PubMed Health⌕ Search

Biomedical subjects

Gerald B Brock

Publications and source records attributed to Gerald B Brock.

17 recordsLinked to original sources
PubMed2006

Nonpalpable scarring of the penile septum as a cause of erectile dysfunction: an atypical form of Peyronie's disease.

INTRODUCTION: Men with nonpalpable isolated septal scars (ISS) identified with color duplex ultrasonography (CDU) comprise a group of previously unrecognized patients with wide-ranging sexual concerns. AIM: We aim to identify the clinical characteristics of patients presenting with this atypical form of Peyronie's disease characterized by the absence of palpable deformity. MATERIALS AND METHODS: Of 482 consecutive patients who presented to a tertiary care erectile dysfunction (ED) clinic and underwent CDU after satisfying inclusion criteria, 27 (5.6%) men with nonpalpable ISS and no dorsal or ventral plaque were identified. MAIN OUTCOME MEASURES: International Index of Erectile Function (IIEF), CDU, and clinical characteristics. RESULTS: The median age of the men with nonpalpable ISS was 49 years. The length of time from onset of symptoms to presentation was 22 months, and the pretreatment IIEF score was 14. The remaining 455 men who underwent CDU were of similar age (48 years) but had a markedly lower IIEF score of 9.5 (statistical median). ISS patients presented with decreased penile rigidity (20), penile shortening (13), chronic pain with erection (13; mean 33 months), and the inability to maintain an erection (7). Fourteen men had failed phosphodiesterase-5 inhibitor therapy, and four reported unsatisfactory results. Management options included retrial with oral agents, intracavernous pharmacotherapy, verapamil injections, and surgery. CONCLUSIONS: The clinician should be suspicious for nonpalpable ISS in men with sexual concerns who present with decreased penile rigidity, length loss, and chronic pain with erection. Our findings support the use of CDU for this patient group, particularly when previous treatment has failed, because men with ISS had a greater likelihood of having no palpable deformity or curvature and ongoing penile pain.

Adult↗
PubMed2006

Through the eyes of women: the partners' perspective on tadalafil.

OBJECTIVES: To evaluate patient and female partner responses on the efficacy of, and overall satisfaction with, tadalafil to treat erectile dysfunction using sexual encounter profile (SEP) diaries. METHODS: Data were pooled from four double-blind, placebo-controlled, 12-week trials that included 746 couples. Patients were randomized to placebo or tadalafil 10 or 20 mg. Efficacy was evaluated by the mean per-patient/per-partner percentage of "yes" responses to patient SEP questions 1, 2, and 5 and partner SEP questions 1 to 3 (erection achievement, penetration, and overall satisfaction with the sexual experience, respectively) for tadalafil versus placebo. For each SEP question, the number of postbaseline intercourse attempts when each couple agreed on the outcome was tabulated and divided by the total number of postbaseline attempts to calculate the mean percentage of agreement by couple. The overall satisfaction with successful postbaseline intercourse attempts was determined. RESULTS: Tadalafil significantly improved the responses for the patient and partner-evaluated SEP questions (P <0.001, both doses versus placebo). Partners tended to report greater overall satisfaction than patients at baseline and postbaseline. The mean percentage of agreement by couple was approximately 98% for erection achievement and penetration and 85% for overall satisfaction. For successful intercourse attempts, patients and partners treated with tadalafil reported more overall satisfaction than those treated with placebo (P <0.05, tadalafil versus placebo comparisons). CONCLUSIONS: Partners reported significantly improved overall sexual satisfaction and corroborated the man's report of improved erections and penetration ability with tadalafil 10 mg or 20 mg. Men reported improved erection achievement, penetration, and overall satisfaction with the sexual experience after taking tadalafil.

Aged↗
PubMed2006

Minimally invasive intracorporeal incision of Peyronie's plaque: initial experiences with a new technique.

