Dapoxetine for the Treatment of Premature Ejaculation: Results from a Randomized,Double-Blind,Placebo-Controlled Phase 3 Trial in 22 Countries

Background

Dapoxetine is being developed for the on-demand treatment of premature ejaculation (PE). Previous clinical trials have demonstrated its safety and efficacy.

Objective

To evaluate the long-term efficacy and safety of dapoxetine in men with PE.

Design, setting, and participants

This randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial, conducted in 22 countries, enrolled men (N = 1162) ≥18 yr of age who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision criteria for PE for ≥6 mo, with an intravaginal ejaculatory latency time (IELT) ≤2 min in ≥75% of intercourse episodes at baseline.

Intervention

Dapoxetine 30 mg or dapoxetine 60 mg or placebo on demand (1–3 h before intercourse) for 24 wk.

Measurements

Stopwatch-measured IELT, Premature Ejaculation Profile (PEP), Clinical Global Impression (CGI) of change, adverse events (AEs).

Results and limitations

The study was completed by 618 men. Mean average IELT increased from 0.9 min at baseline (all groups) to 1.9 min, 3.2 min, and 3.5 min with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively, at study end point; geometric mean IELT increased from 0.7 min at baseline to 1.1 min, 1.8 min, and 2.3 min, respectively, at study end point. All PEP measures and IELTs improved significantly with dapoxetine versus placebo at week 12 and week 24 (p < 0.001 for all). The most common AEs were nausea, dizziness, diarrhea, and headache. AEs led to discontinuation in 1.3%, 3.9%, and 8.2% of subjects with placebo and dapoxetine 30 mg and dapoxetine 60 mg, respectively. Limitations of this study included the exclusion of men who were not in long-term monogamous relationships.

Conclusions

Dapoxetine significantly improved all aspects of PE and was generally well tolerated in this broad population.     

A Novel Treatment of Premature Ejaculation

The investigation of the etiology and treatment of premature ejaculation (PE), a common and significant problem for men and their partners, has been limited by the lack of defined outcomes and differences in clinical trial designs. Currently, no medication has been approved for the treatment for PE worldwide. Recognition of serotonin as a key mediator in ejaculatory signaling has raised interest in the utility of pharmacologic intervention for treating PE. Selective serotonin reuptake inhibitors (SSRIs) have been used off-label for PE, with varied results. However, treatment with currently available SSRIs typically requires chronic dosing that increases drug accumulation and the attendant risk of adverse events. Dapoxetine is an SSRI with a short half-life (1.2 h), developed specifically for the treatment of men with PE. This agent has a unique pharmacokinetic profile characterized by rapid absorption and elimination. Dapoxetine is metabolized by multiple pathways, and no clinically relevant drug–drug interactions have been identified. Furthermore, dapoxetine pharmacokinetics do not appear to be affected by food, age, alcohol, or phosphodiesterase type 5 (PDE5) inhibitors to a relevant degree. In two placebo-controlled phase 3 trials involving >2600 men with PE, dapoxetine 60 mg given as needed over 12 wk significantly prolonged the stopwatch-assessed intravaginal ejaculatory latency time (IELT) from 0.91 min at baseline to 3.32 min (p < 0.0001), increased control over ejaculation, and increased sexual satisfaction for men and their partners compared with placebo (both p < 0.0001). These results suggest that dapoxetine may meet the medical need for on-demand therapy for PE.     

帕罗西汀与达帕西汀的对比，治疗早泄的新的选择性5-羟色胺再摄取抑制剂

达帕西汀氢氯化物是一种选择性5-羟色胺再摄取抑制剂,也是第一种被批准可以按需服用治疗早泄的药物。本文目的为研究按需服用达帕西汀（30mg和H60mg）和每日服用帕罗西汀（20mg）对早泄的疗效。研究募集了150名患者进行了长达1个月的研究。患者被分成3组,每组50人。第一组按需服用达帕西汀30mg。第二组按需服用达帕西汀60mg。第三组每日服用帕罗西汀20mg。治疗结束后,我们的结果检测值相对于基准阴道内射精潜伏期（IELT）延长了。与基准IELT相比,帕罗西汀组、30mg达帕西汀组和60mg达帕西汀组的治疗后IELT分别延长了117％（P〈0．01）,117％（P〈0．01）和170％（P〈0．01）。30mg达帕西汀组和帕罗西汀组的IELT增幅相同（P〉0．05）,而60mg达帕西汀组的IELT增幅明显高于30mg达帕西汀组（P〈0．05和帕罗西汀组P〈0．01）。性交前1～3小时服用达帕西汀60mg是针对早泄的非常有效的治疗方法。然而,与当前普遍使用的帕罗西汀相比,达帕西汀30mg疗效并不显著。     

