Three-Dimensional Printed Total Talus Replacement with a Concurrent Total Ankle Arthroplasty as a Personalized Approach for Advanced Ankle Osteoarthritis A Case Repor.

Ankle arthritis is becoming more common and can be pain-ful and debilitating. As the disease progresses, degenera-tive cystic changes may be found in the distal fibula, distal tibia, and talus. After failure of non-operative modalities, arthrodesis is often considered the surgical intervention of choice, but this leaves the patient with reduced range of motion, altered gait, and can negatively impact adjacent joints of the foot. Total ankle arthroplasty has been found to be an effective surgical option for ankle arthritis but is contraindicated in patients with talar collapse. When this is the case, a more personalized approach for preserving ankle motion is necessary. We present the case of a 65-year-old male with severe right ankle arthritis and talar collapse treated with a custom three-dimensionally printed talus and concurrent total ankle replacement with 2-year follow-up.

Total Hip Arthroplasty in Patients Who Have Marfan Syndrome: Adverse Events and 5-Year Revision Rates.

BACKGROUND: Marfan syndrome is a rare inherited connective tissue disease, which may be present in patients who have advanced hip pathologies that may require total hip arthroplasty (THA). The postoperative course of patients who have Marfan syndrome following THA has not yet been defined. METHODS: Adult patients who have and do not have Marfan syndrome and underwent THA were identified in a national database. Patients diagnosed who had infection, trauma, or neoplasms within the 90 days prior to surgery were excluded. Those who have versus those who did not have Marfan syndrome were matched 1:10 based on age, sex, and a comorbidity index. After matching, 144 patients who have Marfan syndrome and 1,440 who do not have Marfan syndrome were identified. The 90-day postoperative adverse events and 5-year revisions were assessed and compared with multivariable analyses and log rank tests, respectively. RESULTS: Multivariable analyses demonstrated that Marfan syndrome was independently associated with greater odds of 90-day adverse events: venous thromboembolic events (odds ratio [OR]: 2.9, P = .001), cardiac events (OR: 4.5, P = .034), pneumonia (OR: 3.5, P < .001), and urinary tract infections (OR: 5.2, P < .001). There was no significant difference in 5-year rates of revision. CONCLUSIONS: Following THA, Marfan syndrome was independently associated with greater rates of several 90-day adverse events, but not higher 5-year rates of revision. The identified at-risk adverse events may help guide surgeons to improve perioperative care pathways, while having confidence regarding joint survival of THA in this rare disease population.

The correlation of psoriasis and its treatment medications with lumbar discectomy postoperative infections.

BACKGROUND CONTEXT: Psoriasis is a chronic, autoimmune disease of the skin that affects approximately 3% of the US adult population. Patients with psoriasis may be predisposed to spine surgical site infections (SSI) related to the condition and/or related medications following surgeries such as lumbar laminotomy/discectomy. PURPOSE: To assess the potential correlation of psoriasis and its related treatment medications on the risk of infection-related complications after lumbar laminotomy/discectomy. STUDY DESIGN: Retrospective case control, national administrative database study. PATIENT SAMPLE: Adult patients who underwent isolated single-level lumbar discectomy between 2010 and Q1 of 2021 were identified in the PearlDiver Mariner Ortho151 national administrative database (excluding those with concurrent diagnoses of fractures, neoplasms, or infections). OUTCOME MEASURES: Ninety-day postoperative rates of surgical site infection and sepsis. METHODS: Lumbar laminotomy/discectomy patients with versus without psoriasis were matched 1:4 based on age, sex, and Elixhauser Comorbidity Index. The risk of SSI and sepsis in the 90-day postoperative window between the cohorts were compared with multivariable analyses. Five-year reoperation rates were also compared with log rank test. The matched psoriasis cohort was further subdivided by psoriasis treatment regimens - no medication treatment (NT), topical therapies only (TT), topical therapies with oral systemic treatments (TT/OS), and topical therapies with biologics (TT/B). Multivariable logistic regression was used to assess the risk of SSI and sepsis within 90 days after lumbar laminotomy/discectomy for each treatment subgroup compared to patients without psoriasis. RESULTS: In total, 2,262 patients with psoriasis who underwent single-level lumbar laminotomy/discectomy were identified and matched by age, sex, and Elixhauser Comorbidity Index to 9,044 patients without psoriasis. Multivariable logistic regression showed that, compared to the patients without psoriasis, patients with psoriasis had a 1.795 times higher chance of developing SSI (odds ratio [OR]) (p<.001) and sepsis (OR: 1.743, p=.027) within 90 days of surgery. Having psoriasis did not significantly correlate with 5-year reoperation rates. Of those with psoriasis, NT subcohort had 1,038 patients, TT subcohort 571 patients, TT/OS subcohort 226 patients, and TT/B subcohort 140 patients. Based on multivariable analysis and compared to nonpsoriasis patients, those in the NT, TT, TT/OS were not at greater odds of postoperative SSI or sepsis. Conversely, those in the TT/B subcohort were at significantly greater odds of SSI (OR: 3.102, p=.019) and sepsis (OR: 6.367, p=.027). CONCLUSIONS: Of single-level lumbar laminotomy/discectomy patients with psoriasis, only those on topical therapies and biologics were at greater risk of postoperative SSI and sepsis. This subcohort warrants specific attention when undergoing lumbar laminotomy/discectomy and possibly holding such medications for a period prior to surgery may be warranted if possible.