OBJECTIVES: Minimally invasive repairs represent an attractive treatment approach for the surgical correction of Peyronie's disease. We describe a novel intracorporeal incision technique and the results of our ongoing experience. METHODS: In selected patients who had consented to surgical treatment of a localized Peyronie's scar, saline erection confirmed the degree and location of penile deformity. The skin was mobilized using a subcoronal, circumferential incision. After limited mobilization of the neurovascular bundle, a 1-cm incision lateral to the plaque allowed for the introduction of a triangle-shaped scalpel designed for endoscopic carpal tunnel release into the corpora. Multiple intracorporeal incisions were made, preserving the outer layer of the tunica. Saline erection confirmed curvature correction. A single pair of ventral plication sutures was required in select cases. The small corporotomy, Buck's fascia, and skin were then reapproximated. Patients were discharged home within 24 hours. RESULTS: In 23 patients, the degree of curvature ranged from 30 degrees to 90 degrees (median 60 degrees). All patients had stable curvature and difficulty with intromission. The mean follow-up was 25 months. Correction of the deformity was successful in all but 2 patients (less than 10 degrees residual curvature), with 80% of patients reporting erections sufficient for intercourse and treatment satisfaction of 85%. CONCLUSIONS: These results indicate good correction of curvature, minimal difficulties with erectile function, and high patient-reported satisfaction using our technique at a follow-up of 25 months. We continue to offer intracorporeal incision as a primary treatment option for discrete plaques less than 2 cm, using grafting techniques for larger and complex lesions.

Adult↗
PubMed2006

Non-arteritic anterior ischemic optic neuropathy (NAION) and phosphodiesterase type-5 inhibitors.

OBJECTIVE: To determine whether a causative relationship exists between non-arteritic anterior ischemic optic neuropathy (NAION) and the use of phosphodiesterase-5 (PDE-5) inhibitors for the treatment of erectile dysfunction. METHODS: A comprehensive review of the literature was performed to identify the contemporary understanding of NAION pathophysiology, epidemiology, and occurrence in men using the oral PDE-5 inhibitors sildenafil (Viagra, Pfizer), vardenafil (Levitra, Bayer AG), and tadalafil (Cialis, Lilly-ICOS LLC) for the treatment of erectile dysfunction. RESULTS: NAION is the second most common acquired optic neuropathy in men aged 50 years and older. Risk factors for NAION, cardiovascular disease, and erectile dysfunction are shared and include age, dyslipidemia, diabetes, hypertension, and cigarette smoking. To date, less than 50 cases of NAION associated with PDE-5 use have been reported to the United State's Food and Drug Administration (FDA) and five Canadian cases alerted to Health Canada. Given the large number of men safely using these agents and a limited number of events, it is not possible to determine whether NAION is directly linked to the use of PDE-5 inhibitors, underlying cardiovascular risk factors, ocular anatomical defects, a combination of these variables, or as yet unidentified factors. CONCLUSIONS: PDE-5 inhibitors have gained widespread use for the treatment of erectile dysfunction due to their safety, efficacy, and ease of use. Their role in the pathogenesis of NAION remains controversial. Reasonable and informed consent regarding the possible but low risk of NAION with the use of sildenafil, vardenafil and tadalafil is recommended. Loss or decreased vision, whether painful or painless, demands urgent patient assessment and immediate cessation of PDE-5 inhibitor use.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2005

Efficacy and safety of oral tadalafil in the treatment of men in Canada with erectile dysfunction: a randomized, double-blind, parallel, placebo-controlled clinical trial.