Premature ejaculation: do we have effective therapy?

Introduction

Premature ejaculation (PE) is the most common sexual dysfunction, with the majority of PE patients remaining undiagnosed and undertreated. Despite its prevalence, there is a current paucity of data regarding available treatment options and mechanisms. The objective of the current investigation is to review and summarize pertinent literature on therapeutic options for the treatment of PE, including behavioral/psychologic, oral pharmacotherapy, and surgery.

Methods

A pubmed search was conducted on articles reporting data on available treatment options for PE. Articles describing potential mechanisms of action were additionally included for review. Preference was given towards randomized, controlled trials, when available.

Results

PE remains an underdiagnosed and undertreated disease process, with limited data available regarding potential underlying mechanisms and long-term outcomes of treatment options. Psychological/behavioral therapies, including the stop-start, squeeze, and pelvic floor rehabilitation techniques have demonstrated improvements in short-term series, with decreased efficacy with additional follow-up. Topical therapies, which are commonly utilized result in prolonged intravaginal ejaculatory latency time (IELT) at the expense of potential penile/vaginal Hypothesia. Oral therapies similarly demonstrate improved IELTs with variable side effect profiles and include selective serotonin reuptake inhibitors (daily or on demand), phosphodiesterase-5 inhibitors, alpha-1 adrenergic antagonists, and tramadol. Alternative therapies such as acupuncture have shown benefits in limited studies. Surgery is not commonly performed and is not recommended by available guidelines.

Conclusions

PE is a common condition, with limited data available regarding its underlying pathophysiology and treatment. Available therapies include topical, oral, behavioral/psychologic modification, or a combination thereof. Additional research is required to assess the optimal treatment strategies and algorithms as well as to better define the mechanisms for PE and its management.     

Pharmacotherapy of premature ejaculation: a systematic review and network meta-analysis

Purpose

The purpose of the study was to conduct a systematic evaluation of the different general prescribed drugs for premature ejaculation (PE).

Methods

A systematic literature search of MEDLINE, Cochrane Central Register of Controlled Trials, and Web of Science for Systematic Reviews was performed on 1 March 2018. Intravaginal ejaculation latency time (IELT) was the main outcome. Analysis was performed under multivariate random-effects network model and efficacies of drugs were ranked with surface under the cumulative ranking (SUCRA) probabilities.

Results

A total of 48 studies were reviewed and 40 of them were further enrolled into network meta-analysis. The majority of RCTs were of unclear methodological quality. Pooled evidence suggested that topical anaesthetic creams (TAs), tramadol, selective serotonin reuptake inhibitors (SSRIs), and phosphodiesterase type 5 inhibitors (PDE5is) are more effective at prolonging IELT comparing with placebo. TAs (90%) on demand (OD) and PDE5is plus SSRI (89.8%) had the highest SUCRA, which meant the most probable to be the most effective intervention.

Conclusions

We recommend the initial use of dapoxetine 30 mg OD for PE because it has been tested in largest and better designed clinical trials rather than it is more effective than the other drugs studied. TAs and tramadol 50 mg OD can be used as a viable alternative to oral treatment with SSRIs. PDE5is combined with SSRIs are more effective than SSRIs monotherapy but are also associated with more side effects. PDE5is OD can be recommended to PE patients with ED.

