[Interest of a systematic assessment of the treatment of the lower urinary tract symptoms in the management of benign prostatic hypertrophy in general practice (1380 patients) - Study EVALURO]. / Intérêt d'une évaluation systématique du traitement des symptômes du bas appareil urinaire dans la prise en charge d'une hypertrophie bénigne de la prostate en médecine générale (1380 patients) ­ Étude EVALURO.

OBJECTIVE: To evaluate the efficacy of a modification or initiation of treatment by a α-blocker in patients already medically treated for BPH-related LUTS, with persistent urinary symptoms. METHODS: This is a prospective observational study among general practitioners in France. Included patients were over 60 years of age with BPH-related LUTS who had been medically treated for at least 6 months. A treatment by an α-blocker was initiated or modified if the PGI-I (Patient Global Impression of Improvement) did not objective any improvement under treatment and the IPSS (International Prostate Symptom Score) was≥8. Patients were followed up between 1 and 3 months after inclusion. The primary endpoint was the frequency of unsatisfactory progression of patients, assessed by persistence of urinary symptoms under treatment (IPSS≥8 and PGI-I unchanged or worsened). Progress of LUTS (IPSS and PGI-I) following modification of treatment with α-blocker was also assessed at the follow-up visit. RESULTS: Three hundred and fifty-three physicians included 1449 patients between February 2, 2016 and March 9, 2017 (1380 patients were analyzed): the average age was 70.0±6.9 years ; the duration of the LUTS was 4.1±4.2 years; at inclusion, they received mainly plants (n=744; 53.9%) and α-blockers (n=463; 33.6%); the mean IPSS score was 16.4±6.7, it was not correlated with duration of SBAU; the mean PGi-I was 2.6±1.2. In total, 48.8% (612/1255) of patients had a non-satisfactory evaluation of the LUTS; 42.8% (591/1380) of patients had a modification of treatment according to the protocol: 385 (65.6%) had an initiation of a α-blocker, 202 (34.4%) had a modification of treatment by α-blocker (4 missing data). The α-blocker was monotherapy for 484 (81.9%) patients. At the follow-up visit (1 to 3 months), the average IPSS score was 7.7±4.8, significantly lower (18.7±6.1 at inclusion); the average PGI-I of 1.2±0.7 was significantly lower (3.5±0.8 at inclusion); the quality of life (Q8-IPSS) was significantly improved. For the 345 patients under plant extracts having changed for one α-blocker, as well as for the 67 patients under α-blocker having changed for another α-blocker, the 3 scores had decreased significantly. CONCLUSION: A systematic evaluation of medical treatment for BPH showed that 48.8% of patients medically treated for at least 6 months were not improved. A modification of treatment by an α-blocker (initiation or modification) can then significantly improve the LUTS.

An Assessment of the Permeation Enhancer, 1-phenyl-piperazine (PPZ), on Paracellular Flux Across Rat Intestinal Mucosae in Ussing Chambers.

PURPOSE: 1-phenyl piperazine (PPZ) emerged from a Caco-2 monolayer screen as having high enhancement potential due to a capacity to increase permeation without significant toxicity. Our aim was to further explore the efficacy and toxicity of PPZ in rat ileal and colonic mucosae in order to assess its true translation potential. METHODS: Intestinal mucosae were mounted in Ussing chambers and apparent permeability coefficient (Papp) values of [(14)C]-mannitol and FITC-dextran 4 kDa (FD-4) and transepithelial electrical resistance (TEER) values were obtained following apical addition of PPZ (0.6-60 mM). Exposed issues were assessed for toxicity by histopathology and lactate dehydrogenase (LDH) release. Mucosal recovery after exposure was also assessed using TEER readings. RESULTS: PPZ reversibly increased the Papp of both agents across rat ileal and distal colonic mucosae in concentration-dependent fashion, accompanied by TEER reduction, with acceptable levels of tissue damage. The complex mechanism of tight junction opening was part mediated by myosin light chain kinase, stimulation of transepithelial electrogenic chloride secretion, and involved activation of 5-HT4 receptors. CONCLUSIONS: PPZ is an efficacious and benign intestinal permeation enhancer in tissue mucosae. However, its active pharmacology suggest that potential for further development in an oral formulation for poorly permeable molecules will be difficult.