INTRODUCTION: Erectile dysfunction (ED) is a highly prevalent, often undertreated condition. AIM: This 12-week, double-blind, parallel, placebo-controlled study was conducted at 25 sites in Canada to evaluate the efficacy and safety of oral tadalafil, a phosphodiesterase type 5 inhibitor, for the treatment of ED. METHODS: Men with ED of organic, psychogenic, or mixed etiology were stratified by baseline ED severity then randomly assigned to placebo (N = 50), tadalafil 10 mg (N = 103), or tadalafil 20 mg (N = 100), taken as needed (maximum, once daily). MAIN OUTCOME MEASURES: Efficacy was assessed by the International Index of Erectile Function (IIEF), a Sexual Encounter Profile diary, and a global assessment question (GAQ). RESULTS: Tadalafil 10 mg and tadalafil 20 mg significantly improved erectile function compared with placebo (P < 0.001, all measures). At end point, the mean IIEF erectile function (EF) domain scores were 14.5, 21.2, and 23.3 of a possible score of 30 for placebo, tadalafil 10 mg, and tadalafil 20 mg, respectively. Patients treated with tadalafil reported greater change from baseline on the IIEF EF domain score compared with placebo, regardless of baseline ED severity. During treatment, the mean per-patient proportion of successful intercourse attempts was higher for tadalafil 10 mg and 20 mg than for placebo (placebo, 31.9%; tadalafil 10 mg, 56.7%; and tadalafil 20 mg, 61.5%), and a greater proportion of patients reported improved erections with tadalafil (GAQ; placebo, 22.0%; tadalafil 10 mg, 67.0%; tadalafil 20 mg, 79.0%). Fifty percent and 62% of patients treated with tadalafil 10 mg and 20 mg, respectively, achieved successful sexual intercourse after their first dose, compared with 31% with placebo. Treatment-emergent adverse events were generally mild or moderate. CONCLUSION: Tadalafil was an effective, well-tolerated therapy for ED of broad-spectrum etiology and severity.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Regulation of intracellular Ca2+ release in corpus cavernosum smooth muscle: synergism between nitric oxide and cGMP.

Tonic contraction of corpus cavernosum smooth muscle cells (SMCs) maintains the flaccid state of the penis, and relaxation is initiated by nitric oxide (NO), leading to erection. Our aim was to investigate the effect of NO on the smooth muscle cellular response to adrenergic stimulation in corpus cavernosum. Fura-2 fluorescence was used to record intracellular Ca(2+) concentration ([Ca(2+)](i)) from freshly isolated SMCs from rat and human. Phenylephrine (PE) transiently elevated [Ca(2+)](i) in the presence and absence of extracellular Ca(2+), indicating release from intracellular stores. Whereas the NO donor S-nitroso-N-acetylpenicillamine (SNAP) with sildenafil citrate (SIL) caused no change in basal [Ca(2+)](i), the PE-induced rise of [Ca(2+)](i) was reversibly inhibited by 27 +/- 7% (n = 21, P < 0.005) in rat and by 55 +/- 15% (n = 9, P < 0.01) in human SMCs. SNAP and SIL also reduced the contractile response to PE. To investigate the mechanism, we applied mediators alone or in combination. The soluble guanylyl cyclase inhibitor ODQ reduced the effect of SNAP and SIL. SIL, cGMP analogs, and NO donors without SIL did not reduce the PE-induced rise of [Ca(2+)](i). However, the combination of 8-bromo-cGMP with SNAP reduced the Ca(2+) peak by 42 +/- 9% (n = 22, P < 0.01). Our results demonstrate that NO and cGMP act synergistically to reduce Ca(2+) release from intracellular stores. Reduction of intracellular Ca(2+) release may contribute to relaxation of the corpus cavernosum, leading to erection.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2004

Double-blind randomized controlled trial assessing the safety and efficacy of intravesical agents for ureteral stent symptoms after extracorporeal shockwave lithotripsy.

BACKGROUND AND PURPOSE: Ureteral stents are a significant source of pain and discomfort for many urologic patients. A novel approach to addressing this problem is the intravesical instillation of a selected pharmacologic agent after stent insertion. The purpose of this study was to assess the safety and efficacy of intravesical instillation of various agents in reducing ureteral stent-associated discomfort in patients requiring a stent after extracorporeal shockwave lithotripsy (SWL). PATIENTS AND METHODS: In this double-blind prospective trial, 42 patients were randomized to receive intravesical instillation of one of three agents (oxybutynin, alkalinized lidocaine, or ketorolac) or a control solution (0.9% sodium chloride) immediately after stent insertion at time of SWL. The four groups of patients were demographically similar. Preoperative, intraoperative, and postoperative data were collected prospectively and analyzed statistically. The primary outcome measure was reduction in ureteral stent symptoms, and the secondary outcome measure was the safety of intravesical instillation of each agent through assessment of drug-related adverse events. RESULTS: There were no intraoperative or postoperative complications, nor were there any serious side effects attributable to any of the intravesically instilled agents. There was a statistically significant decrease in stent-related discomfort at the 1-hour time point in the group of patients who received intravesical ketorolac compared with the control group. CONCLUSIONS: Intravesical instillation represents a novel approach to the problem of ureteral stent-related discomfort. From our results, ketorolac appears to be the most effective intravesical agent in reducing stent-related patient discomfort, and we have established that intravesical instillation of ketorolac is safe in humans.