Opioid Prescription Patterns 90 Days After Arthroscopic Rotator Cuff Repair: A 10-Year National Database Analysis.

Background: Arthroscopic rotator cuff repair (ARCR) is a common procedure that typically requires opioid prescription for postoperative pain management. Purpose: To investigate the current prescription patterns and factors influencing 90-day postoperative opioid prescription trends for opioid-naïve patients who underwent ARCR. Study Design: Case series; Level of evidence, 4. Methods: Opioid-naïve adult patients who underwent ARCR between January 2010 and September 2020 and had a record of opioid prescriptions during the 90-day postoperative period were identified in the PearlDiver Mariner91 national administrative database. Exclusions included patients with prior shoulder procedures, a history of chronic pain, and opioid prescription records dated earlier than 4 weeks before surgery. Covariates included age group, sex, Elixhauser Comorbidity Index, and prescriber specialty (orthopaedic or nonorthopaedic). The primary outcome-90-day postoperative morphine milligram equivalents (MMEs) prescribed per patient-was compared using univariate and multivariate regression analyses, and 90-day postoperative opioid prescription trends over the 10-year study period were analyzed with linear regression. Results: In total, 55,345 ARCR cases were identified. The mean ± SD amount prescribed within the first 90 days was 742.4 ± 256.5 MMEs, and the median was 487.5 MMEs. Multivariate linear regression analysis predicted higher 90-day postoperative MMEs for female patients and younger patients (P < .01 for both). From 2010 to 2020, there was a 66% decrease in mean MME prescribed per patient (▵ = 660.4 MME; P < .01), with a mean reduction of 55.1 MME per patient per year. In 2020, the mean 90-day postoperative amount prescribed was 341.1 MME, which is equivalent to 51 tablets of 5-mg oxycodone (Percocet). Conclusion: Female sex and younger age were predictors of more MME being prescribed after ARCR. While opioid prescriptions following ARCR have substantially decreased over the past decade, the amount prescribed warrants further attention.

Treatment of an Infected Tibial Shaft Non-Union Using a Novel 3D-Printed Titanium Mesh Cage: A Case Report.

Treating large bone defects resulting from trauma, tumors, or infection can be challenging, as current methods such as external fixation with bone transport, bone grafting, or amputation often come with high costs, high failure rates, high requirements for follow-up, and potential complications. In this case report, we present the successful treatment of a complicated, infected tibial shaft non-union by using a personalized three-dimensional (3D)-printed titanium mesh cage. This case adds to the existing body of literature by demonstrating successful integration of bone into a titanium implant and a demonstration of immediate postoperative weight bearing in the setting of suboptimal operative and psychosocial conditions. Futhermore, this report highlights the flexibility of 3D-printing technology and its ability to allow for continued limb salvage, even after a planned bone transport procedure has been interrupted. The use of 3D-printed implants customized to the patient's specific needs offers a promising new avenue for treating complex tibial pathologies, and the technology's versatility and ability to be tailored to individual patients makes it a promising tool for addressing a wide range of bone defects.

