Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers.

AIMS: ALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for µ receptor, α1A -adrenoceptor, α1B -adrenoceptor, NMDA receptor and sigma non-opioid intracellular receptor 1. This first-in-human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets. METHODS: In 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco-EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated. Neuroendocrine effects (cortisol, prolactin, growth hormone) were measured. Data were analysed over the 12-hour post-dose period using mixed-effects model for repeated measure (MMRM) with baseline as covariate. RESULTS: ALKS 7119 demonstrated linear PK and was generally well tolerated. QTcF interval increases of 30-60 ms compared to baseline were observed with ALKS 7119 doses of ≥50 mg without related adverse events. Significant increases in left and right pupil/iris ratio were observed at dose levels ≥50 mg (estimate of difference [95% CI], P-value) (0.04 [0.01; 0.07], P < .01) and (0.06 [0.03; 0.09], P = .01), respectively. From dose levels ≥50 mg significant increases (% change) of serum cortisol (51.7 [8.4; 112.3], P = .02) and prolactin (77.9 [34.2; 135.8], P < .01) were observed. CONCLUSION: In line with ALKS 7119's in vitro pharmacological profile, the clinical profile observed in this study is most comparable to SERT inhibition.

Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing-remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF's distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. OBJECTIVE: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. METHODS: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. RESULTS: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1-98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13-0.20). CONCLUSION: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

Corrigendum to "RPN (Radius, Position of tumour, iNvasion of renal sinus) Classification and Nephrometry Scoring System: An Internationally Developed Clinical Classification To Describe the Surgical Difficulty for Renal Masses for Which Robotic Partial Nephrectomy Is Planned" [Eur. Urol. Open Sci. 54 (2023) 33-42].

[This corrects the article DOI: 10.1016/j.euros.2023.05.007.].

Monomer Selection for In Situ Polymerization Infusion Manufacture of Natural-Fiber Reinforced Thermoplastic-Matrix Marine Composites.

Awareness of environmental issues has led to increasing interest from composite researchers in using "greener" materials to replace synthetic fiber reinforcements and petrochemical polymer matrices. Natural fiber bio-based thermoplastic composites could be an appropriate choice with advantages including reducing environmental impacts, using renewable resources and being recyclable. The choice of polymer matrix will significantly affect the cost, manufacturing process, mechanical properties and durability of the composite system. The criteria for appropriate monomers are based on the processing temperature and viscosity, polymer mechanical properties, recyclability, etc. This review considers the selection of thermoplastic monomers suitable for in situ polymerization during resin, now monomer, infusion under flexible tooling (RIFT, now MIFT), with a primary focus on marine composite applications. Given the systems currently available, methyl methacrylate (MMA) may be the most suitable monomer, especially for marine composites. MMA has low process temperatures, a long open window for infusion, and low moisture absorption. However, end-of-life recovery may be limited to matrix depolymerization. Bio-based MMA is likely to become commercially available in a few years. Polylactide (PLA) is an alternative infusible monomer, but the relatively high processing temperature may require expensive consumable materials and could compromise natural fiber properties.

Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study.

BACKGROUND: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile. OBJECTIVES: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing-remitting multiple sclerosis. METHODS: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing-remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. RESULTS: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39-0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%). CONCLUSIONS: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT03093324).

A rare case of acute presentation of trocar site hernia from robot-assisted laparoscopic partial nephrectomy.

Trocar site hernia is not a common acute complication encountered after robot-assisted surgery, especially in the urological cohort of patients. A few case reports of small bowel obstruction secondary to incarceration by trocar site hernia have been described in gynaecological surgery and prostatectomies. As the clinical presentation is non-specific, late diagnosis has significant implication on morbidity and mortality. Here, we present a rare case of a patient with recent robot-assisted laparoscopic partial nephrectomy for a renal cell carcinoma presented with features of impending bowel obstruction secondary to incarcerated small bowel in the trocar site. We also reviewed the literature focusing on clinical features of trocar site hernia and preventive measures.

Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study.

INTRODUCTION: Diroximel fumarate (DRF) is a novel oral fumarate in development for patients with relapsing forms of multiple sclerosis (MS). Clinical findings from the DRF development program suggest that rates of gastrointestinal (GI) treatment-emergent adverse events (TEAEs) and discontinuation due to GI TEAEs are low, based on clinical and real-world observations of other fumaric acid esters, including dimethyl fumarate (DMF). The incidence of GI TEAEs varies from 40 to 88% in clinical and real-world studies of DMF. The objective of this study is to present GI tolerability findings from the EVOLVE-MS-1 study and present biologic hypotheses for the improved GI properties of DRF. METHODS: GI TEAEs and treatment discontinuation because of GI TEAEs were assessed in DRF-treated patients with relapsing-remitting MS who were participating in the ongoing, 96-week, open-label, phase 3 EVOLVE-MS-1 study. RESULTS: As of March 30, 2018, a total of 696 patients were enrolled in EVOLVE-MS-1. GI TEAEs were reported in 30.9% (215/696) of patients; the vast majority (96%; 207/215) experienced events that were mild or moderate in severity. When GI AEs did occur, they occurred early in treatment, resolved (88.8%; 191/215), and were of short duration [median 7.5 (range 1-87) days] in most patients. GI TEAEs led to < 1% of patients discontinuing treatment. CONCLUSIONS: We suggest that the distinct chemical structure of DRF contributes to the observed low rates of GI TEAEs and GI-associated treatment discontinuations, possibly due to a combination of several factors. We hypothesize that these factors may include less reactivity with off-target proteins and/or lower production of a methanol leaving group that may contribute to GI irritation. A direct comparison of GI tolerability with DRF versus DMF is being evaluated in the EVOLVE-MS-2 study. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02634307. FUNDING: Alkermes Inc. (Waltham, MA, USA) and Biogen (Cambridge, MA, USA).