Clinical progression, acute urinary retention, prostate-related surgeries, and costs in patients with benign prostatic hyperplasia taking early versus delayed combination 5α-reductase inhibitor therapy and α-blocker therapy: a retrospective analysis.

BACKGROUND: Two previous retrospective database analyses compared early combination therapy with an α-blocker (AB) and 5-α reductase inhibitor (5-ARI) to delayed combination therapy and found that patients receiving the delayed combination therapy were more likely to have clinical progression, acute urinary retention (AUR), and surgery. Although these studies indicate the clinical benefits of early treatment, both studies failed to take into account important baseline clinical measures, such as prostate-specific antigen (PSA) values. OBJECTIVE: This study was designed to compare clinical and cost differences in men with benign prostatic hyperplasia (BPH) who initiated early versus delayed combination therapy with a 5-ARI + an AB, factoring in baseline PSA values. METHODS: This retrospective claims data analysis assessed data from >14 million US men with linked medical data, pharmacy data, laboratory results, and enrollment information from January 1, 2000, to December 31, 2009. Men aged 50 or older and treated for BPH with a 5-ARI + an AB were identified. Patients were required to be eligible for services at least 6 months before and 12 months after the index medication date. Patients were assigned to 1 of 2 treatment groups based on therapy (early or delayed) and 3 cohorts based on availability of PSA laboratory values (patients with a PSA value, patients with a PSA value >1.5 and <10, and all patients). Using a logistic model, the likelihood of clinical progression (defined as the occurrence of AUR or prostate surgery) during the 12 months after the date of first prescription fill was compared between BPH patients receiving early versus delayed combination therapy. BPH-related medical costs (excluding pharmacy costs) were assessed using generalized linear models. RESULTS: Among the 13,551 patients identified for study inclusion, the highest risks for clinical progression, AUR, and prostate-related surgery were consistently demonstrated in patients with a PSA >1.5 and <10. Across all 3 cohorts, the delayed combination-treatment group was more likely to have clinical progression, AUR, and prostate-related surgeries versus the early combination-treatment group. The incremental difference in BPH-related costs between the delayed and early combination-treatment groups was $190 per patient overall; the greatest incremental difference ($397) was observed in patients with PSA >1.5 and <10. CONCLUSIONS: The results suggest that early initiation of combination therapy with 5-ARI + an AB, compared with delayed initiation, can reduce the risks for clinical progression, AUR, and prostate-related surgeries, as well as BPH-related medical costs, in patients with BPH.

Are metabolic risk factors and target organ damage more frequent in masked hypertension than in white coat hypertension?

Patients with masked hypertension (MH) tend to have a higher risk than those with white-coat hypertension (WCH). Therefore, we evaluated the characteristics of MH and WCH in Korean patients receiving medical treatment for hypertension. We enrolled 1019 outpatients (56 ± 10 y, 488 males) with diagnosed hypertension who had not changed oral anti-hypertensive medication for 6 months. Clinic blood pressure (CBP) was checked by a nurse and doctor twice per visit. Home BP (HBP) was checked every morning and evening for 1 week. In the MH patients, mean CBP was 130/80 mmHg, whereas HBP was 137/86 mmHg. In the WCH patients, mean CBP was 149/86 mmHg by physician and 143/85 mmHg by nurse and mean HBP was 124/75 mmHg. Age and gender did not differ between the groups. Waist and hip circumferences and the level of fasting glucose were higher in patients with MH than in patients with WCH (p = 0.008, 0.016, 0.009, respectively). Metabolic risk factors were more frequent in patients with WCH, MH, and uncontrolled hypertension than in patients with controlled hypertension. The incidence of metabolic risk factors, however, did not differ between patients with WCH and MH. Heart damage was more frequent in MH than in WCH (p = 0.03). The incidence of metabolic risk factors did not differ between patients with WCH and those with MH. Target organ damage was more closely related to MH than to WCH. Home BP measurement was a useful tool for discriminating WCH and MH in patients with hypertension.

Erectile dysfunction in spinal cord injury: a cost-utility analysis.