Anterior Cervical Discectomy and Fusion Outcomes in Patients With and Without Bariatric Surgery-Weight Loss Does Make a Difference.

STUDY DESIGN: A retrospective comparative cohort study. OBJECTIVE: To compare outcomes of elective non-obese anterior cervical discectomy and fusion (ACDF) patients with those that underwent bariatric surgery (BS). SUMMARY OF BACKGROUND DATA: Morbid obesity (MO) has been associated with an increased risk of complications following procedures such as elective ACDF. While pre-emptive BS has been considered for those with MO (body mass index [BMI] ≥35 kg/m 2 ), the impact of this intervention on BMI and its resultant correlation with surgical outcomes remains limited. METHODS: The PearlDiver 2010-Q1 2020 MSpine database was used to identify patients undergoing elective isolated ACDF. Three sub-cohorts were defined as follows: (1) Non-obese controls without a history of BS, (2) patients with BS procedure within two years with a BMI <35 kg/m 2 (BS+MO-), and (3) patients with BS procedure within the two years with a BMI ≥35 kg/m 2 (BS+MO+). Univariate and multivariate regression analyses were performed to compare 90-day adverse event rates adjusting for age, sex, Elixhauser Comorbidity Index, and length of stay. Kaplan-Meier analysis was performed to assess five-year cervical reoperation rates. RESULTS: Of 160,166 elective ACDF patients, prior BS was identified for 479. Of these, 136 patients were BS+MO- and 343 were BS+MO+. On multivariate analysis, BS+MO- were not at increased odds of adverse events, but BS+MO+ were at greater odds of 90-day pulmonary embolism (odds ratio 3.28, P =0.043), wound dehiscence (5.02, P <0.001), hematomas (2.52, P =0.042), and overall minor adverse events (1.61, P =0.011) compared with controls. Five-year reoperation rates were not significantly different between the groups. CONCLUSION: Twenty-eight percent of those with BS before ACDF fell out of the categorization of MO. Among this group, the odds of adverse events were similar to non-obese patients. These findings suggest that the psychological preparation and BS alone are insufficient to reduce the risk of adverse events after ACDF. Weight reduction must be achieved as well, ideally moving patients out of the BMI range for morbid obesity.

Assessing the Quality of YouTube Videos on Adhesive Capsulitis.

Introduction  YouTube is the most popular video-based source of information on the Internet. It is accessed by over 1 billion users, which approximates to almost one-third of all Internet users. Orthopaedic video content published on YouTube is not screened and does not go through an editorial process, and most videos do not have information about authorship or appropriate references. Users who do not have the knowledge to assess the accuracy and reliability of the source may be misinformed about their medical condition. Previous studies have evaluated the quality of YouTube content for information in orthopaedics such as meniscus,kyphosis, and anterior cruciate ligament (ACL), but the quality of frozen shoulder videos on YouTube has not been investigated. The purpose of this study is to evaluate the quality and educational value of YouTube videos concerning adhesive capsulitis. Methods A YouTube search was performed using the term "frozen shoulder." Videos were excluded if they had no audio, were in a language other than English, or were longer than 10 minutes. A total of 70 videos were screened, and the first 50 videos that met the inclusion criteria were evaluated by three observers. Six video characteristics were extracted, and videos were categorized by source and content. Quality and educational value were assessed using the DISCERN (score range, 0-5), Global Quality score (GQS; score range, 0-4), and a Frozen Shoulder-Specific Score (FSSS; score range, 0-16). Results  The mean video duration was 242.46 ± 164.32 seconds. The mean number of views was 137,494 ± 262,756 and the total view count across 50 videos was 6,874,706. The mean DISCERN, GQS, and FSSS scores were 2.72 ± 0.85, 2.37 ± 0.895, and 4.42 ± 3.15, respectively. The video sources were primarily from non-physician healthcare professionals (32%), and most of the video content was focused on disease-specific information (50%). Significant between-group effects were observed for the DISCERN score and video source (P = .005), with videos from academic sources having the highest mean DISCERN score. DISCERN scores also differed significantly based on video content (P = .007), with disease content having the highest DISCERN score. Both GQS and FSSS scores differed significantly based on video content (both P < .001) but did not differ significantly based on the video source. Conclusions Information about frozen shoulder on YouTube is low quality and has limited educational value. Thus, providers for orthopaedic conditions should warn their patients and provide better alternatives for education.

