ObjectiveTo examine the safety of intralesional injection of collagenase Clostridium histolyticum (CCH) for the treatment of Peyronie's disease (PD), using a pooled safety analysis of patients who received at least one dose of CCH in any of six clinical studies. Patients and MethodsPatients from six clinical studies, including three randomised, double-blind, placebo-controlled studies and three open-label safety and efficacy studies, were included if they had received at least one dose of 0.58 mg CCH. Adverse events (AEs), including treatment-emergent AEs, treatment-related AEs, and serious AEs (SAEs), were characterised. Potential immunogenicity-related AEs were evaluated through examination of increased anti-AUX-I and anti-AUX-II antibody levels, AEs, and reported terms possibly associated with immunological or hypersensitivity events. ResultsOverall, 85.8% of 1 044 pooled patients reported at least one treatment-related AE. The most frequently reported (≥25.0% of patients) treatment-related AEs included penile haematoma (82.7% had the verbatim 'penile bruising'), penile pain, and penile swelling. Most patients (75.2%) had mild-or moderate-severity treatment-related AEs, and 14.2% had no treatment-related AEs. Nine patients (0.9%) had treatment-related SAEs: five with penile haematoma and four with corporal rupture. There was no association between AEs and anti-AUX-I or anti-AUX-II antibody levels across treatment cycles, and no systemic hypersensitivity reactions occurred. ConclusionsThis pooled safety analysis shows that although non-serious and serious treatment-related AEs can occur after CCH treatment for PD, most were non-serious and the SAEs were manageable. Providers should be prepared to manage possible SAEs. Keywordspenile induration, Peyronie's disease, microbial collagenase, safety IntroductionPeyronie's disease (PD) is characterised by the formation of a fibrous collagen scar or plaque of the tunica albuginea, resulting in penile curvature deformity during erection (manifested as bending, narrowing, hinging, or shortening) and has been associated with significant concern about erection pain or appearance, with potential impact on sexual intercourse, and emotional and relationship distress [1,2]. Based on safety and efficacy demonstrated in the identical phase III, placebo-controlled Investigation for Maximal Peyronie's Reduction Efficacy and Safety Studies (IMPRESS) I and II trials, intralesional injection therapy with collagenase Clostridium histolyticum (CCH) was approved by the USA Food and Drug Administration (FDA) for the treatment of adult men with PD with a palpable plaque and curvature deformity of at least 30°at the start of therapy. CCH studies, including a phase IIb study and IMPRESS I and II, showed significant improvement in both penile curvature deformity and PD-specific psychosexual aspects (i.e., Peyronie's Disease Questionnaire PD Symptom Bother domain score), compared with placebo [3,4].CCH is a purified mixture of two microbial collagenases, AUX-I and AUX-II; studies suggest tha...

Objective Peroxisome proliferator-activated receptor α agonists reduce blood pressure in rodents, but clinical trials provide conflicting data regarding their effects in humans. We tested the hypothesis that the effect of fenofibrate on blood pressure depends on salt sensitivity. Methods Thirty-one hypertensive volunteers (17 salt-resistant, 14 salt-sensitive) completed a randomized, crossover, double-blind protocol with three dietary phases: low salt diet (10 mmol/day) followed by two consecutive high salt diets (200 mmol/day), each for 6 days. During high salt, volunteers were randomized to fenofibrate 160 mg/day or placebo. Hemodynamic and metabolic parameters were measured on the last morning of each treatment arm. Results Fenofibrate reduced triglycerides similarly in salt-sensitive and salt-resistant volunteers. Fenofibrate did not affect blood pressure in salt-resistant volunteers. In salt-sensitive volunteers, fenofibrate significantly decreased diastolic (P =0.02 versus placebo) and mean arterial (P = 0.04 versus placebo) blood pressure during high salt. In all volunteers, the decrease in systolic pressure during fenofibrate correlated inversely with the salt sensitivity of mean arterial pressure as a continuous variable. Fenofibrate significantly decreased heart rate, plasma renin activity, and renal vascular resistance during high salt in salt-sensitive volunteers, but not salt-resistant volunteers. Fenofibrate did not affect sodium excretion or weight gain during high salt. The effect of salt intake and fenofibrate on plasma and urine epoxyeicosatrienoic acid concentrations differed in salt-resistant and salt-sensitive volunteers. Conclusion Fenofibrate reduces blood pressure, heart rate and renal vasoconstriction in salt-sensitive volunteers, but not in salt-resistant volunteers. These findings have implications for the treatment of hyperlipidemia in hypertensive individuals.

Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

Aims Renin-angiotensin system antagonists have been found to improve glucose metabolism in obese hypertensive and type 2 diabetic subjects. The mechanism of these effects is not well understood. We hypothesized that the angiotensin receptor antagonist losartan would improve insulin-mediated vasodilation, and thereby improve insulin-stimulated glucose uptake in skeletal muscle of insulin resistant subjects. Materials and Methods We studied subjects with obesity and insulin resistance but without hypertension, hypercholesterolemia or dysglycemia (age 39.0±9.6 yrs [mean±SD], BMI 33.2±5.9 kg/m2, BP 115.8±12.2/70.9±7.2 mmHg, LDL 2.1±0.5 mmol/L). Subjects were randomized to 12 weeks’ double-blind treatment with losartan 100 mg once daily (n=9) or matching placebo (n=8). Before and after treatment, under hyperinsulinemic euglycemic clamp conditions we measured whole-body insulin stimulated glucose disposal, insulin-mediated vasodilation, and insulin-stimulated leg glucose uptake by the limb balance technique. Results Whole-body insulin-stimulated glucose disposal was not significantly increased by losartan. Insulin-mediated vasodilation was augmented following both treatments (increase in leg vascular conductance: pre-treatment 0.7±0.3 L*min−1*mmHg−1[losartan, mean ±SEM] and 0.9±0.3 [placebo], post-treatment 1.0±0.4 [losartan] and 1.3±0.6 [placebo]) but not different between treatment groups (p=0.53). Insulin’s action to augment NO production and to augment endothelium-dependent vasodilation were also not improved. Leg glucose uptake was not significantly changed by treatments, and not different between groups (p=0.11). Conclusions These findings argue against the hypothesis that losartan might improve skeletal muscle glucose metabolism by improving insulin-mediated vasodilation in normotensive insulin resistant obese subjects. The metabolic benefits of angiotensin receptor blockers may require the presence of hypertension in addition to obesity-associated insulin resistance.

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