Administration, Intravesical↗
PubMed2004

Guidelines for the surveillance of localized renal cell carcinoma based on the patterns of relapse after nephrectomy.

PURPOSE: We characterized relapse patterns in patients with sporadic renal cell carcinoma (RCC) following radical and partial nephrectomy, and developed surveillance guidelines. MATERIALS AND METHODS: Between 1989 and 2000, 495 patients underwent nephrectomy for RCC at 1 of 5 Canadian referral centers. Median followup was 42 months. RESULTS: The rate of relapse, time to relapse and site of relapse were associated with pathological stage. Five-year progression-free probability was 93% for pT1, 81% for pT2, 67% for pT3A and 57% for pT3B (p <0.001). Compared to patients with pT1-2 those with pT3A-B lesions had earlier relapse after nephrectomy (median 12 vs 26 months, p = 0.001) and were at higher risk for relapse at abdominal sites (14% vs 1.8%, p < 0.001). Abdominal relapse was detected in the absence of symptoms, abnormal biochemical profile or thoracic metastases detectable by chest x-ray in 7 patients (1.4%) overall, including 3 (0.9%) with pT1, 3 (4%) with pT3A and 1 (3%) with pT3B. CONCLUSIONS: The risk and the pattern of relapse of RCC after nephrectomy are associated with pathological stage. For the surveillance of recurrent disease after nephrectomy we recommend annual clinical assessment and chest x-ray in pT1-2 cases. Patients with pT3A-B should be followed every 6 months for the first 3 years with clinical assessment and chest x-ray, and annual followup thereafter. The higher risk of abdominal relapse in patients with pT3A-B indicates that they should receive surveillance abdominal imaging. We recommend abdominal computerized tomography 6, 12, 24 and 36 months postoperatively.

Adult↗
PubMed2004

Tadalafil in the treatment of erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy: a randomized, double-blind, placebo controlled trial.

PURPOSE: We evaluated the efficacy and safety of tadalafil 20 mg, taken on demand, in men with erectile dysfunction following bilateral nerve sparing radical retropubic prostatectomy (BNSRRP). MATERIALS AND METHODS: This randomized, double-blind, placebo controlled multicenter study consisted of a 4-week treatment-free run-in period (baseline) followed by 12 weeks of treatment. A total of 303 men (mean age 60 years) with preoperative normal erectile function who had undergone a BNSRRP 12 to 48 months before study were randomized (2:1) to tadalafil (201) or placebo (102). The 3 co-primary end points were changes from baseline in the International Index of Erectile Function erectile function domain score, and the percentage of positive responses to Sexual Encounter Profile questions 2 (successful penetration) and 3 (successful intercourse). The Global Assessment Question and the Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire were secondary end points. We defined a priori a subgroup of 201 patients reporting evidence of postoperative tumescence, defined as 50% or greater "yes" responses to Sexual Encounter Profile question 1 (ability to achieve at least some erection) during baseline intercourse attempts and stratified randomization based on this criterion. RESULTS: Patients receiving tadalafil reported greater improvement on all primary and secondary end points (p <0.001) compared to placebo. For all randomized patients and for the subgroup with evidence of postoperative tumescence, the mean International Index of Erectile Function erectile function domain score increased for patients receiving tadalafil (mean +/- SEM 5.3 +/- 0.5 and 5.9 +/- 0.7, respectively, p <0.001 vs placebo for both). For all randomized patients who received tadalafil, the mean percentage of successful penetration attempts was 54% and the mean percentage of successful intercourse attempts was 41%. For the subgroup with evidence of postoperative tumescence these values were 69% and 52%, respectively. Of all patients randomized to tadalafil 62% and of the subgroup patients randomized to tadalafil 71% reported improved erections. Patients receiving tadalafil reported greater treatment satisfaction on the Erectile Dysfunction Inventory of Treatment Satisfaction than those receiving placebo. Headache (21%), dyspepsia (13%) and myalgia (7%) were the most commonly reported adverse events. CONCLUSIONS: Tadalafil 20 mg, taken on-demand, was an efficacious and well tolerated treatment for erectile dysfunction following BNSRRP.

