Monotherapy with tadalafil or tamsulosin similarly improved lower urinary tract symptoms suggestive of benign prostatic hyperplasia in an international, randomised, parallel, placebo-controlled clinical trial

Background

Tadalafil improved lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (BPH; LUTS/BPH) in clinical studies but has not been evaluated together with an active control in an international clinical study.

Objective

Assess tadalafil or tamsulosin versus placebo for LUTS/BPH.

Design, setting, and participants

A randomised, double-blind, international, placebo-controlled, parallel-group study assessed men ≥45 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) ≥13, and maximum urinary flow rate (Q_max) ≥4 to ≤15 ml/s. Following screening and washout, if needed, subjects completed a 4-wk placebo run-in before randomisation to placebo (n = 172), tadalafil 5 mg (n = 171), or tamsulosin 0.4 mg (n = 168) once daily for 12 wk.

Measurements

Outcomes were assessed using analysis of covariance (ANCOVA) or ranked analysis of variance (ANOVA) (continuous variables) and Cochran-Mantel-Haenszel test or Fisher exact test (categorical variables).

Results and limitations

IPSS significantly improved versus placebo through 12 wk with tadalafil (−2.1; p = 0.001; primary efficacy outcome) and tamsulosin (−1.5; p = 0.023) and as early as 1 wk (tadalafil and tamsulosin both −1.5; p < 0.01). BPH Impact Index significantly improved versus placebo at first assessment (week 4) with tadalafil (−0.8; p < 0.001) and tamsulosin (−0.9; p < 0.001) and through 12 wk (tadalafil −0.8, p = 0.003; tamsulosin −0.6, p = 0.026). The IPSS Quality-of-Life Index and the Treatment Satisfaction Scale–BPH improved significantly versus placebo with tadalafil (both p < 0.05) but not with tamsulosin (both p > 0.1). The International Index of Erectile Function–Erectile Function domain improved versus placebo with tadalafil (4.0; p < 0.001) but not tamsulosin (−0.4; p = 0.699). Q_max increased significantly versus placebo with both tadalafil (2.4 ml/s; p = 0.009) and tamsulosin (2.2 ml/s; p = 0.014). Adverse event profiles were consistent with previous reports. This study was limited in not being powered to directly compare tadalafil versus tamsulosin.

Conclusions

Monotherapy with tadalafil or tamsulosin resulted in significant and numerically similar improvements versus placebo in LUTS/BPH and Q_max. However, only tadalafil improved erectile dysfunction.

Trial registration

Clinicaltrials.gov ID NCT00970632     

Elevated plasma levels of TIMP-1 in patients with rotator cuff tear

Background and purpose

Extracellular matrix remodeling is altered in rotator cuff tears, partly due to altered expression of matrix metalloproteinases (MMPs) and their inhibitors. It is unclear whether this altered expression can be traced as changes in plasma protein levels. We measured the plasma levels of MMPs and their tissue inhibitors (TIMPs) in patients with rotator cuff tears and related changes in the pattern of MMP and TIMP levels to the extent of the rotator cuff tear.

Methods

Blood samples were collected from 17 patients, median age 61 (39–77) years, with sonographically verified rotator cuff tears (partial- or full-thickness). These were compared with 16 age- and sex-matched control individuals with sonographically intact rotator cuffs. Plasma levels of MMPs and TIMPs were measured simultaneously using Luminex technology and ELISA.

Results

The plasma levels of TIMP-1 were elevated in patients with rotator cuff tears, especially in those with full-thickness tears. The levels of TIMP-1, TIMP-3, and MMP-9 were higher in patients with full-thickness tears than in those with partial-thickness tears, but only the TIMP-1 levels were significantly different from those in the controls.