     

Pharmacokinetic and pharmacodynamic features of dapoxetine, a novel drug for 'on-demand' treatment of premature ejaculation

OBJECTIVE: To describe the relationship between the pharmacokinetic and pharmacodynamic properties of dapoxetine, a drug specifically developed for treating premature ejaculation (PE). METHODS: Data from various stages of the clinical development programme were analysed using validated methods for assessing ejaculatory latency. The clinical characteristics were then compared with the pharmacokinetic profile, determined from measured plasma drug concentrations. RESULTS: Pharmacodynamic and pharmacokinetic measurements confirm that 'on demand' dapoxetine has a rapid onset of action and is rapidly cleared after sexual intercourse. CONCLUSION: Dapoxetine may represent the first of a new category of selective serotonin transport inhibitors. Although dapoxetine has pharmacological similarities to other selective serotonin transport inhibitors, its efficacy after acute administration sets it apart and suggests a different mode of action. Its physicochemical and pharmacokinetic properties and its clinical efficacy make dapoxetine suitable for on-demand treatment of PE.     

Penile Incarceration with Metallic Foreign Bodies: Management and Review of Literature

Introduction

Penile strangulation from constricting metallic objects disorders is an uncommon urological emergency which requires prompt intervention to prevent complications. The treatment modalities are diverse and characterized by lack of consensus.

Material and Methods

Three cases with penile incarceration due to constricting metallic objects who presented to our department were included in this study. All 3 patients required different management options highlighting the diversity of clinical presentation and need for customization of treatment as per the clinical scenario.

Results

The 3 patients required different approach for treatment. First patient could be managed by degloving of penile skin while second patient required mechanical removal of the foreign body and debridement of local necrotic tissues. The third patient had to undergo excision of gangrenous penile skin and skin grafting.

Conclusion

The study emphasizes the diversity of clinical presentations and the need for employing different surgical techniques to achieve the desired results.Key Words: Penile strangulation, Constricting objects, Penile amputation     

Menorrhagia: a synopsis of management focusing on herbal and nutritional supplements, and chiropractic

Introduction

To make chiropractors more aware of menorrhagia and how they can serve a role in their patient’s care and education since women make up 60% of the population seeking chiropractic care.

Method

A review of the biomedical literature on menorrhagia was conducted. Items that were retrieved were synthesized and interpreted in order to give the best information to practicing chiropractors.

Discussion

Most of the information available relative to menorrhagia is medically oriented. Other treatment options can include: chiropractic, various types of herbs, and nutritional supplements.

Conclusion

Knowledge of medical treatment, nutritional supplements, along with chiropractic treatment options may be beneficial to doctors in their practice.     

SURGICAL TREATMENT OF HEMORRHOIDS: A CRITICAL APPRAISAL OF THE CURRENT OPTIONS

Introduction

Surgical treatment of hemorrhoids is still a dilemma. New techniques have been developed leading to a lower rate of postoperative pain; however, they are associated with a greater likelihood of recurrence.

Aim

To review current indications as well as the results and complications of the main techniques currently used in the surgical treatment of hemorrhoidal disease.

Methods

A systematic search of the published data on the options for treatment of hemorrhoids up to December 2012 was conducted using Medline/PubMed, Cochrane, and UpToDate.

Results

Currently available surgical treatment options include procedure for prolapse and hemorrhoids (PPH), transanal hemorrhoidal dearterialization (THD), and conventional hemorrhoidectomy techniques. Excisional techniques showed similar results regarding pain, time to return to normal activities, and complication rates. PPH and THD were associated with less postoperative pain and lower complication rates; however, both had higher postoperative recurrence rates.

Conclusion

Conventional surgical techniques yield better long-term results. Despite good results in the immediate postoperative period, PPH and THD have not shown consistent long-term favorable results.     

The Management of Spinal Metastases from Renal Cell Carcinoma

INTRODUCTION

Osseous metastases occur in 50% of patients with renal cell carcinoma; of these, 15% occur in the spine. The treatment options for spinal metastases secondary to renal cell carcinoma are limited. This paper considers the current management options available for spinal metastases secondary to renal cell carcinoma.

PATIENTS AND METHODS

A review of four patients with spinal metastases secondary to renal cell carcinoma.

RESULTS

The presentation of four cases highlighting the current management options for spinal metastases secondary to renal cell carcinoma.