Carbolines↗
PubMed2003

Tadalafil in the treatment of erectile dysfunction.

Oral phosphodiesterase-5 inhibitors have emerged as the preferred first-line treatment for erectile dysfunction worldwide because of patient convenience, efficacy, and safety. Clinical trials have shown that tadalafil significantly enhances erectile function across a wide range of etiologies and provides a prolonged period of effectiveness independent of food or alcohol. In this review, the pharmacokinetic and pharmacodynamic characteristics, efficacy, and safety of tadalafil are discussed.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Tadalafil: a new agent for erectile dysfunction.

Oral phosphodiesterase 5 (PDE5) inhibitors for the treatment of erectile dysfunction are preferred by most men, and are recommended in guidelines as first-line therapy, because of convenience, high efficacy, and low rates of side effects. Tadalafil (Cialis) is a new agent that has been studied in different patient populations. It has a different molecular structure than other PDE5 inhibitors, and a different pharmacologic profile that provides a longer period of effectiveness than other agents. This article will review clinical trials on tadalafil, to provide a comprehensive overview of its efficacy and safety.

Administration, Oral↗
PubMed2002

Ca2+-activated Cl- channels in corpus cavernosum smooth muscle: a novel mechanism for control of penile erection.

Little is known of the excitatory mechanisms that contribute to the tonic contraction of the corpus cavernosum smooth muscle in the flaccid state. We used patch-clamp electrophysiology to investigate a previously unidentified inward current in freshly isolated rat and human corporal myocytes. Phenylephrine (PE) contracted cells and activated whole cell currents. Outward current was identified as large-conductance Ca(2+)-activated K(+) current. The inward current elicited by PE was dependent on the Cl(-) gradient and was inhibited by niflumic acid, indicative of a Ca(2+)-activated Cl(-) (Cl(Ca)) current. Furthermore, spontaneous transient outward and inward currents (STOCs and STICs, respectively) were identified in both rat and human corporal myocytes and derived from large-conductance Ca(2+)-activated K(+) and Cl(Ca) channel activity. STICs and STOCs were inhibited by PE and A-23187, and combined 8-bromoadenosine cAMP and 8-bromoadenosine cGMP decreased their frequency. When studied in vivo, chloride channel blockers transiently increased intracavernosal pressure and prolonged nerve-evoked erections. This report reveals for the first time Cl(Ca) current in rat and human corpus cavernosum smooth muscle cells and demonstrates its key functional role in the regulation of penile erection.

Adrenergic alpha-Agonists↗
PubMed2002

Efficacy and safety of tadalafil for the treatment of erectile dysfunction: results of integrated analyses.

PURPOSE: We conducted integrated analyses of the efficacy and safety of tadalafil, a potent, selective phosphodiesterase 5 inhibitor, for the treatment of erectile dysfunction. MATERIALS AND METHODS: A total of 1,112 men with a mean age of 59 years (range 22 to 82) and mild to severe erectile dysfunction of various etiologies were randomized to placebo or tadalafil, taken as needed without food or alcohol restrictions, at fixed daily doses of 2.5 mg, 5 mg, 10 mg, or 20 mg up to a maximum of once daily [DOSAGE ERROR CORRECTED] in 5 randomized, double-blind, placebo controlled trials lasting 12 weeks. The 3 co-primary outcomes were changes from baseline in the erectile function domain of the International Index of Erectile Function and the proportion of "yes" responses to questions 2 and 3 of the Sexual Encounter Profile. Additional efficacy instruments included a Global Assessment Question. RESULTS: Compared with placebo, tadalafil significantly enhanced all efficacy outcomes. Patients receiving 20 mg. tadalafil experienced a significant mean improvement of 7.9 in International Index of Erectile Function erectile function domain score from baseline (p <0.001 versus placebo), 75% of intercourse attempts (Sexual Encounter Profile question 3, a secondary efficacy outcome) were successfully completed (p <0.001 versus placebo) and 81% reported improved erections at end point compared with 35% in the control group (p <0.001). Tadalafil was consistently efficacious across disease severities and etiologies, as well as in patients of all ages. Tadalafil was well tolerated, and headache and dyspepsia were the most frequent adverse events. CONCLUSIONS: Tadalafil was effective and well tolerated in this patient population.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMedDate not supplied

Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction.