BACKGROUND: There is a high incidence of erectile dysfunction after spinal cord injury. This can have a profound effect on quality of life. Treatment options for erectile dysfunction include sildenafil, intracavernous injections of papaverine/alprostadil (Caverject), alprostadil/papaverine/phentolamine ("Triple Mix"), transurethral suppository (MUSE), surgically implanted prosthetic device and vacuum erection devices. However, physical impairments and accessibility may preclude patient self-utilization of non-oral treatments. METHODS: The costs and utilities of oral and non-oral erectile dysfunction treatments in a spinal cord injury population were examined in a cost-utility analysis conducted from a government payer perspective. Subjects with spinal cord injury (n=59) reported health preferences using the standard gamble technique. RESULTS: There was a higher health preference for oral therapy. The cost-effectiveness results indicated that sildenafil was the dominant economic strategy when compared with surgically implanted prosthetic devices, MUSE(R) and Caverject. The incremental cost-utility ratios comparing sildenafil with triple mix and vacuum erection devices favoured sildenafil, with ratios less than CAN$20,000 per quality adjusted life year gained. CONCLUSION: Based on this study, we conclude that sildenafil is a cost-effective treatment for erectile dysfunction in the spinal cord injury population.

Clinical and duplex US assessment of effects of sildenafil on cavernosal arteries of the penis: comparison with intracavernosal injection of vasoactive agents--initial experience.

PURPOSE: To prospectively evaluate the clinical response and hemodynamic changes in cavernosal arteries after oral administration of sildenafil without and with audiovisual sexual stimulation and to compare those responses with responses from intracavernosal injections of vasoactive agents. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained. Thirteen consecutive patients (age range, 22-77 years; mean, 60.4 years) with erectile dysfunction were evaluated with clinical assessment and cavernosal duplex ultrasonography (US). The patients were examined at two sessions 3 weeks apart. First, each patient received 100 mg of sildenafil citrate orally and was examined 60 minutes later without any sexual stimulation. Each patient then underwent repeat clinical and duplex US assessment after audiovisual sexual stimulation. Three weeks later, the patients underwent identical clinical evaluation and duplex US after intracavernosal injection of a commercially available combination of papaverine, prostaglandin E1, and phentolamine. Clinical and duplex US data (ie, peak systolic velocity [PSV]) were examined by using the Wilcoxon signed rank test for matched pairs. RESULTS: At rest, the overall mean cavernosal artery PSV was 1.08 cm/sec and remained unchanged after intake of sildenafil without any audiovisual stimulation, with no clinical evidence of erection. With the addition of audiovisual sexual stimulation, eight (62%) of 13 patients had penile congestion or erection, and six (46%) had a PSV greater than 25 cm/sec. With intracavernosal injection of the combination of three drugs, all 13 patients achieved congestion or erection, and 10 (77%) had a PSV greater than 25 cm/sec. Both clinical and duplex US responses to intracavernosal injection were significantly greater than they were to sildenafil with audiovisual sexual stimulation (P = .04 and .003, respectively). CONCLUSION: Oral sildenafil with audiovisual sexual stimulation led to a significant clinical response and increment in blood flow in the cavernosal arteries. However, more patients responded to intracavernosal injection of the combination of three drugs than to sildenafil, and the clinical response was significantly better.

Clinical assessment of drug-induced QT prolongation in association with heart rate changes.