CONCLUSIONS

Historically, spinal metastases from renal cell carcinoma have been poorly managed; however, as the treatment of the primary disease improves, better treatment of the secondary disease is needed. Cement augmentation, used alone for prophylactic stabilisation or in conjunction with a posterior decompression and fixation, provides a useful addition in the management of these patients optimising their chance to remain ambulant, continent, and pain-free.     

Breast ecchymosis: Unusual complication of an antidepressant agent

INTRODUCTION

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) that is safely used for treatment of psychosomatic disorders. Despite being associated with a low side effect profile, it has been reported to cause hematological side effects including vaginal bleeding, epistaxis, purpura, hematuria, intracranial bleeding, and rectal bleeding. Isolated breast ecchymosis is one of exceedingly rare SSRI-induced hematological abnormalities.

PRESENTATION OF CASE

In this case study, we report a case of left breast ecchymosis in a 75-year-old woman that developed in conjunction with use of the SSRI fluoxetine.

DISCUSSION

The use of SSRIs has surged over the past decades due to increased diagnosis and focus on clinical management of depression and anxiety disorders, especially in developed nations. The low side effect profiles of the eight currently marketed SSRI agents has further promoted their use in the general population. While the most commonly reported side effects are mild and relatively tolerable, a risk of SSRI-related abnormal bleeding exists and may represent a life-threatening side effect. The most frequent SSRI-related bleeding manifestation is ecchymosis, but cases of isolated breast ecchymosis are exceedingly rare and to date only one report of SSRI-induced breast ecchymosis is included in the publicly available literature.

CONCLUSION

Three factors may have played a role in lack of reports describing SSRI-induced breast ecchymosis in literature. First, SSRIs indeed very seldom cause breast ecchymosis; second, physicians are not aware of such a causal relationship; and third, physicians find this side effect not worth to publish.     

Guyon Canal Syndrome: lack of management in a case of unresolved handlebar palsy

Objective:

To present the clinical diagnostic features including management of Guyon canal syndrome in a case with unresolved sensory deficits in a young female cyclist.

Clinical Presentation:

After 14 days of cycling across Canada, a 23-year old female experienced sensory loss, followed by atrophy and a “claw” hand appearance of her left hand.

Intervention and Outcome:

Treatment included cervical chiropractic manipulation, soft tissue therapy and the use of cycling gloves. Seven years after the initial injury a lack of sensation in the ulnar nerve distribution of her left hand has persisted.

Discussion:

This case demonstrates that a lack of proper management can lead to permanent sensory loss and is worth highlighting. Various therapists evaluated the patient’s symptoms and provided minimal care. No diagnosis was given, nor were appropriate measures taken for her to understand the risks of continuing to ride.

Summary:

Although treatment for Guyon Canal Syndrome can be as easy as cessation from cycling until symptoms subside, other treatment options could be utilized to help manage ulnar nerve compression injuries in cyclists.     

A multidisciplinary approach including the use of platelet-rich plasma to treat an elite athlete with patellar tendinopathy – a case report

Objective:

Patellar tendinopathy affects a substantial proportion of athletes involved in jumping or kicking activities. Platelet rich plasma (PRP) injections may be a promising treatment used in conjunction with common traditional therapies.

Clinical Features:

Patellar tendinopathy is often the result of repetitive or excessive overload on the patellar tendon. Activity modification, cryotherapy, eccentric exercises, shockwave therapy, and PRP have been indicated as treatment options during various stages of this condition.

Intervention and Outcome:

A 23 year old female, elite track and field athlete was managed for patellar tendinopathy with a combination of traditional therapeutic interventions as well as a PRP injection. This athlete returned to pre-injury level of competition six months post-injection.

Conclusion:

Emerging literature on PRP appears to be promising for patellar tendinopathy, however, it remains unclear which patients may benefit most and whether the stage of the disorder has an impact on the clinical outcome.     

A morphometric cadaver study of the anterior lumbar epidural space

Introduction

Free disc fragments end often up in the concavity of the anterior epidural space. This space consists of two compartments. The discrepancy between the impressive magnetic resonance imaging findings, clinical symptoms in patients and the problem of treatment options led us to the anatomical determination of anterior epidural space volumes.