Oxidative stress is believed to affect the development of diabetic-associated vasculopathy, endothelial dysfunction, and neuropathy within erectile tissue. Our hypothesis is that, given adequate concentrations of the oxygen free radical scavenger vitamin E, enhanced levels of circulating nitric oxide (NO) should improve erectile function with the potential for a synergistic effect with a phosphodiesterase type 5 (PDE5) inhibitor. Twenty adult male Sprague-Dawley streptozotocin-induced (60 mg/kg intraperitoneally) diabetic rats were placed in 4 therapeutic groups (n = 5 per group) as follows: 1) peanut oil only (diabetic control), 2) 20 IU of vitamin E per day, 3) 5 mg/kg of sildenafil per day, and 4) vitamin E plus sildenafil using oral gavage for 3 weeks. In addition, 5 age-matched rats served as normal nondiabetic controls (normal). Erectile function was assessed by measuring the rise in intracavernous pressure (ICP) following cavernous nerve electrostimulation. Penile tissue was evaluated for neuronal NO synthase (nNOS), smooth muscle alpha-actin, nitrotyrosine, and endothelial cell integrity. Urine nitrite and nitrate (NOx) concentration was quantified, and electrolytes were tested by a serum biochemistry panel. A significant decrease in ICP was recorded in the diabetic animals, with improvement measured in the animals receiving PDE5 inhibitors either with or without vitamin E; the controls had a pressure of 54.8 +/- 5.3 cm H2O, the vitamin E group had a pressure of 73.5 +/- 6.6 cm H2O, the sildenafil group had a pressure of 78.4 +/- 10.77 cm H2O, and the vitamin E plus sildenafil group had a pressure of 87.9 +/- 5.5 cm H2O (P <.05), compared with the normal cohorts at 103.0 +/- 4.8 cm H2O. Histoexaminations showed improved nNOS, endothelial cell, and smooth muscle cell staining in the vitamin E plus sildenafil group compared to the control animals. Urine NOx increased significantly in all the diabetic groups but was blunted in the vitamin E and vitamin E plus sildenafil groups. A significant increase in positive staining for nitrotyrosine was observed in the vitamin E plus sildenafil group. Vitamin E enhanced the therapeutic effect of the PDE5 inhibitor in this study, supporting the potential use of oxygen free radical scavengers in salvaging erectile function in diabetic patients.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMedDate not supplied

Combined transurethral and laparoscopic partial cystectomy and robot-assisted bladder repair for the treatment of bladder endometrioma.

A 40-year-old nulliparous woman with a 7-year history of progressive abdominal discomfort and lower urinary tract symptoms was diagnosed with a deeply infiltrating 4-cm bladder endometrioma. After failing conservative therapy, she was treated with simultaneous transurethral and laparoscopic partial cystectomy and robot-assisted bladder reconstruction. She remained symptom free at last follow-up.

Adult↗
PubMedDate not supplied

Intracavernous pharmacotherapy for erectile dysfunction.

With the advent of phosphodiesterase type-5 inhibition as oral therapy, intracavernous injection of vasoactive agents has been relegated to second-line therapy for most patients with erectile dysfunction. However, the future of this category of agents remains bright as an ever-expanding number and combination of agents in use and under investigation will likely make intracavernous injection more appealing as greater efficacy, tolerability, and more rapid onset is attained. In this article, functional anatomy and physiology of human penile erection is reviewed, as are current clinical vasoactive agents including prostaglandin E-1, papaverine, and phentolamine. Emerging therapies discussed include guanylate cyclase activators, potassium channel openers, nitric oxide donors, vasoactive intestinal polypeptide, calcitonin gene-related peptide, selective alpha-1 receptor antagonists, and gene therapy. Ongoing research continues to define new roles for this effective and safe technique, which has withstood the test of time, restoring erectile function among patients with diverse ED etiologies and a variety of co-morbidities.

Adrenergic alpha-Antagonists↗