A digital pathology tool for quantification of color features in histologic specimens.

In preclinical research, histological analysis of tissue samples is often limited to qualitative or semiquantitative scoring assessments. The reliability of this analysis can be impaired by the subjectivity of these approaches, even when read by experienced pathologists. Furthermore, the laborious nature of manual image assessments often leads to the analysis being restricted to a relatively small number of images that may not accurately represent the whole sample. Thus, there is a clear need for automated image analysis tools that can provide robust and rapid quantification of histologic samples from paraffin-embedded or cryopreserved tissues. To address this need, we have developed a color image analysis algorithm (DigiPath) to quantify distinct color features in histologic sections. We demonstrate the utility of this tool across multiple types of tissue samples and pathologic features, and compare results from our program to other quantitative approaches such as color thresholding and hand tracing. We believe this tool will enable more thorough and reliable characterization of histological samples to facilitate better rigor and reproducibility in tissue-based analyses.

Development and Performance of a Web-Based Tool to Adjust Urine Toxicology Testing Frequency: Retrospective Study.

BACKGROUND: Several pain management guidelines recommend regular urine drug testing (UDT) in patients who are being treated with chronic opioid analgesic therapy (COAT) to monitor compliance and improve safety. Guidelines also recommend more frequent testing in patients who are at high risk of adverse events related to COAT; however, there is no consensus on how to identify high-risk patients or on the testing frequency that should be used. Using previously described clinical risk factors for UDT results that are inconsistent with the prescribed COAT, we developed a web-based tool to adjust drug testing frequency in patients treated with COAT. OBJECTIVE: The objective of this study was to evaluate a risk stratification tool, the UDT Randomizer, to adjust UDT frequency in patients treated with COAT. METHODS: Patients were stratified using an algorithm based on readily available clinical risk factors into categories of presumed low, moderate, high, and high+ risk of presenting with UDT results inconsistent with the prescribed COAT. The algorithm was integrated in a website to facilitate adoption across practice sites. To test the performance of this algorithm, we performed a retrospective analysis of patients treated with COAT between June 2016 and June 2017. The primary outcome was compliance with the prescribed COAT as defined by UDT results consistent with the prescribed COAT. RESULTS: 979 drug tests (867 UDT, 88.6%; 112 oral fluid testing, 11.4%) were performed in 320 patients. An inconsistent drug test result was registered in 76/979 tests (7.8%). The incidences of inconsistent test results across the risk tool categories were 7/160 (4.4%) in the low risk category, 32/349 (9.2%) in the moderate risk category, 28/338 (8.3%) in the high risk category, and 9/132 (6.8%) in the high+ risk category. Generalized estimating equation analysis demonstrated that the moderate risk (odds ratio (OR) 2.1, 95% CI 0.9-5.0; P=.10), high risk (OR 2.0, 95% CI 0.8-5.0; P=.14), and high risk+ (OR 2.0, 95% CI 0.7-5.6; P=.20) categories were associated with a nonsignificantly increased risk of inconsistency vs the low risk category. CONCLUSIONS: The developed tool stratified patients during individual visits into risk categories of presenting with drug testing results inconsistent with the prescribed COAT; the higher risk categories showed nonsignificantly higher risk compared to the low risk category. Further development of the tool with additional risk factors in a larger cohort may further clarify and enhance its performance.

Continuing Anti-thrombotic Medication During Low-to-Intermediate Risk Spinal Procedures: A Retrospective Evaluation.