Comparison of a new-generation electroconductive spark lithotripter and the Dornier Compact Delta for ureteral calculi in a quaternary referral center.

PURPOSE: The Technomed Sonolith Vision is the most recently developed electroconductive lithotripter. Using a case-control study, we compared the treatment outcomes of this machine with those of the Dornier Compact Delta for ureteral calculi. PATIENTS AND METHODS: Patients (N = 107) with calculi from the ureteropelvic to the ureterovesical junction undergoing primary lithotripsy using the Technomed Sonolith Vision were identified between September 2004 and February 2005. All patients had 2-week and 3-month follow-up. These patients were compared with 524 patients from our database treated between October 2000 and August 2004 with a Dornier Compact Delta. The two groups were similar at baseline. Outcome variables measured were stone-free rate at 3 months, retreatment rate, and requirement for intravenous analgesia during the procedure. RESULTS: There was a superior stone-free rate for the Technomed, reaching significance for calculi up to 7 mm. The Technomed had a significantly lower re-treatment rate for calculi <13 mm. There was no statistical difference in the requirement for intravenous analgesia. The Efficiency Quotient was superior for the Technomed (0.67 v 0.56). CONCLUSIONS: This latest-generation electroconductive lithotripter in its first 6 months of use has shown stone-free and re-treatment rates superior to those of the Dornier Compact Delta and approaching that of the Dornier HM-3. Lithotripsy remains our first-line treatment for all radiopaque ureteral calculi.

A large, benign prostatic cyst presented with an extremely high serum prostate-specific antigen level.

We report a case of a patient who presented with an extremely high serum prostate specific antigen (PSA) level and underwent radical prostatectomy for presumed prostate cancer. Surprisingly, the whole mount prostatectomy specimen showed only small volume, organ-confined prostate adenocarcinoma and a large, benign intraprostatic cyst, which was thought to be responsible for the PSA elevation.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a µ- and κ-opioid partial agonist, buprenorphine, and a µ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression. METHOD: A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S). RESULTS: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation. CONCLUSIONS: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

Evaluation of opioid modulation in major depressive disorder.

Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a µ-opioid partial agonist, buprenorphine (BUP), and a potent µ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist-antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.

Laparoscopic donor nephrectomy.

BACKGROUND: Kidney transplantation is a definitive treatment of end-stage renal disease. Laparoscopic donor nephrectomy (LDN) has been widely accepted around the world since its introduction in 1995 as a minimum invasive procedure. We report our clinical experience of 141 consecutive LDNs performed in two tertiary hospitals in Western Australia. METHODS: From December 2000 (Royal Perth Hospital) and January 2005 (Sir Charles Gairdner Hospital) to January 2009, 141 LDNs were performed in two tertiary hospitals by four urologists. All donors underwent rigorous work-up prior to surgery. Donor age ranged from 23 years to 81 years (49.85 ± 11.30 years). The male to female ratio was 1 to 1.3. Donor body mass index (BMI) was 26.77 ± 4.31, and glomerular filtration rate was 96.25 ± 12.33 mL/min/1.73 sqm. The laparoscopic technique was transperitoneal approach exclusively. RESULTS: All LDNs were performed successfully without hand assistance. The warm ischaemic time ranged from 3 to 11 min. The hospital stay was 4.16 ± 1.30 days. The overall complication rate was 17.0%, with three major complications (2.1%): a splenetic infarction, a chylous ascites and a pulmonary embolism occurred. Donors' demographic data (age, sex, BMI, side of surgery) did not show a statistically significant association with surgical complications. CONCLUSIONS: Transperitoneal laparoscopic live donor nephrectomy is a safe and effective procedure. Combined use of vascular stapler and Hem-o-Lok is very important for management of the renal artery stump. It is our current practice to administer anticoagulants during and post-surgery for at least 2 weeks.

Flexible ureterorenoscopy and laser lithotripsy in children.

