group. These differences were statistically significant (P < 0.05). CONCLUSION: Add-on treatment with 0.3 mg/day moxonidine in hypertensive patients with renal failure is well tolerated and not inferior to 20 mg/day nitrendipine with respect to the incidence of specific adverse events. The idea of a sympatholytic drug to be renoprotective is appealing but needs further evaluation.

Prospective evaluation of early abciximab and primary percutaneous intervention for patients with ST elevation myocardial infarction complicated by cardiogenic shock: results of the REO-SHOCK trial.

OBJECTIVE: Patients with acute myocardial infarction complicated by cardiogenic shock have a high mortality despite the use of early reperfusion therapies with thrombolysis or percutaneous coronary intervention (PCI). Therefore, there is still need to evaluate therapy strategies in these patients. DESIGN: The REO-SHOCK trial was a prospective, non-randomized study, aimed at evaluation of a routine strategy of early abciximab and PCI in a high-risk group of acute ST elevation myocardial infarction (STEMI) patients with cardiogenic shock. RESULTS: Patients (n = 40) planned for coronary angioplasty or stenting received abciximab (0.25 mg/kg bolus followed by 0.125 mg/kg/minute over 12 hours), heparin and aspirin. The intervention was successful in 92.5% of the patients and achieved Thrombolysis In Myocardial Infarction (TIMI) grade 3 patency in 32 patients (80%). The primary endpoint, total mortality after 30 days, was observed in 42.5% (17/40), and was significantly different between patients aged > 75 years and patients aged 75 years (91% versus 24%, respectively; p < 0.001). Major bleeding occurred in 2 patients (5%), but stroke occurred in none. CONCLUSION: A strategy of abciximab with primary PCI in high-risk patients with cardiogenic shock is safe, associated with a high procedural success rate and seems to improve outcomes in patients < 75 years old.

Duloxetine in the treatment of stress urinary incontinence.

Stress urinary incontinence (SUI) is the most common form of urinary incontinence and occurs more frequently in women than in men. Duloxetine is a balanced dual serotonin (5-HT) and norepinephrine (NE) reuptake inhibitor and shows no relevant binding affinity for histaminergic, dopaminergic, cholinergic, and adrenergic receptors. The efficacy of duloxetine in SUI is based on the inhibition of the presynaptic reuptake of 5-HT and NE in Onuf's nucleus of the sacral spinal cord, whereby it may increase the concentration of 5-HT and NE in the synaptic cleft. The effectiveness of duloxetine was studied in a cat model of acetic acid-induced bladder irritation. The results showed that in cats with previous irritated bladder function, there was a dosage-dependent improvement of bladder capacity and periurethral electromyography (EMG) activity. In women with SUI, it is assumed that the clinical efficacy of duloxetine is based on stronger urethral contraction and persistent sphincter tone during the storage phase. In clinical trials in women with SUI, duloxetine has demonstrated efficacy in reducing incontinence episodes and increasing quality of life. Nausea was the most common adverse event and the main cause for discontinuation. In summary, duloxetine appears to be a promising new option for the treatment of SUI.

Duloxetine: mechanism of action at the lower urinary tract and Onuf's nucleus.

Urinary incontinence is the inability to willingly control bladder voiding. Stress urinary incontinence (SUI) is the most frequently occurring type of incontinence in women. No widely accepted or approved drug therapy is yet available for the treatment of stress urinary incontinence. Numerous studies have implicated the neurotransmitters, serotonin and norepinephrine in the central neural control of the lower urinary tract function. The pudendal somatic motor nucleus of the spinal cord is densely innervated by 5HT and NE terminals. Pharmacological studies confirm central modulation of the lower urinary tract activity by 5HT and NE receptor agonists and antagonists. Duloxetine is a combined serotonin/norepinephrine reuptake inhibitor currently under clinical investigation for the treatment of women with stress urinary incontinence. Duloxetine exerts balanced in vivo reuptake inhibition of 5HT and NE and exhibits no appreciable binding affinity for receptors of neurotransmitters. The action of duloxetine in the treatment of stress urinary incontinence is associated with reuptake inhibition of serotonin and norepinephrine at the presynaptic neuron in Onuf's nucleus of the sacral spinal cord. In cats, whose bladder had initially been irritated with acetic acid, a dose-dependent improvement of the bladder capacity (5-fold) and periurethral EMG activity (8-fold) of the striated sphincter muscles was found. In a double blind, randomized, placebo-controlled, clinical trial in women with stress urinary incontinence, there was a significant reduction in urinary incontinence episodes under duloxetine treatment. In summary, the pharmacological effect of duloxetine to increase the activity of the striated urethral sphincter together with clinical results indicate that duloxetine has an interesting therapeutic potential in patients with stress urinary incontinence.

Laboratory monitoring of heparin and the combination of heparin and the platelet glycoprotein IIb/IIIa receptor antibody fragment abciximab (c7E3) in patients undergoing percutaneous transluminal coronary angioplasty (PTCA).

BACKGROUND: Previous studies in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have restricted laboratory monitoring to the activated clotting time (ACT). It remains unknown whether the ACT-prolonging effect of abciximab is clinically equivalent to a comparable degree of anti-coagulation by heparin. PATIENTS AND METHODS: 30 patients undergoing PTCA received 100 IU of heparin/kg body weight. Another 30 patients received an initial bolus of 70 IU of heparin/kg + abciximab. We determined ACT, laboratory and onsite activated partial thromboplastin time (APTT) and plasma heparin levels. RESULTS: Despite markedly different preintervention heparin dosing, the ACTs were not significantly different between groups. After termination of PTCA, the median ACTs of both study groups were nearly equivalent (267 vs. 272 s; p = 0.79). The median ACT-prolonging effect of abciximab could be equated with 0.68 IU/ml heparin. Both APTT assays were not suitable for monitoring the anticoagulant effects during PTCA due to their high sensitivity. By contrast, the plasma heparin levels clearly reflected the different heparin doses. The weak correlation (r = 0.23) between ACTs and heparin levels in patients receiving heparin + abciximab was due to excessively prolonged ACTs in six patients (540-1,245 s). These data could be attributed to an unusually high response to abciximab. By contrast, the ACT was a reliable measure of the anticoagulant effect of heparin in patients receiving exclusively heparin. CONCLUSIONS: ACT reflects both heparin and abciximab therapy, whereas heparin levels reflect only heparin dose. The APTT assays were not suitable for monitoring the anticoagulant effects during PTCA.