BACKGROUND: The current American Society of Regional Anesthesia (ASRA) guidelines recommend discontinuing anti-thrombotic therapy prior to any interventional spine procedures to decrease the incidence of bleeding complications. However, discontinuing anti-thrombotics may pose considerable danger in terms of cerebrovascular and cardiovascular events. Recent evidence suggests that some spinal interventions may still be performed safely with anti-thrombotics on board and some practitioners thus elect to continue certain anti-thrombotics for these procedures. OBJECTIVE: To assess the rate of adverse events in patients undergoing spine procedures that are currently classified by the ASRA guidelines as "low-to-intermediate bleeding risk," while being on continued anti-thrombotic therapy. STUDY DESIGN: Retrospective cohort study. SETTING: Interventional pain management practice. METHODS: A retrospective chart review was performed on patients who underwent low-to-intermediate risk spine procedures with variable anti-thrombotic medications continued throughout the course of treatment. RESULTS: Between October 2015 and May 2016, out of 2,204 patients who underwent low-to-intermediate risk spine procedures, we identified 490 patients on anti-thrombotic medications. These included aspirin (N = 275), P2Y12 inhibitors (N = 129), warfarin (N = 62), heparin (N = 10), factor Xa inhibitors (N = 55), and dipyridamole (N = 1). Forty-two patients were on multiple anti-thrombotics. Anti-thrombotics were continued throughout the procedure for 467 of 490 patients (88%). One bleeding complication (injection site bleeding) occurred in a patient that continued clopidogrel and aspirin during a lumbar radiofrequency ablation. We encountered no bleeding complications attributable to anti-thrombotics in the other 466 procedures in which anti-thrombotics were continued during lumbar (N = 260), thoracic (N = 18), and cervical (N = 40) medial branch injections, sacroiliac injections (N = 47), and during lumbar (N = 87) thoracic (N = 2), and cervical (N = 12) medial branch radiofrequency ablations. LIMITATIONS: The retrospective nature of the study and its reliance on electronic medical records are potential limitations. CONCLUSIONS: Continuing anti-thrombotic medication during medial branch and sacroiliac injections may be possible. KEY WORDS: Interventional pain management, thrombotic complications, hemostasis, anti-coagulation, bleeding complications.

Efficacy of Avanafil 15 Minutes after Dosing in Men with Erectile Dysfunction: A Randomized, Double-Blind, Placebo Controlled Study.

PURPOSE: We examined the therapeutic effects of avanafil 15 minutes after dosing in men with mild to severe erectile dysfunction. MATERIALS AND METHODS: This randomized, double-blind, placebo controlled, 12-week study (4-week run-in and 8-week treatment) randomized 145 men to placebo, 147 to avanafil 100 mg and 148 to avanafil 200 mg on demand. The primary efficacy variable was the per subject proportion of sexual attempts during the treatment period in which subjects achieved erection sufficient for vaginal penetration within approximately 15 minutes after dosing as measured by a stopwatch. The attempt had to enable successful completion of sexual intercourse according to SEP question 3. RESULTS: Significantly greater mean per subject percentages of successful intercourse attempts within approximately 15 minutes after dosing were observed for avanafil 100 mg (mean 25.9%, LS mean ± SE 24.7% ± 2.9%) and 200 mg (mean 29.1%, LS mean 28.2% ± 2.9%) vs placebo (mean 14.9%, LS mean 13.8% ± 2.9%, p = 0.001 and <0.001, respectively). After treatment we noted a statistically significant difference between avanafil and placebo in the average per subject proportion of successful intercourse attempts according to SEP question 3 as early as 10 minutes in the 200 mg group and 12 minutes in the 100 mg group. Treatment emergent adverse events included headache, upper respiratory tract infection and nasal congestion, and most such events were mild or moderate in severity. CONCLUSIONS: Avanafil was efficacious within approximately 15 minutes of dosing compared to placebo. A statistically significant treatment difference in the percentage of successful sexual attempts was demonstrated as early as 10 minutes after treatment.

Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity.

Weight loss can reduce the increased cardiovascular risk associated with obesity. Pharmacotherapy is a recognized weight loss treatment option; however, cardiovascular safety issues with some previous weight loss drugs raise concerns for newly approved pharmacotherapies. Phentermine is approved for short-term obesity treatment in conjunction with lifestyle modifications, but is commonly used chronically. Topiramate, approved for treating epilepsy and preventing migraines, also induces weight loss. A single-dose combination of low-dose phentermine and topiramate extended-release was recently approved by the United States Food and Drug Administration as an adjunct to lifestyle intervention for the chronic treatment of overweight/obese adults. This review summarizes and evaluates the cardiovascular risk/benefit profile associated with phentermine and topiramate, individually and in combination. Cardiovascular data associated with long-term use of phentermine and topiramate extended-release indicate that this combination may be a safe and effective option for reducing weight in overweight/obese patients at low-to-intermediate cardiovascular risk.

