Collagenase Clostridium Histolyticum for the Treatment of Edematous Fibrosclerotic Panniculopathy (Cellulite): A Randomized Trial.

BACKGROUND: Edematous fibrosclerotic panniculopathy (EFP; cellulite) is associated with thickening and contraction of collagen-rich subdermal septae. Collagenase clostridium histolyticum (CCH) may disrupt collagen-rich septae. OBJECTIVE: To evaluate the safety and efficacy of CCH for treatment of EFP. MATERIALS AND METHODS: In a randomized, double-blind study, women with moderate or severe EFP of the buttocks or posterolateral thighs (i.e., Clinician Reported Photonumeric Cellulite Severity Scale [CR-PCSS] and Patient Reported Photonumeric Cellulite Severity Scale [PR-PCSS] ratings of 3 to 4, and Hexsel Cellulite Severity Scale score ≤13) received up to 3 treatment sessions (Days 1, 22, and 43) of subcutaneous CCH 0.84 mg or placebo injections. End points included the percentage of 2-level and 1-level composite responders (i.e., had ≥2-level or ≥1-level improvement in CR-PCSS and PR-PCSS) at Day 71. RESULTS: Three hundred seventy-five women (mean age, 46.5 years; 86.4% white) were randomly assigned to CCH (n = 189) or placebo (n = 186). At Day 71, the percentages of 2-level and 1-level composite responders were greater with CCH (10.6% and 44.6%, respectively) versus placebo (1.6% and 17.9%; p < .001 for both). The most common adverse events were injection-site related. CONCLUSION: CCH significantly improved EFP appearance versus placebo; further evaluation of CCH for EFP (cellulite) is warranted.

Converting from Transdermal to Buccal Formulations of Buprenorphine: A Pharmacokinetic Meta-Model Simulation in Healthy Volunteers.

Objective: To develop a model to predict buprenorphine plasma concentrations during transition from transdermal to buccal administration. Design: Population pharmacokinetic model-based meta-analysis of published data. Methods: A model-based meta-analysis of available buprenorphine pharmacokinetic data in healthy adults, extracted as aggregate (mean) data from published literature, was performed to explore potential conversion from transdermal to buccal buprenorphine. The time course of mean buprenorphine plasma concentrations following application of transdermal patch or buccal film was digitized from available literature, and a meta-model was developed using specific pharmacokinetic parameters (e.g., absorption rate, apparent clearance, and volumes of distribution) derived from analysis of pharmacokinetic data for intravenously, transdermally, and buccally administered buprenorphine. Results: Data from six studies were included in this analysis. The final transdermal absorption model employed a zero-order input rate that was scaled to reflect a nominal patch delivery rate and time after patch application (with decline in rate over time). The transdermal absorption rate constant became zero following patch removal. Buccal absorption was a first-order process with a time lag and bioavailability term. Simulations of conversion from transdermal 20 mcg/h and 10 mcg/h to buccal administration suggest that transition can be made rapidly (beginning 12 hours after patch removal) using the recommended buccal formulation titration increments (75-150 mcg) and schedule (every four days) described in the product labeling. Conclusions: Computer modeling and simulations using a meta-model built from data extracted from publications suggest that rapid and straightforward conversion from transdermal to buccal buprenorphine is feasible.

Pharmacokinetics, Clinical Efficacy, Safety Profile, and Patient-Reported Outcomes in Patients Receiving Subcutaneous Testosterone Pellets 900 mg for Treatment of Symptoms Associated With Androgen Deficiency.