BACKGROUND: Flexible ureterorenoscopy (FUR) and laser lithotripsy (LL) are techniques used in the management of upper urinary tract disorders. These techniques, so far established in adults, are now being used in children as well. We report our experience with 26 cases of pediatric upper urinary tract disorders treated using these techniques. METHODS: In the period from 1997 to 2006, FUR was performed in 26 children (14 males and 12 females) in the age group of three months to 15 years with a mean age of 8.2 years. Twenty five were stented prior to undergoing FUR and 24 presented with suspected upper tract stones (17 pelvicalyceal and seven midureteric). Two cases showed JJ stent migration post-pyeloplasty. RESULTS: Eight cases involved diagnostic procedures. Six excluded the presence of renal calculi, one had focal medullary sponge kidney, and one had calcified papillae. There were 15 cases of therapeutic FUR. Of these, 12 had LL with only one had incomplete stone fragmentation which subsequently passed spontaneously. Other therapeutic procedures included removal of migrated JJ stents and FUR with the basket removal of a midureteric calculus. Three cases failed ureterorenoscopy due to technical difficulties. The overall success rate was 88.5% for FUR. CONCLUSION: FUR and LL are valuable minimally invasive techniques for the examination and treatment of pediatric upper urinary tract conditions. Preoperative stenting improves passage of the ureteroscope and with progressive miniaturization of instruments, the lower weight limit will decrease.

Painful ejaculation.

We reviewed previous publications on post-orgasmic pain with reference to prevalence, epidemiology and treatment options, using the Ovid and PubMed (updated May 2006) databases to comprehensively search MEDLINE for reports on post-orgasmic pain that included peer-reviewed English-language articles. Official proceedings of internationally known scientific societies were also assessed. Because of the heterogeneity of the studies we did not apply meta- analytic techniques to the data. The incidence of post-orgasmic pain is 1-9.7%. The ejaculatory pain is associated with prostatitis, chronic pelvic pain syndrome, benign prostatic hyperplasia, and ejaculatory duct obstruction; it is also described in patients after procedures like radical prostatectomy. Aetiopathogenic theories include those referring to bladder neck closure and pudendal neuropathy. The treatment options vary from self-care, a 'perineal hyperprotection programme' to medication with the alpha-blocker, topiramate, and even surgical procedures like removing a section of the sacrotuberous ligament, neurolysis of the pudendal nerve or removing a section of the sacrospinous ligament. This is the first update of the subject, with reference to prevalence, epidemiology and treatment options. There is a need for adequately powered, prospective randomized trials on aetiology and treatment options.

Prevention and management of complications in urological laparoscopic port site placement.

OBJECTIVES: To review complications associated with urological laparoscopic port-site placement and outline techniques for their prevention and management. METHODS: Review of the literature using Medline. RESULTS: Laparoscopy now plays a key role in urological surgery. Its applications are expanding with experience and evolving data confirming equivalent long-term outcome. Although significant port-site complications are uncommon, their occurrence impacts significantly on perioperative morbidity and rate of recovery. The incidence of such complications is inversely related to surgeon experience. Ports now utilise bladeless tips to reduce the incidence of vascular and visceral injuries, and subsequently port-site herniation. Metastases occurring at the port site are preventable by adhering to certain measures. CONCLUSIONS: Whether performing standard or robot-assisted laparoscopy, port-site creation and maintenance is critical in ensuring minimal invasiveness in laparoscopic urological surgery. Although patient factors can be optimised perioperatively and port design continues to improve, it is clear that adequate training is central in the prevention, early recognition, and treatment of complications related to laparoscopic access.

Idiopathic retroperitoneal fibrosis: the case for nonsurgical treatment.

OBJECTIVE: To review a 10-year experience of medical treatment for idiopathic retroperitoneal fibrosis (RPF), a rare condition of unknown causes, which may obstruct the ureter and for which treatment includes ureterolysis and relief of obstruction, and medical treatment with steroids with or without immunosuppressive medication. PATIENTS AND METHODS: Of 31 patients with RPF treated between 1996 and 2004, 28 had idiopathic disease. Ureteric stents were used to relieve the obstruction in all patients, 12 had previous nephrostomies, 16 were given steroids and only one was treated with ureterolysis. RESULTS: In all, 28 patients were followed for a mean of 51.17 months; the symptoms were relieved in all cases. Renal function, where impaired, improved dramatically in all patients. Fifteen patients (54%) are free of stents and medication after a mean (range) follow-up of 60.9 (24-110) months. CONCLUSION: Idiopathic RPF responds well to conservative management consisting of relief of urinary tract obstruction and steroids.

In vitro interactions of water-soluble garlic components with human cytochromes p450.

Eight water-soluble components of aged garlic extract were evaluated to assess their potential to inhibit the activity of human cytochrome-P450 (CYP) enzymes. The in vitro model consisted of human liver microsomes with index reactions chosen to profile the activity of the following six CYP isoforms: CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. With only 2 exceptions, none of the 8 garlic components produced >50% inhibition even at high concentrations (100 micromol/L). S-methyl-L-cysteine and S-allyl-L-cysteine at 100 micromol/L produced modest inhibition of CYP3A, reducing activity to 20-40% of control. However available clinical evidence does not indicate CYP3A inhibition in vivo. The findings suggest that drug interactions involving inhibition of CYP3A enzymes by aged garlic extract are very unlikely.