Prevention of type 2 diabetes in subjects with prediabetes and metabolic syndrome treated with phentermine and topiramate extended release.

OBJECTIVE To evaluate over 108 weeks the effect of phentermine and topiramate extended release (PHEN/TPM ER) treatment on progression to type 2 diabetes and/or cardiometabolic disease in subjects with prediabetes and/or metabolic syndrome (MetS) at baseline. RESEARCH DESIGN AND METHODS Subanalysis of a phase 3, randomized, placebo-controlled, double-blind study of overweight/obese subjects (BMI ≥27 to ≤45 kg/m(2)) with two or more comorbidities. Subjects were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg (7.5/46), or PHEN 15 mg/TPM ER 92 mg (15/92) plus lifestyle modifications for 108 weeks. Percent weight loss in the intent-to-treat population using multiple imputation (ITT-MI), annualized incidence rate of progression to type 2 diabetes, and changes in glycemia, lipid parameters, blood pressure, and waist circumference were evaluated. RESULTS At baseline, 475 subjects met the criteria for prediabetes and/or MetS. After 108 weeks, subjects with prediabetes and/or MetS in the placebo, 7.5/46, and 15/92 groups experienced mean percent weight loss of 2.5, 10.9, and 12.1%, respectively (ITT-MI; P < 0.0001 vs. placebo), associated with reductions of 70.5 and 78.7% in the annualized incidence rate of type 2 diabetes for those receiving 7.5/46 and 15/92, respectively (ITT, P < 0.05), versus placebo. The ability of PHEN/TPM ER to prevent diabetes was related to degree of weight lost and was accompanied by significant improvements in cardiometabolic parameters. PHEN/TPM ER was well tolerated by this subgroup over 2 years. CONCLUSIONS PHEN/TPM ER plus lifestyle modification produced significant weight loss and markedly reduced progression to type 2 diabetes in overweight/obese patients with prediabetes and/or MetS, accompanied by improvements in multiple cardiometabolic disease risk factors.

Changes in cardiovascular risk associated with phentermine and topiramate extended-release in participants with comorbidities and a body mass index ≥27 kg/m(2).

The aim of this analysis was to evaluate changes in cardiovascular risk factors in obese patients with dyslipidemia and/or hypertension receiving phentermine (PHEN) and topiramate extended-release (TPM ER). In the 56-week, randomized, double-blind, placebo-controlled, multicenter CONQUER trial, PHEN/TPM ER demonstrated significant weight loss compared with placebo in overweight or obese participants with ≥2 weight-related co-morbidities. Participants with body mass indexes of 27 to 45 kg/m(2) were randomized to placebo, PHEN 7.5 mg/TPM ER 46 mg, or PHEN 15 mg/TPM ER 92 mg; participants also received lifestyle modification counseling. Primary end points were percentage weight loss and the proportion of participants achieving ≥5% weight loss. Additional end points were changes in lipid variables in the dyslipidemia population and blood pressure in the hypertensive population, stratified by treatment and magnitude of weight loss. PHEN/TPM ER produced significantly greater dose-related mean percentage weight loss compared with placebo in the subgroups of participants with dyslipidemia and those with hypertension. Regardless of treatment group assignment, participants with dyslipidemia who lost ≥5% of their baseline weight experienced significantly greater reductions in triglycerides (-14.5% to -39.8%), and in non-high-density lipoprotein cholesterol (-9.4% to -14.8%) than those losing <5% of their weight (p <0.05). Similarly, participants with hypertension at baseline showed reduced systolic blood pressure by -7.5 to -11.8 mm Hg (p <0.001 vs those with <5% weight loss). In conclusion, the dose-related weight loss induced by PHEN/TPM ER treatment was accompanied by significant improvements in cardiovascular disease risk factors in participants who had dyslipidemia or hypertension at baseline, suggesting that facilitating weight loss by augmenting lifestyle changes with pharmacotherapies may decrease the risk for cardiovascular disease in obese and overweight patients with co-morbidities.

A phase 3, placebo controlled study of the safety and efficacy of avanafil for the treatment of erectile dysfunction after nerve sparing radical prostatectomy.