BACKGROUND: Implantation of testosterone doses of at least 150 to 450 mg (ie, two to six pellets) is common clinical practice despite a lack of prospective data. AIM: To evaluate pharmacokinetics, clinical efficacy, safety, and patient-reported outcomes in men with androgen deficiency who received implantation of testosterone pellets (900 mg) in an open-label study. METHODS: Men with androgen deficiency (serum testosterone < 300 ng/dL [10.4 nmol/L]) were screened and received 12 testosterone pellets (900 mg). Serum hormone measurements (total and free testosterone, dihydrotestosterone, and estradiol) were obtained on days 1, 5, 8, 15, 29, 57, 85, and 113. All hormones were assayed using validated liquid chromatography and tandem mass spectrometry. OUTCOMES: Pharmacokinetics of selected hormones was determined. The patient-reported International Index of Erectile Function (IIEF), Center for Epidemiologic Studies Depression (CES-D), and Androgen Deficiency in the Aging Male (qADAM) questionnaires also were performed. Patients rated their satisfaction on a scale from 1 (very satisfied) to 5 (very dissatisfied). Adverse events were monitored throughout. RESULTS: Fifteen patients were included (mean age = 54.5 years, SD = 8.6 years). Mean baseline total testosterone concentration was 241.6 ng/dL (SD = 88.8 ng/dL; mean = 8.4 nmol/L, SD = 3.1 nmol/L). Mean testosterone serum concentrations fluctuated during the first 2 weeks (range = 300-1,000 ng/dL, 10.4-34.7 nmol/L) but remained higher than or equal to 300 ng/dL (10.4 nmol/L) through day 113. Concentrations of free testosterone, dihydrotestosterone, and estradiol mirrored that of total testosterone. Male functioning (IIEF score), depression (CES-D total score), and androgen-deficiency symptoms (qADAM total score) improved from baseline. Most patients were "very satisfied" (40.0%) or "quite satisfied" (26.7%) with treatment. Testosterone pellets were well tolerated. Pellet extrusion and polycythemia occurred in one patient each. CLINICAL IMPLICATIONS: Implantation of high doses (900 mg) of testosterone pellets are generally well tolerated and could provide clinical benefit for some patients. STRENGTHS AND LIMITATIONS: This study provides standardized data for the implantation of 12 testosterone pellets. However, the open-label uncontrolled design of this study and its small and ethnically non-diverse patient population limit the interpretation of these data, particularly the patient-reported outcomes. CONCLUSION: Implantation of 12 testosterone pellets (900 mg) was well tolerated and provided adequate and sustained serum testosterone concentrations. Additional randomized controlled trials are needed to confirm efficacy and safety findings. McMahon CG, Shusterman N, Cohen B. Pharmacokinetics, Clinical Efficacy, Safety Profile, and Patient-Reported Outcomes in Patients Receiving Subcutaneous Testosterone Pellets 900 mg for Treatment of Symptoms Associated With Androgen Deficiency. J Sex Med 2017;14:883-890.

Current topics in opioid therapy for pain management: addressing the problem of abuse.

Opioids are an established therapy for cancer pain and have become an accepted therapy for chronic noncancer pain. However, increased prescribing of opioids in recent years has been accompanied by an increase in prescription opioid abuse. All opioids have inherent potential for abuse, but gaps in healthcare provider understanding of or adherence to best prescribing practices may facilitate the misdirection of opioids for abuse. To address these concerns, the US Food and Drug Administration has required pharmaceutical manufacturers to develop Risk Evaluation and Mitigation Strategies (REMS) for prescribers of extended-release/long-acting (ER/LA) opioids and has encouraged research to develop opioid formulations that are less easily abused or less attractive for abuse. The ER/LA opioid REMS require a partnership between the pharmaceutical industry, regulators, and healthcare providers to develop educational materials for physicians and patients that are not promotional. This article addresses challenges associated with improving the quality of pain care through support of prescriber education, developing formulations that combine efficacy with tamper-resistant properties, and encouraging collaborative efforts by regulatory bodies, legislators, healthcare providers, and patient advocacy groups to achieve these ends.

Risk-benefit assessment of angiotensin II receptor antagonists.

Inhibiting the renin-angiotensin-aldosterone system through the use of angiotensin-converting enzyme (ACE) inhibitors has proven very useful in the treatment of hypertension, congestive heart failure (CHF) and progressive renal failure. More recently, agents that directly block the angiotensin II Type 1 (AT(1)) receptor--angiotensin II receptor antagonists (AIIRAs)--have been developed. These agents are thought to have a more specific mechanism of action since they do not affect other hormone systems as do the ACE inhibitors. Whether such specificity results in a different efficacy profile is still being determined. However, these drugs are extremely well-tolerated and very safe. AIIRAs are effective in the reduction of both systolic and diastolic blood pressure and compare favourably to other classes of agents. Recent results indicate that at least one AIIRA has a favourable effect on stroke in hypertensive patients with left ventricular hypertrophy. Additional studies with other members of the class will provide further information on similar outcomes. In CHF patients, ACE inhibitors remain the drug of choice and AIIRAs are best utilised in patients who cannot tolerate an ACE inhibitor or in those receiving an ACE inhibitor who cannot tolerate a beta-blocker and need additional therapy. AIIRAs are effective in slowing the progression of renal failure in patients with Type II diabetes and may be effective in other proteinuric conditions. Whether they are more or less effective than ACE inhibitors is unknown. Overall, AIIRAs represent an important addition to the armamentarium of cardiovascular therapies with an excellent safety record and an emerging profile of utility in multiple cardiovascular conditions.