BACKGROUND: The formulas for heart rate (HR) correction of QT interval have been shown to overcorrect or undercorrect this interval with changes in HR. A Holter-monitoring method avoiding the need for any correction formulas is proposed as a means to assess drug-induced QT interval changes. METHODS: A thorough QT study included 2 single doses of the alpha1-adrenergic receptor blocker alfuzosin, placebo, and a QT-positive control arm (moxifloxacin) in 48 healthy subjects. Bazett, Fridericia, population-specific (QTcN), and subject-specific (QTcNi) correction formulas were applied to 12-lead electrocardio-graphic recording data. QT1000 (QT at RR = 1000 ms), QT largest bin (at the largest sample size bin), and QT average (average QT of all RR bins) were obtained from Holter recordings by use of custom software to perform rate-independent QT analysis. RESULTS: The 3 Holter end points provided similar results, as follows: Moxifloxacin-induced QT prolongation was 7.0 ms (95% confidence interval [CI], 4.4-9.6 ms) for QT1000, 6.9 ms (95% CI, 4.8-9.1 ms) for QT largest bin, and 6.6 ms (95% CI, 4.6-8.6 ms) for QT average. At the therapeutic dose (10 mg), alfuzosin did not induce significant change in the QT. The 40-mg dose of alfuzosin increased HR by 3.7 beats/min and induced a small QT1000 increase of 2.9 ms (95% CI, 0.3-5.5 ms) (QTcN, +4.6 ms [95% CI, 2.1-7.0 ms]; QTcNi, +4.7 ms [95% CI, 2.2-7.1 ms]). Data corrected by "universal" correction formulas still showed rate dependency and yielded larger QTc change estimations. The Holter method was able to show the drug-induced changes in QT rate dependence. CONCLUSIONS: The direct Holter-based QT interval measurement method provides an alternative approach to measure rate-independent estimates of QT interval changes during treatment.

[Primary antiphospholipid syndrome associated with malignant hypertension]. / Síndrome antifosfolipídico primario e HTA maligna.

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies and recurrent thrombosis, affecting the venous system more frequently than the arterial one. Renal involvement is only observed in approximately 20-25% of cases, main renal artery thrombosis has been exceptionally described. We report a 39-year-old woman with previous history of recurrent thrombosis diagnosed as primary antiphospholipid syndrome, who presented malignant hypertension in the context of a renal artery thrombosis. She had a high IgG anticardiolipin antibody titre and positive lupus anticoagulant. An isotopic renogram demonstrated asymmetrical activity (60% right vs 40% left kidney). Renal arteriography demonstrated preoclusive thrombosis in the left renal artery. Blood pressure was well controlled by the use of ACE-inhibitor and alpha blockers.

The incidence and management of priapism in Western Australia: a 16 year audit.

The objective of the study was to conduct a retrospective audit of patients who presented with priapism in Western Australia during the years 1985-2000. We searched the records of the teaching hospitals in metropolitan Perth and those of the Keogh Institute for Medical Research for the diagnostic code for priapism. A total of 82 episodes of priapism in 63 patients occurred over this 16 year period. In all, 62 episodes occurred after intracavernosal injections (ICI) and 20 were due to other causes. Treatment of priapism included simple aspiration of blood, intracavernosal injection of alpha-adrenergic agents and surgical shunt procedures. Priapism occurring outside the setting of ICI was more likely to require surgery; seven of 20 episodes. After ICI therapy, eight of 62 episodes required shunts. The use of prostaglandin E1 as the drug of choice in ICI therapy in 1989 led to a fall in the incidence of ICI-induced priapism. Priapism is a major side effect of ICI therapy and an uncommon, although important, side effect of other conditions. The incidence of priapism has fallen with the introduction of prostaglandin E1 monotherapy as the favoured drug for ICI therapy of erectile failure.

The effects of new topical treatments on management of glaucoma in Scotland: an examination of ophthalmological health care.

BACKGROUND: The management of glaucoma has been changed in the past decade by the introduction of new drugs. The impact of these changes on clinical care of patients was examined by examining operation and prescribing rates for glaucoma in four geographical areas of Scotland for the years 1994 to 1999. METHODS: A retrospective analysis of national health statistics: primary care prescribing data, hospital derived operation rates, consultant numbers, optometrist numbers, and eye test data, expressed by estimated population at risk of glaucoma. The outcome measures were prescribing volume and cost for glaucoma medications, and operation rates, corrected for population estimated to be at risk of glaucoma (PEG), for trabeculectomy, for Scotland as a whole, and for four geographical "regions" (north east, south east, central, and south west Scotland). RESULTS: Prescribed items per 1000 population estimated to have glaucoma (PEG) increased by 24.9% between 1994 and 1999. This was above the general increase in prescribing in Scotland (17.8%). This increase varied in the four health regions evaluated (14.3% to 31.9%). Prescribing of topical beta blockers increased little (6.4%), but there was a large increase in the use of new products (topical prostaglandins, carbonic anhydrase inhibitors, and alpha(2) agonists), at the expense of miotics (47.7% fall), and older sympathomimetics. This change in prescribing pattern was accompanied by a 61.5% increase in cost (range 42.2% to 73.4% in the four regions). New drugs accounted for more than half of total glaucoma expenditure in 1999. Operation rates (corrected for PEG) fell by 45.9% (range 43.1 to 58.6%) between 1994 and 1999. Other indicators suggested increased activity in ophthalmic areas (for example, cataract operations, eye tests, numbers of optometrists and ophthalmic surgeons all increased). Within north east Scotland operation rates decreased and prescribing increased less than in other regions, both from lowest regional baseline in 1994. CONCLUSIONS: The introduction of new drug classes has had dramatic effects on the prescribing of glaucoma treatments. There has been a decline in older treatments and an increase in new agents, which has been associated with a large reduction in operation rates for glaucoma in Scotland over 6 years. Comparison of prescribing and operation data indicates regional differences in healthcare delivery for glaucoma.