PURPOSE: We evaluated the safety and efficacy of 100 and 200 mg avanafil for the treatment of adult males with erectile dysfunction after bilateral nerve sparing radical prostatectomy. MATERIALS AND METHODS: This was a double-blind, placebo controlled, parallel group, phase 3 study in males age 18 to 70 years with a history of erectile dysfunction of 6 months or more after bilateral nerve sparing radical prostatectomy. Patients were randomized to 100 or 200 mg avanafil or placebo (taken 30 minutes before sexual activity) for 12 weeks. Primary end points included successful vaginal insertion (Sexual Encounter Profile [SEP] question 2), successful intercourse (SEP3) and change in score on the erectile function domain of the International Index of Erectile Function (IIEF-EF) questionnaire. RESULTS: A total of 298 patients were randomized and 84.6% completed the study. At baseline 16.1% were age 65 years or older and 71.5% had severe erectile dysfunction (mean overall IIEF-EF domain score 9.2). After 12 weeks there were significantly greater increases in SEP2 and SEP3 and change in mean IIEF-EF domain score with 100 and 200 mg avanafil vs placebo (p <0.01). Following dosing with avanafil 36.4% (28 of 77) of sexual attempts (SEP3) at 15 minutes or less were successful vs 4.5% (2 of 44) for placebo (p <0.01). Avanafil was generally well tolerated. No serious adverse events were reported and fewer than 2% of patients discontinued the study due to an adverse event. CONCLUSIONS: Avanafil in 100 and 200 mg doses was effective and well tolerated in improving erectile function after prostatectomy. Results suggest a rapid onset of action and sustained duration of effect, with all 3 primary end points being achieved at both dose levels.

Avanafil for the treatment of erectile dysfunction: a multicenter, randomized, double-blind study in men with diabetes mellitus.

OBJECTIVE: To prospectively assess the safety and effectiveness of the investigational phosphodiesterase 5 inhibitor avanafil to treat erectile dysfunction in men with diabetes mellitus. PATIENTS AND METHODS: This 12-week, multicenter, double-blind, placebo-controlled study conducted between December 15, 2008, and February 11, 2010, randomized 390 men with diabetes and erectile dysfunction 1:1:1 to receive avanafil, 100 mg (n=129), avanafil, 200 mg (n=131), or placebo (n=130). Coprimary end points assessed changes in the percentage of sexual attempts in which men were able to maintain an erection of sufficient duration to have successful intercourse (Sexual Encounter Profile [SEP] 3), percentage of sexual attempts in which men were able to insert the penis into the partner's vagina (SEP 2), and International Index of Erectile Function erectile function domain score. RESULTS: Compared with placebo, least-squares mean change from baseline to study end in SEP 3, SEP 2, and International Index of Erectile Function erectile function domain score were significantly improved with both avanafil, 100 mg (P≤.002), and avanafil, 200 mg (P<.001). Additional analyses indicated that successful intercourse could be initiated in 15 minutes or less through more than 6 hours after avanafil dosing. Adverse events most commonly reported with avanafil treatment were headache, nasopharyngitis, flushing, and sinus congestion. CONCLUSION: Avanafil was safe and effective for treating erectile dysfunction in men with diabetes and was effective as early as 15 minutes and more than 6 hours after dosing. The adverse events seen with avanafil were similar to those seen with other phosphodiesterase 5 inhibitors. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00809471.

Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors are indicated for the treatment of erectile dysfunction (ED); however, they can also inhibit other PDE isozymes, affecting their target tissues (e.g., PDE1: heart; PDE6: retina; and PDE11: skeletal muscle), which in some cases can cause unwanted side effects and therapy discontinuation. Data from in vitro studies showed that avanafil, a PDE5 inhibitor for the treatment of ED, exhibited strong selectivity toward PDE5 and against all other PDE isozymes. AIM: To review the inhibitory effects of avanafil for PDE isozymes compared with those of sildenafil, tadalafil, and vardenafil and to discuss these results within the context of clinical trial safety observations. METHODS: Review of in vitro selectivity data for avanafil (published primary data from a peer-reviewed journal and scientific congress abstracts); PubMed search for pertinent publications on PDE5 inhibitor safety data; and review of published articles and abstracts from avanafil phase 1, 2, and 3 clinical trials. MAIN OUTCOME MEASURES: A low incidence of some PDE-related adverse events may be reflected by the high selectivity of avanafil against non-PDE5 isozymes. RESULTS: Avanafil is highly selective toward PDE5 and against all other PDE isozymes tested. Lower selectivity against PDE1, PDE6, and PDE11 is consistent with results from randomized, placebo-controlled, phase 3 trials in which musculoskeletal and hemodynamic adverse events were reported in <2% of patients and no color vision-related abnormalities were reported with avanafil doses up to 200 mg once daily. CONCLUSIONS: Data suggest that avanafil may confer a safety benefit, in terms of a lower incidence of specific adverse events, by virtue of its high specificity to PDE5 and its overall selectivity against other PDE isozymes.

