Effects of terazosin therapy on blood pressure in men with benign prostatic hyperplasia concurrently treated with other antihypertensive medications.

OBJECTIVES: To review and assess the cardiovascular safety of the alpha1-blocker terazosin when used to treat symptomatic benign prostatic hyperplasia (BPH) in patients taking concurrent antihypertensive medications. METHODS: This retrospective analysis focused on blood pressure changes and blood pressure-related side effects in 555 of 2084 patients randomized to either terazosin or placebo in the Hytrin Community Assessment Trial (HYCAT) study who were following either single or combination antihypertensive regimens (treated patients). We also compared results in normotensive and hypertensive patients, whether treated or not. RESULTS: The addition of terazosin lowered mean systolic blood pressure by 5.3 mm Hg for untreated patients and 6.7 mm Hg for treated patients. For patients hypertensive on entry, mean reductions in systolic blood pressure in those untreated and treated were 12.1 and 11.1 mm Hg, respectively. The addition of terazosin to an existing antihypertensive regimen had its greatest impact (a mean reduction of 12.3 mm Hg) in those receiving diuretic therapy alone. Diastolic pressure changes followed a similar pattern. The incidences of blood pressure-related side effects in patients on terazosin were comparable between untreated (13.5%) and treated patients (14.3%), as were premature withdrawal rates, with 4.2% of untreated patients and 4.5% of treated patients withdrawing due to blood pressure-related side effects. CONCLUSIONS: Terazosin can be safely used to treat patients with symptomatic BPH regardless of their blood pressure status and antihypertensive regimen. Terazosin may be safely added to ongoing antihypertensive therapy.

Protamine reversal of heparin affects platelet aggregation and activated clotting time after cardiopulmonary bypass.

UNLABELLED: Bleeding after cardiopulmonary bypass (CPB) is related to multiple factors. Excess protamine weakens clot structure and decreases platelet function; therefore, an increased activated clotting time (ACT) after protamine reversal of heparin may be misinterpreted as residual heparin anticoagulation. We evaluated the effects of protamine, recombinant platelet factor 4 (rPF4), and hexadimethrine on ACT in blood obtained after CPB. In addition, we examined the effect of protamine on in vitro platelet aggregation. Incremental doses of protamine, rPF4, and hexadimethrine were added to heparinized blood from CPB, and ACTs were performed. Incremental concentrations of protamine were added to heparinized platelet-rich plasma, and aggregometry was induced by adenosine diphosphate (ADP) and collagen. The mean heparin concentration at the end of CPB was 3.3 U/mL. Protamine to heparin ratios >1.3:1 produced a significant prolongation of the ACT that was not seen with rPF4 and was observed only with 5:1 hexadimethrine to heparin ratios. ADP-induced platelet aggregation was reduced with protamine administration > or =1.3:1. Excessive protamine reversal of heparin prolongs ACT and alters ADP-induced platelet aggregation in a dose-dependent manner in vitro. Additional protamine administered to treat a prolonged ACT may further increase clotting time, reduce platelet aggregation, and potentially contribute to excess bleeding after CPB. IMPLICATIONS: We found that excess protamine prolonged the activated clotting time and altered platelet function after cardiopulmonary bypass, whereas heparin antagonists, such as recombinant platelet factor 4 and hexadimethrine, exhibited a wider therapeutic range without adversely affecting the activated clotting time. Approaches to avoid excess protamine or use of alternative heparin antagonists after cardiopulmonary bypass may be beneficial.

Serial prostate-specific antigen measurements in men with clinically benign prostatic hyperplasia during a 12-month placebo-controlled study with terazosin. HYCAT Investigator Group. Hytrin Community Assessment Trial.

OBJECTIVES: To prospectively analyze whether the treatment of men with clinically benign prostatic hyperplasia (BPH) with alpha blocking agents affects the serum prostate-specific antigen (PSA) levels, and to determine the magnitude of such effect. METHODS: Serial PSA measurements were performed using the Abbott IMx assay over 1 year in 134 men over the age of 55 years participating in the Hytrin Community Assessment Trial (HYCAT). HYCAT is a 1-year, randomized, placebo-controlled, double-blinded study of the alpha1-adrenergic antagonist terazosin. All men had lower urinary tract symptoms and a clinical diagnosis of BPH with an American Urological Association (AUA) symptom index of 13 points or more, an AUA bother score of 8 points or more, and a peak urinary flow rate of less than 15 mL/s. PSA was measured at baseline and at 8, 26, 39, and 52 (end of study) weeks. RESULTS: Baseline serum PSA levels weakly correlated with patients' age at study entry, and modestly with residual urine (positive correlation) and peak flow rate (negative correlation), although none of the levels were statistically significant. Changes of serum PSA during the course of the study did not correlate with either one of the symptom severity or bother assessment tools, residual urine, or peak flow rate. Mean PSA increased from a baseline of 2.5+/-0.22 ng/mL (mean+/-SE) by 0.5+/-0.11 ng/mL in the placebo-, and from 2.7+/-0.23 ng/mL by 0.3+/-0.11 ng/mL in the terazosin-treated patients (P = 0.36 by ANOVA). There were no differences in the changes in serum PSA when patients were stratified by decade of life according to the age-specific PSA reference ranges, or by the final dose of terazosin (2, 5, or 10 mg daily). CONCLUSIONS: The treatment of men with lower urinary tract symptoms and clinical BPH with the alpha1-adrenergic antagonist terazosin does not affect serum PSA concentration, and thus does not confound longitudinal monitoring of serum PSA levels in patients at risk for prostate carcinoma.