Trends in alpha-blocker treatment of patients with benign prostatic hyperplasia and hypertension: dosing regimens and cost comparisons.

Dosing regimen is an important determinant of both drug cost and patient compliance. This retrospective analysis evaluated dosing regimens and drug acquisition costs for 101 patients identified from medical records in a large metropolitan hospital as having hypertension and/or benign prostatic hyperplasia and receiving alpha-blocker therapy with either doxazosin or terazosin. Although once-daily administration is generally recommended for both drugs, 25 (38%) of 66 patients receiving terazosin were treated twice daily compared with 6 (17%) of 35 patients treated twice daily with doxazosin. This difference was statistically significant. The average (mean +/- SD) daily treatment cost per patient for all individuals receiving terazosin during the period of the record review was $1.68 +/- 0.60. For patients treated with doxazosin, the average was $0.96 +/- 0.65-a highly statistically significant result. If all 66 patients receiving terazosin had been converted to doxazosin at the beginning of the study, annual savings would have been $17,345.00. These results demonstrate the importance of reviewing actual dosing regimens. The fact that doxazosin could be administered to a significantly higher percentage of patients once daily rather than twice daily substantially decreased its cost relative to terazosin. A once-daily treatment regimen may also enhance patient compliance, thereby improving the chances of therapeutic success.

Goals of antihypertensive therapy.

Antihypertensive therapy has been used for almost 40 years to reduce blood pressure and to prevent morbidity and mortality related to the hypertensive state. Cardiovascular events are related to the initial elevation of blood pressure; the benefits of treating malignant, severe or moderate hypertension are well established. Although large scale clinical trials have demonstrated a decrease in morbid events when mildly elevated blood pressures is treated, the benefits are neither universal or dramatic and treatment is certainly less cost effective than no treatment. Recently it has been emphasised that the absolute risk of cardiovascular events is determined only in part by blood pressure, and that it is also influenced by age, gender, race and the presence of other cardiovascular risk factors. For example, in older individuals where the absolute risk of vascular complications is greater than in younger individuals for any given level of blood pressure, the benefits of therapy will be greater. It has been suggested that in younger individuals with mild hypertension and a low absolute risk of developing cardiovascular morbid events it may be more appropriate to monitor the effects of drug therapy on measures of cardiac and vascular damage that are associated with the hypertensive state. Drug therapy has been shown to be extremely effective in reducing the incidence of stroke, congestive cardiac failure and renal failure associated with elevated blood pressure. Meta-analysis of randomised large scale clinical trials indicates that drug therapy may not reduce coronary events to the extent expected in patients with hypertension. One plausible explanation is that the trials have been of insufficient duration to detect the benefit of blood pressure lowering on coronary heart disease. It has also been suggested that certain adverse metabolic effects associated with the use of thiazide diuretics and beta-blockers employed in these trials may have partially offset the benefits of blood pressure reduction. However, the clinical significance of these drug-induced metabolic disturbances remains unclear. Experimental data suggesting differences in the ability of antihypertensive drugs to inhibit atherosclerosis in animal models are also of interest, but again the relation of the findings to the clinical situation is unknown. Thiazide diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and alpha-blockers can produce regression of left ventricular hypertrophy (LVH). While LVH is clearly a strong and independent predictor for coronary disease, it remains to be shown that a lower risk for coronary morbid events exists in patients whose LVH has undergone regression over and above that attributable to blood pressure reduction.(ABSTRACT TRUNCATED AT 400 WORDS)

Safety assessment of terazosin in the treatment of patients with symptomatic benign prostatic hyperplasia: a combined analysis.