Interpretation

The observed elevation of TIMP-1 in plasma might reflect local pathological processes in or around the rotator cuff, or a genetic predisposition in these patients. That the levels of TIMP-1 and of certain MMPs were found to differ significantly between partial and full-thickness tears may reflect the extent of the lesion or different etiology and pathomechanisms.The subacromial pain syndrome includes a range of disorders from reversible inflammation to massive rotator cuff tearing (Shindle et al. 2011). The etiology appears to be multifactorial, and several anatomic structures may be involved. Repetitive damage of the supraspinatus tendon by mechanical wear from the coraco-acromial ligament and the anterior acromion was described by Neer 1972, and for a long time it was considered the major cause of cuff tearing (Neer 1983). Others have reported age-related tendon degeneration, associated with alterations in extracellular matrix remodeling as a contributing factor (Lo et al. 2004, Millar et al. 2009, Pasternak and Aspenberg 2009, Shindle et al. 2011). Histopathological changes associated with rotator cuff tendinosis have been documented, but it is unclear whether they are a result of a subacromial impingement or an endogenous process, and whether tendinosis might predispose to tendon tears (Lo et al. 2004).Regardless of whether mechanical or degenerative factors initiates tearing, there are alterations in the cellular and extracellular matrix (Gwilym et al. 2009). It has been suggested that genetic factors may influence apoptosis or regeneration (Gwilym et al. 2009, Shindle et al. 2011). Still, the molecular changes associated with rotator cuff tearing are largely unknown (Lo et al. 2004, Garofalo et al. 2011). Turnover of the extracellular matrix (ECM) is mediated by matrix metalloproteinases (MMPs), a family of at least 24 zinc-dependent endopeptidases. The MMPs are classified according to their main degradative activity, into for example collagenases, gelatinases, and stromelysins (Pasternak and Aspenberg 2009). Their activity is regulated by endogenous inhibitors: tissue inhibitors of metalloproteinases (TIMPs). There are 4 known TIMPs, which reversibly inhibit all MMPs by 1:1 interaction with the zinc-binding site (Lo et al. 2004, Pasternak and Aspenberg 2009). MMP production is induced by factors such as cytokines and tumor necrosis factor-α. MMPs are secreted by connective tissue and inflammatory cells and then activated in the extracellular space (Garofalo et al. 2011). The composition of the ECM is dependent on the balance between MMPs and TIMPs (Lo et al. 2004, Pasternak and Aspenberg 2009, Garofalo et al. 2011). Levels of MMP mRNA and TIMP mRNA were found to be altered in biopsies from torn rotator cuff tendon (Lo et al. 2004). It is not known, however, whether these changes are causative or whether they are secondary to tendon tearing.Studies on MMP and TIMP levels in patients with rotator cuff syndrome and cuff tears have used samples collected at surgery from the subacromial bursa, synovial fluid, or the tendons (Lo et al. 2004, Lakemeier et al. 2010, Shindle et al. 2011). To date, there have been no data on systemic levels. Alterations in MMP and TIMP levels in systemic blood samples have been identified in other musculoskeletal diseases such as Dupuytren’s disease, ankylosing spondylitis, and fracture non-union, suggesting that alterations associated with rotator cuff disease may also be measurable systemically (Ulrich et al. 2003, Henle et al. 2005, Pasternak and Aspenberg 2009). In osteoarthritis, circulating MMP-3 has been suggested to be a marker of disease severity and has been used as a prognostic tool (Lohmander et al. 2005).We measured plasma levels of MMPs and TIMPs in patients with rotator cuff tears and compared partial- and full-thickness tears, in order to find disease-associated changes in the expression patterns of MMP and TIMP.     

Isovolaemic hemodilution with gelatin and hydroxyethylstarch 130/0.42: effects on hemostasis in piglets

Objectives: Artificial colloids, frequently used to prevent hemorrhagic shock in children, impair blood coagulation. To determine the impact of acute isovolaemic hemodilution with artificial colloids on clot formation, we conducted an experimental study in a pediatric animal model. Methods: Fifteen piglets underwent hemorrhage by withdrawing 40 ml·kg^?1 of blood volume in steps of 10 ml·kg^?1 each within 1 hour. After each withdrawal, the blood loss was randomly compensated by administering 4% gelatin (GEL) or hydroxylethyl starch 130/0.42 (HES) in a ratio of 1 : 1, or isotonic crystalloid solution (ICS) in a ratio of 1 : 4 for isovolaemic hemodilution. Quality of clot formation and platelet function was measured using Thrombelastometry (ROTEM^®) and Multiple electrode impedance aggregometry (Multiplate^®) after 10, 20, and 40 ml·kg^?1 blood replacement. Results: Moderate hemodilution (10–20 ml·kg^?1 blood replacement) caused no significant differences among groups (e.g. INTEM^®‐MCF after 20 ml·kg^?1 blood replacement (ICS vs GEL vs HES, P > 0.05). Profound hemodilution with 40 ml·kg^?1 blood replacement showed a significant difference between ICS and both colloids (P < 0.05), but no significant differences between GEL and HES. Conclusions: Impairment of clot formation by moderate isovolaemic hemodilution did not significantly differ between ICS, GEL, and HES. Profound hemodilution of more than 50% of the estimated blood volume with GEL and HES caused significant impairment of clot formation in comparison to ICS and has to be considered when using high amounts of these synthetic colloids.     