A randomized, double-blind, placebo-controlled evaluation of the safety and efficacy of avanafil in subjects with erectile dysfunction.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors have become standard treatment for erectile dysfunction (ED). AIM: To prospectively evaluate the safety and efficacy of avanafil, a novel PDE5 inhibitor, in men with mild to severe ED. METHODS: In this multicenter, double-blind, Phase 3 trial, 646 subjects were randomized to receive avanafil (50 mg, 100 mg, 200 mg) or placebo throughout a 12-week treatment period. Subjects were instructed to take study drug 30 minutes prior to initiation of sexual activity. At least a 12-hour separation time between doses was required; no restrictions were placed on food or alcohol intake. MAIN OUTCOME MEASURES: Improvement in erectile function (EF) was measured by Sexual Encounter Profile questions 2 and 3 (SEP2 and SEP3) and by the EF domain of the International Index of Erectile Function (IIEF) questionnaire. RESULTS: Mean change in percentage of successful sexual attempts (SEP2 and SEP3) and IIEF-EF domain score significantly favored all doses of avanafil over placebo (P ≤ 0.001). Secondary analyses demonstrated achievement of successful intercourse by subjects within 15 minutes of dosing. Of the 300 sexual attempts made during this interval, 64% to 71% were successful in avanafil-treated subjects compared with 27% in placebo-treated subjects. Successful intercourse was also demonstrated >6 hours post dosing, with 59% to 83% of the 80 sexual attempts successful in avanafil-treated subjects compared with 25% of placebo-treated subjects. The most commonly reported adverse events in subjects taking avanafil included headache, flushing, and nasal congestion; there were no drug-related serious adverse events. CONCLUSION: Following 12 weeks of avanafil treatment without food or alcohol restrictions, significant improvements in sexual function were observed with all 3 doses of avanafil compared with placebo. Successful intercourse was observed as early as 15 minutes and >6 hours after dosing in some subjects. Avanafil was generally well tolerated for the treatment of ED.

Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP).

A 56-week randomized controlled trial was conducted to evaluate safety and efficacy of a controlled-release combination of phentermine and topiramate (PHEN/TPM CR) for weight loss (WL) and metabolic improvements. Men and women with class II and III obesity (BMI ≥ 35 kg/m(2)) were randomized to placebo, PHEN/TPM CR 3.75/23 mg, or PHEN/TPM CR 15/92 mg, added to a reduced-energy diet. Primary end points were percent WL and proportions of patients achieving 5% WL. Secondary end points included waist circumference (WC), systolic and diastolic blood pressure (BP), fasting glucose, and lipid measures. In the primary analysis (randomized patients with at least one postbaseline weight measurement who took at least one dose of assigned drug or placebo), patients in the placebo, 3.75/23, and 15/92 groups lost 1.6%, 5.1%, and 10.9% of baseline body weight (BW), respectively, at 56 weeks (P < 0.0001). In categorical analysis, 17.3% of placebo patients, 44.9% of 3.75/23 patients, and 66.7% of 15/92 patients, lost at least 5% of baseline BW at 56 weeks (P < 0.0001). The 15/92 group had significantly greater changes relative to placebo for WC, systolic and diastolic BP, fasting glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL). The most common adverse events were paresthesia, dry mouth, constipation, dysgeusia, and insomnia. Dropout rate from the study was 47.1% for placebo patients, 39.0% for 3.75/23 patients, and 33.6% of 15/92 patients. PHEN/TPM CR demonstrated dose-dependent effects on weight and metabolic variables in the direction expected to be beneficial with no evidence of serious adverse events induced by treatment.