Materials and methods

For the first time, the left and right anterior epidural volume between the peridural membrane and the posterior concavity of the lumbar vertebral bodies L3–S1 were determined for each segment. A CT scan and a polyester resin injection were used for the in vitro measurements.

Results

The volumes determined in human cadavers using this method ranged from 0.23 ccm for L3 to 0.34 ccm for L5. The CT concavity volume determination showed this increase in volume from cranial to caudal, as well.

Conclusion

This volume is large enough to hold average-sized slipped discs without causing neurological deficits. A better understanding of the anterior epidural space may allow a better distinction of patient treatment options.     

Guidelines on Male Sexual Dysfunction: Erectile Dysfunction and Premature Ejaculation

Context

Erectile dysfunction (ED) and premature ejaculation (PE) are the two most prevalent male sexual dysfunctions.

Objective

To present the updated version of 2009 European Association of Urology (EAU) guidelines on ED and PE.

Evidence acquisition

A systematic review of the recent literature on the epidemiology, diagnosis, and treatment of ED and PE was performed. Levels of evidence and grades of recommendation were assigned.

Evidence synthesis

ED is highly prevalent, and 5–20% of men have moderate to severe ED. ED shares common risk factors with cardiovascular disease. Diagnosis is based on medical and sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to the patient's complaints and risk factors. Treatment is based on phosphodiesterase type 5 inhibitors (PDE5-Is), including sildenafil, tadalafil, and vardenafil. PDE5-Is have high efficacy and safety rates, even in difficult-to-treat populations such as patients with diabetes mellitus. Treatment options for patients who do not respond to PDE5-Is or for whom PDE5-Is are contraindicated include intracavernous injections, intraurethral alprostadil, vacuum constriction devices, or implantation of a penile prosthesis.PE has prevalence rates of 20–30%. PE may be classified as lifelong (primary) or acquired (secondary). Diagnosis is based on medical and sexual history assessing intravaginal ejaculatory latency time, perceived control, distress, and interpersonal difficulty related to the ejaculatory dysfunction. Physical examination and laboratory testing may be needed in selected patients only.Pharmacotherapy is the basis of treatment in lifelong PE, including daily dosing of selective serotonin reuptake inhibitors and topical anaesthetics. Dapoxetine is the only drug approved for the on-demand treatment of PE in Europe. Behavioural techniques may be efficacious as a monotherapy or in combination with pharmacotherapy. Recurrence is likely to occur after treatment withdrawal.

Conclusions

These EAU guidelines summarise the present information on ED and PE. The extended version of the guidelines is available at the EAU Web site (http://www.uroweb.org/nc/professional-resources/guidelines/online/).     

The present state of treatments for articular cartilage defects in the knee

INTRODUCTION

Chondral and osteochondral lesions of the knee are notoriously difficult to treat due to the poor healing capacity of articular cartilage and the hostile environment of moving joints, ultimately causing disabling pain and early osteoarthritis. There are many different reconstructive techniques used currently but few are proven to be of value. However, some have been shown to produce a better repair with hyaline-like cartilage rather than fibrocartilage.

METHODS

A systematic search of all available online databases including PubMed, MEDLINE® and Embase™ was undertaken using several keywords. All the multiple treatment options and methods available were considered. These were summarised and the evidence for and against them was scrutinised.

RESULTS

A total of 460 articles were identified after cross-referencing the database searches using the keywords. These revealed that autologous and matrix assisted chondrocyte implantation demonstrated both ‘good to excellent’ histological results and significant improvement in clinical outcomes.

CONCLUSIONS

Autologous and matrix assisted chondrocyte implantation have been shown to treat symptomatic lesions successfully with significant histological and clinical improvement. There is, however, still a need for further randomised clinical trials, perfecting the type of scaffold and the use of adjuncts such as growth factors. A list of recommendations for treatment and the potential future trends of managing these lesions are given.     

Therapeutic options to minimize allogeneic blood transfusions and their adverse effects in cardiac surgery: A systematic review

Introdution

Allogeneic blood is an exhaustible therapeutic resource. New evidence indicates that blood consumption is excessive and that donations have decreased, resulting in reduced blood supplies worldwide. Blood transfusions are associated with increased morbidity and mortality, as well as higher hospital costs. This makes it necessary to seek out new treatment options. Such options exist but are still virtually unknown and are rarely utilized.