Atrial fibrillation in patients undergoing coronary artery surgery is associated with adverse outcome

Abstract

Background: The aim was to determine the association between atrial fibrillation (AF) and outcome in patients undergoing coronary artery bypass grafting (CABG).

Methods: All patients undergoing CABG between January 2010 and June 2013 were identified in the Swedish Heart Surgery Registry. Outcomes studied were all-cause mortality, cardiovascular mortality, myocardial infarction, congestive heart failure, ischemic stroke, and recurrent AF. Patients with history of AF prior to surgery (preoperative AF) and patients without history of AF but with AF episodes post-surgery (postoperative AF) were compared to patients with no AF using adjusted Cox regression models.

Results: Among 9,107 identified patients, 8.1% (n?=?737) had preoperative AF, and 25.1% (n?=?2,290) had postoperative AF. Median follow-up was 2.2?years. Compared to no AF, preoperative AF was associated with higher risk of all-cause mortality, adjusted hazard ratio with 95% confidence interval (HR) 1.76 (1.33–2.33); cardiovascular mortality, HR 2.43 (1.68–3.50); and congestive heart failure, HR 2.21 (1.72–2.84). Postoperative AF was associated with risk of all-cause mortality, HR 1.27 (1.01–1.60); cardiovascular mortality, HR 1.52 (1.10–2.11); congestive heart failure, HR 1.47 (1.18–1.83); and recurrent AF, HR 4.38 (2.46–7.78). No significant association was observed between pre- or postoperative AF and risk for myocardial infarction and ischemic stroke.

Conclusions: Approximately 1 in 3 patients undergoing CABG had pre- or postoperative AF. Patients with pre- or postoperative AF were at higher risk of all-cause mortality, cardiovascular mortality, and congestive heart failure, but not of myocardial infarction or ischemic stroke. Postoperative AF was associated with higher risk of recurrent AF.     

Effects of hypobaric pressure on human skin: implications for cryogen spray cooling (part II)

BACKGROUND AND OBJECTIVES: Clinical results have demonstrated that dark purple port wine stain (PWS) birthmarks respond favorably to laser induced photothermolysis after the first three to five treatments. Nevertheless, complete blanching is rarely achieved and the lesions stabilize at a red-pink color. In a feasibility study (Part I), we showed that local hypobaric pressure on PWS human skin prior to laser irradiation induced significant lesion blanching. The objective of the present study (Part II) is to investigate the effects of hypobaric pressures on the efficiency of cryogen spray cooling (CSC), a technique that assists laser therapy of PWS and other dermatoses. STUDY DESIGN/MATERIALS AND METHODS: Experiments were carried out within a suction cup and vacuum chamber to study the effect of hypobaric pressure on the: (1) interaction of cryogen sprays with human skin; (2) spray atomization; and (3) thermal response of a model skin phantom. A high-speed camera was used to acquire digital images of spray impingement on in vivo human skin and spray cones generated at different hypobaric pressures. Subsequently, liquid cryogen was sprayed onto a skin phantom at atmospheric and 17, 34, 51, and 68 kPa (5, 10, 15, and 20 in Hg) hypobaric pressures. A fast-response temperature sensor measured sub-surface phantom temperature as a function of time. Measurements were used to solve an inverse heat conduction problem to calculate surface temperatures, heat flux, and overall heat extraction at the skin phantom surface. RESULTS: Under hypobaric pressures, cryogen spurts did not produce skin indentation and only minimal frost formation. Sprays also showed shorter jet lengths and better atomization. Lower minimum surface temperatures and higher overall heat extraction from skin phantoms were reached. CONCLUSIONS: The combined effects of hypobaric pressure result in more efficient cryogen evaporation that enhances heat extraction and, therefore, improves the epidermal protection provided by CSC.     

Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents III: The 2023 Geneva revision

The set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby-Mogensen et al., Acta Anaesthesiol Scand 1996, 40 , 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs-Buder et al., Acta Anaesthesiol Scand 2007, 51 , 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three-dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high-quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies. There is growing awareness of the importance of consensus-based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.     