OBJECTIVES: This study reviews and assesses the safety of terazosin for the treatment of symptomatic benign prostatic hyperplasia (BPH). METHODS: Six placebo-controlled trials (including two unpublished series) involving 996 patients provide the database for this evaluation. Six hundred thirty-six patients received terazosin from 1 to 20 mg daily for a total of 229 patient-years of exposure to terazosin. The most common final dose of terazosin was 10 mg once daily. RESULTS: Side effects were generally mild or moderate in severity and resolved following cessation of therapy. Side effects resulted in premature withdrawal in 9% of terazosin-treated patients and 7% of placebo-treated patients (difference not significant). Dizziness (2.0%) and headache (1.1%) were the most common symptoms leading to premature withdrawal from the studies. Although postural symptoms and dizziness were slightly more common in those terazosin-treated patients 65 or more years old compared with patients less than 65 years old, this difference was not statistically significant. Only 4 of the 636 patients (0.6%) had syncopal episodes; 2 of these occurred at initiation of terazosin therapy or at dose escalation. Minimal reductions in blood pressure were observed in normotensive patients and patients with hypertension controlled by concomitant medication, whereas patients with untreated hypertension had substantial decreases in both systolic and diastolic blood pressures. Statistically significant increases in high density lipoprotein to cholesterol ratio and reductions in total cholesterol, low density lipoprotein, and triglycerides were also seen. CONCLUSIONS: This combined analysis suggests that terazosin can be safely administered to both normotensive and hypertensive patients with symptomatic BPH.

A preliminary, clinical pharmacological assessment of L-659,066, a novel alpha 2-adrenoceptor antagonist.

1. The alpha 2-adrenoceptor antagonist activity of L-659,066 has been investigated in studies of healthy normotensive males to whom doses of up to 8 mg were administered by short intravenous infusion. 2. L-659,066 had no effect on basal levels of glucose or insulin and no significant effect on the plasma glucose and plasma insulin time profiles following an intravenous glucose load. 3. There was a non-significant trend for plasma noradrenaline concentrations to be higher after L-659,066. 4. L-659,066 had no significant effects on mood changes or on physical symptom scores. 5. There were no significant effects on supine blood pressure but there were consistent increases in heart rate both supine (non-significant) and erect (P < 0.01). 6. Ex vivo platelet aggregation studies confirmed alpha 2-adrenoceptor antagonist activity with L-659,066 but with an approximately 9-fold lesser potency than yohimbine. 7. While L-659,066 has alpha 2-adrenoceptor antagonist activity these results suggest that it is unlikely to present a new therapeutic approach for improving insulin release.

Assessment of left ventricular systolic and diastolic function with Doppler echocardiography in hypertensive patients receiving intravenous medroxalol.

Intravenous medroxalol, an alpha- and beta-adrenergic blocking agent, causes an immediate hypotensive effect. In 14 subjects with mild-to-moderate hypertension, cardiac output (CO) and cardiac index (CI) were significantly decreased without significant changes in stroke volume, reflecting the fact that a reduced CO and CI were related to decreases in heart rate. The vasodilator effect of intravenous medroxalol was not apparent with the dosages used in this study. Transient changes noted in two Doppler diastolic velocity indexes--mitral early diastolic peak flow velocity (PFVE) and the ratio of mitral late-to-early diastolic peak flow velocity (PFVA/E)--are suggestive of an improvement in left ventricular (LV) diastolic filling during medroxalol infusion, possibly related to changes in loading conditions. Systolic and diastolic blood pressure did not correlate with any of the Doppler diastolic and systolic indexes in our patient population. Reduced aortic peak flow velocity, rate of aortic flow acceleration, and the rate of mitral early diastolic deceleration were noted with increasing LV mass index, independent of age or blood pressure. Doppler echocardiography may be a useful tool in the assessment and follow-up of LV systolic and diastolic function in patients undergoing pharmacologic interventions.