Objective

To gather and describe in a systematic, objective, and practical way all clinical and surgical strategies as effective therapeutic options to minimize or avoid allogeneic blood transfusions and their adverse effects in surgical cardiac patients.

Methods

A bibliographic search was conducted using the MeSH term “Blood Transfusion” and the terms “Cardiac Surgery” and “Blood Management.” Studies with titles not directly related to this research or that did not contain information related to it in their abstracts as well as older studies reporting on the same strategies were not included.

Results

Treating anemia and thrombocytopenia, suspending anticoagulants and antiplatelet agents, reducing routine phlebotomies, utilizing less traumatic surgical techniques with moderate hypothermia and hypotension, meticulous hemostasis, use of topical and systemic hemostatic agents, acute normovolemic hemodilution, cell salvage, anemia tolerance (supplementary oxygen and normothermia), as well as various other therapeutic options have proved to be effective strategies for reducing allogeneic blood transfusions.

Conclusion

There are a number of clinical and surgical strategies that can be used to optimize erythrocyte mass and coagulation status, minimize blood loss, and improve anemia tolerance. In order to decrease the consumption of blood components, diminish morbidity and mortality, and reduce hospital costs, these treatment strategies should be incorporated into medical practice worldwide.     

Ganglion cyst of the foot treated with electroacupuncture: A case report

Objective:

To present the clinical management of a ganglion cyst presenting on the dorsolateral aspect of the foot.

Clinical Features:

A 45-year-old female cyclist complaining of ganglion cyst following training period.

Intervention and Outcome:

Patient was treated with high-frequency electroacupuncture in four consecutive sessions over four weeks, and reported resolution of the cyst following therapeutic intervention.

Conclusions:

Ganglion cysts of the foot are relatively rare connective tissue tumours with variable treatment approaches. Electroacupuncture may be a novel and non-invasive conservative approach for the treatment of ganglion cysts. Further evaluation of the efficacy of such treatment is warranted.     

Evolving paradigm in treatment of Merkel cell carcinoma of the digit from ray resection to wide local excision and flap coverage

Background

Merkel cell carcinoma is a rare cutaneous neuroendocrine neoplasm that typically presents on the head and neck. Merkel cell carcinoma (MCC) of the digits is rare, and thus limited treatment options have been presented.

Methods

In contrast to the current treatment recommendation of ray resection of the affected digit, two patients were treated by sentinel node biopsy, wide local excision, and flap coverage of the defect.

Results

No local recurrences or metastases have been seen 24 months postoperatively.

Conclusion

We suggest that the paradigm of ray amputation of a digit affected by MCC should evolve to initial treatment with a sentinel lymph node biopsy (SLNB) with subsequent local excision with wide margins and local flap coverage.     

Polyethylene thickness is a risk factor for wear necessitating insert exchange

Purpose

The aim of this observational study was to investigate the optimal minimal polyethylene (PE) thickness in total knee arthroplasty (TKA) and identify other risk factors associated with revision of the insert due to wear.

Methods

A total of 84 TKA were followed for 11–16 years. All patients received the same prosthesis design (Interax; Howmedica/ Stryker) with halfbearings: separate PE-inserts medially and laterally. Statistical analysis comprised Cox-regression to correct for confounding.

Results

Eight knees (9.5%) had been revised due to thinning inserts and an additional patient is scheduled for revision. PE thickness, diagnosis, BMI and weight are risk factors for insert exchange. For each millimetre decrease in PE thickness, the risk of insert exchange increases 3.0 times, which remains after correction for age, gender, weight, diagnosis and femoral-tibial angle. Insert exchange was 4.73 times more likely in OA-patients compared to RA-patients. For every unit increase in BMI and weight the risk for insert exchange increases 1.40 times and 1.14 times, respectively.

Conclusions

In conclusion we therefore advise against the use of thin PE inserts in modular TKA and recommend PE inserts with a minimal 8-mm thickness.