Glycoproteins in the urothelium and in the urine of the epidermal growth factor induced growing urinary tract in rats

Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. We have previously described that the EGF stimulated urothelium in Goettingen minipigs accumulates glycoproteins. The aim of the present study was to examine and partly characterize glycoproteins in the urothelium and in the urine from rats treated with EGF. Seventy-two female Wistar rats were allocated into five groups receiving EGF treatment (150 μg/kg per day) for 0 (controls), 1, 2, 3 and 4 weeks before being killed. Glycoconjugates were characterized by means of lectins on tissue sections, and using Western blotting, in bladder extracts and in urine. The characterization mostly focused on the expression of the mucin-type core structures T and Tn using the lectins peanut agglutinin (PNA) and Vicia villosa (VVA) and specific monoclonal antibodies. The thickened EGF-stimulated urothelium retained the normal differentiation pattern as judged from the appearance on electron microscopy and from the expression of carbohydrate structures. Within the urothelium and in the urine there was increased expression of mucin-type glycoproteins suggesting increased urothelial production and excretion of mucin-type glycoproteins. In conclusion, the EGF stimulated hyperplastic urothelium most probably excretes increased amounts of mucin-type glycoproteins to the urine but it retains the normal pattern of differentiation as assessed by lectin characterization. Received: 5 February 1997 / Accepted: 29 October 1997     

MR-sequences for prostate cancer diagnostics: validation based on the PI-RADS scoring system and targeted MR-guided in-bore biopsy

Purpose

This study evaluated the accuracy of MR sequences [T2-, diffusion-weighted, and dynamic contrast-enhanced (T2WI, DWI, and DCE) imaging] at 3T, based on the European Society of Urogenital Radiology (ESUR) scoring system [Prostate Imaging Reporting and Data System (PI-RADS)] using MR-guided in-bore prostate biopsies as reference standard.

Methods

In 235 consecutive patients [aged 65.7?±?7.9 years; median prostate-specific antigen (PSA) 8 ng/ml] with multiparametric prostate MRI (mp-MRI), 566 lesions were scored according to PI-RADS. Histology of all lesions was obtained by targeted MR-guided in-bore biopsy.

Results

In 200 lesions, biopsy revealed prostate cancer (PCa). The area under the curve (AUC) for cancer detection was 0.70 (T2WI), 0.80 (DWI), and 0.74 (DCE). A combination of T2WI + DWI, T2WI + DCE, and DWI + DCE achieved an AUC of 0.81, 0.78, and 0.79. A summed PI-RADS score of T2WI + DWI + DCE achieved an AUC of 0.81. For higher grade PCa (primary Gleason pattern?≥?4), the AUC was 0.85 for T2WI + DWI, 0.84 for T2WI + DCE, 0.86 for DWI + DCE, and 0.87 for T2WI + DWI + DCE. The AUC for T2WI + DWI + DCE for transitional-zone PCa was 0.73, and for the peripheral zone 0.88. Regarding higher-grade PCa, AUC for transitional-zone PCa was 0.88, and for peripheral zone 0.96.

Conclusion

The combination of T2WI + DWI + DCE achieved the highest test accuracy, especially in patients with higher-grade PCa. The use of ≤2 MR sequences led to lower AUC in higher-grade and peripheral-zone cancers.

Key Points

? T2WI + DWI + DCE achieved the highest accuracy in patients with higher grade PCa ? T2WI + DWI + DCE was more accurate for peripheral- than for transitional-zone PCa ? DCE increased PCa detection accuracy in the peripheral zone ? DWI was the leading sequence in the transitional zone     

The effects of exogenous epidermal growth factor on the developing urinary tract in rats: a stereological description

Systemic treatment with epidermal growth factor (EGF) induces growth of all wall layers of the urinary tract in pigs and rats. In this study, we describe the time-dependent growth of the ureter and bladder. Forty-eight female Wistar rats were allocated into five groups receiving EGF treatment (150 μg/kg per day) for 0 (controls), 1, 2, 3 or 4 weeks before being killed. The 24-h urine excretion was increased only in the group treated for 4 weeks with EGF. Measured by a simple infusion device, EGF significantly increased the bladder capacity by more than 50% in all the EGF-treated groups. The volumes of the wall layers of the ureter and bladder were quantified using stereology. After 4 weeks of treatment with EGF, the total volumes of the ureter and bladder were 1.8- and 2.1-fold larger than in the control group (the urothelium was 2.8- and 3.5-fold larger and the muscular coat 1.6- and 1.6-fold larger in the ureter and bladder, respectively). In conclusion, the EGF-induced growth of the urinary tract is characterized by increased bladder capacity, and increased volume of all wall layers – most prominently the urothelium. Received: 5 February 1997 / Accepted: 29 October 1997