Exogenous and endogenous transforming growth factors-beta influence elastin gene expression in cultured lung fibroblasts.

Elastin, an important structural protein of the extracellular matrix, confers elastic properties on the pulmonary alveolar interstitium. In the alveolar wall, elastin is primarily produced postnatally by fibroblasts. The mechanisms that regulate lung fibroblast (LF) elastin gene expression have not been completely defined, although both transcriptional and posttranscriptional mechanisms appear to be involved. Transforming growth factors-beta (TGF-beta s) have been shown to increase elastin production by cultured neonatal rat LF. Analyses of elastin gene transcription and mRNA stability indicate that exogenous TGF-beta 1 increases the half-life of tropoelastin mRNA by 1.5-fold and does not alter elastin gene transcription. Interference with the functions of endogenous TGF-beta 1 in cultured LF, through the addition of neutralizing antibodies or antisense oligodeoxynucleotides, decreases tropoelastin and tropoelastin mRNA production by these cells. The content of total (latent plus active) TGF-beta s was approximately 4.5-fold greater in lungs obtained from rats on postnatal day 8 than in lungs obtained from adults. These findings indicate that endogenous TGF-beta s, in cultured LF, regulate elastin gene expression, most likely by a posttranscriptional mechanism. Since others have shown that elastin mRNA appears to have a longer half-life in neonatal than in adult rat lungs, we hypothesize that the higher content of TGF-beta s could contribute to the greater elastin mRNA stability in neonatal lungs.

Peroxisome proliferators alter lipid acquisition and elastin gene expression in neonatal rat lung fibroblasts.

During the alveolar stage of lung development, lipid droplet-laden interstitial cells are present at the base of elongating alveolar septa. These cells that have been named lipid interstitial cells or lipofibroblasts (LFs) may supply lipids for surfactant production, the synthesis of membrane phospholipids, and/or energy metabolism. They also have myofibroblastic characteristics and participate in the generation of the interstitial elastic fiber network, that is, in the pulmonary alveolar septum. To understand how this cell regulates its lipid-storing and elastin-producing properties, we have examined the effects of peroxisome proliferators on the expression of the genes that are associated with an elastin-producing myofibroblastic phenotype or an adipocyte-like phenotype. Two known ligands for peroxisome proliferator-activated receptors, 5,8,11,14-eicosatetraynoic acid (ETYA) and 15-deoxy-delta-12,14-prostaglandin J2 (15-dPGJ2), decrease elastin gene transcription and the steady-state levels of tropoelastin (TE) and alpha-smooth muscle actin mRNAs in cultured LFs. Concurrently, cultured LFs increase the expression of adipocyte lipid binding protein, which is regarded as an adipocyte-specific protein, and accumulate lipid droplets. Their abilities to store lipids and express desmin intermediate filaments, alpha-smooth muscle actin, and smooth muscle myosin heavy chain in contractile filaments in vitro illustrate similarities among the pulmonary LF, the hepatic lipocyte, and the contractile interstitial cell, which contribute to the repair reaction in the lung after pulmonary injury.

Stratification of sudden death risk in patients receiving long-term amiodarone treatment for sustained ventricular tachycardia or ventricular fibrillation.

One hundred twenty-two patients treated chronically with amiodarone for sustained ventricular tachycardia or ventricular fibrillation after failing conventional antiarrhythmic therapy were analyzed to determine which factors were predictive of sudden cardiac death during follow-up. The mean left ventricular ejection fraction in the study group was 0.32, and 87% of the patients had coronary artery disease with a prior myocardial infarction. During a median follow-up of 19.5 months, 30 patients died suddenly. The only variable that was predictive of sudden death was left ventricular ejection fraction. Twenty-nine of the 84 patients with ejection fractions < 0.40 died suddenly, compared with 1 of 35 patients with ejection fractions > or = 0.40. The actuarial probability of sudden death at 5 years was 49% when the ejection fraction was < 0.40, and 5% when the ejection fraction was > or = 0.40 (p = 0.0004). These results indicate that patients treated with amiodarone for sustained ventricular tachycardia or ventricular fibrillation whose ejection fractions are > or = 0.40 are at low risk for sudden death. Patients with ejection fractions < 0.40 remain at high risk for sudden death, and should be considered for additional or alternative therapy.