Long-term improvement in the appearance of hypertrophic scars following a single treatment with acoustic subcision-A single center proof-of-concept study.

INTRODUCTION AND OBJECTIVES: Fibrosis, including hypertrophic scar formation, is a pathological condition characterized by excessive production and accumulation of collagen, and loss of tissue architecture, in response to wound healing. Alterations in the extracellular matrix (ECM) biomechanical properties may be important in modulating myofibroblasts and fibrosis formation. The acoustic subcision device uses rapid acoustic pulse technology to noninvasively improve the appearance of hypertrophic scars through both microdisruption of scar tissue matrix and downregulation of fibrotic fibroblasts leading to scar remodeling. The objective of this single-site proof-of-concept IRB-approved human clinical study was to evaluate the efficacy of acoustic subcision device for the improvement in the appearance of hypertrophic scars. METHOD: Eleven hypertrophic scars in 10 participants were treated with a single 6-minute acoustic subcision application without anesthesia. Posttreatment adverse events (AEs) and tolerability were recorded. At 12 and 89 weeks posttreatment, scar heights and volumes were measured, and participant satisfaction questionnaires were completed. Finally, at the last visit the scar appearance was assessed by the Principal Investigator (PI) using the Mecott Modified Scar Scale (MMSS). RESULTS: Immediately following the acoustic subcision treatment, only mild, moderate erythema or pinpoint bleeding were noted. The treatment sessions were considered tolerable by all participants with an average pain score of 2.2 (on a 0-10 pain score with 10 being the worse possible pain). The 12- and 89-week assessments demonstrated mean height reductions of 46.3% and 56.8%, respectively from baseline. The differences in scar height were statistically significant (p < 0.01). The 12- and 89-week assessments demonstrated a mean volume reduction of 63.2% and 58.1% respectively from baseline. The differences in the scar volume were statistically significant (p < 0.001). The PI graded an average improvement of 33.7% in scar appearance using the MMSS, a statistically significant change (p < 0.001). Finally, >90% of participants reported satisfaction with the improvement in their scar. CONCLUSION: This proof-of-concept study showed that a single noninvasive acoustic subcision treatment session can safely provide statistically significant improvement in the appearance of hypertrophic scars with minimal treatment pain and meaningful participant satisfaction. More work is needed on a larger number of scars to verify this finding. Further improvement in appearance is expected with multiple acoustic subcision treatments and/or treatments in combination with currently available options. Additional trials to verify this are planned.

Improvement in the appearance of cellulite and skin laxity resulting from a single treatment with acoustic subcision: Findings from a multicenter pivotal clinical trial.

INTRODUCTION AND OBJECTIVES: Surface depressions and skin laxity together play a role in the appearance of cellulite. Cellulite depressions can be improved through disruption of the subcutaneous fibrous structures. Some currently utilized approaches accomplish this through invasive techniques requiring local anesthesia and potential down time. Skin laxity can exacerbate the appearance of cellulite, however current invasive approaches do little to improve skin laxity. The objective of this study was to evaluate a noninvasive approach to improving both cellulite depressions and skin laxity through the use of rapid acoustic pulses (acoustic subcision). Safety, efficacy, tolerability, and participant satisfaction results were measured. METHODS: Women (n = 56) with moderate to severe cellulite were treated in a single acoustic subcision treatment session without anesthesia. Posttreatment adverse events (AEs) and tolerability were recorded. At 12-weeks cellulite outcomes were assessed using a 6-point simplified Cellulite Severity Scale (CSS), Global Aesthetic Improvement Scale (GAIS), and a participant satisfaction questionnaire. Additionally, laxity improvement was measured using a 4-point Laxity Score (LS) and GAIS. RESULTS: Improvement in cellulite appearance measured at 12-weeks showed that participants (n = 56) had a mean CSS reduction of 1.01 (a 29.5% reduction from baseline). The posttreatment photograph was correctly identified by blinded independent reviewers from randomized pairs of pre/posttreatment photographs for 96.4% of participants. Cellulite was graded as improved, much improved or very much improved using the GAIS at 90.9% of treated locations. Finally, 92.9% of participants reported positive satisfaction responses. Scoring for improvement in skin laxity appearance at 12-weeks showed a mean LS reduction of 0.57 (a 27.9% reduction from baseline). GAIS for laxity was graded as improved, much improved or very much improved in 67.3% of treated areas. No unexpected or serious AEs were noted at treatment or follow-up. Overall average pain score during treatment was 2.4 (0-10 pain scale) and 0.3 immediately posttreatment. CONCLUSION: A single noninvasive acoustic subcision session can safely provide meaningful improvement in the appearance of cellulite in terms of depressions, as well as skin laxity, with minimal treatment pain and no posttreatment down time. Further improvement in appearance is expected with multiple treatments over time. Additional trials to verify this are planned.

Increased Tattoo Fading in a Single Laser Tattoo Removal Session Enabled by a Rapid Acoustic Pulse Device: A Prospective Clinical Trial.

BACKGROUND AND OBJECTIVES: The ability to provide improved tattoo fading using multiple laser passes in a single office laser tattoo removal session is limited. In part, this is due to the loss of laser effectiveness caused by epidermal and dermal vacuole "whitening" generated during the initial laser pass at the tattoo site. The Rapid Acoustic Pulse (RAP) device generates acoustic shock wave pulses that clear epidermal and dermal vacuoles to enable multiple laser passes in a single office laser tattoo removal session. The objectives of this study were to determine if the RAP device, when used as an accessory to the 1064 nm Nd:YAG Q-switched (QS) laser can enable delivery of multiple laser passes in a single office laser tattoo removal session, and therefore result in increased tattoo fading compared to the clinical standard single-pass QS laser tattoo removal session. STUDY DESIGN/MATERIALS AND METHODS: The RAP device was evaluated in a single-center (SkinCare Physicians), prospective, IRB approved study. A total of 32 black ink tattoos, from 21 participants, were divided into three zones and treated with either multiple QS laser passes, each followed by 1 minute of RAP device application (Laser + RAP) in zone one and single-pass QS laser treatment (Laser-Only) in zone two, separated by an untreated control zone. The treatment sites were assessed for the number of laser passes and adverse events immediately, 6 weeks, and 12 weeks following the treatment session. Photographs of the treatment sites were assessed for percent fading at 12 weeks post-treatment by three blinded reviewers. RESULTS: When the RAP device was applied as an accessory to the QS laser in a multi-pass laser tattoo removal treatment, an average of 4.2 laser passes were delivered in a single session, with no unexpected or serious RAP device-related adverse events. At the 12-week follow-up, tattoos treated with Laser + RAP showed a statistically significant increase in average fading (44.2%) compared with tattoos treated with Laser-Only (24.8%) (P < 0.01). Additionally, a significantly higher overall proportion of tattoos treated with Laser + RAP (37.5%) had a response of >50% fading compared with tattoos treated with QS Laser-Only (9.4%) (P < 0.01) as well as a response of >75% fading from Laser + RAP treatment (21.9%) compared with Laser-Only treatment (3.1%) (P < 0.05). CONCLUSIONS: The RAP device, applied as an accessory to the 1064 nm Nd:YAG QS laser, safely enables multiple QS laser treatments in a single office laser tattoo removal session by clearing the whitening caused by the previous QS laser pass. Enabling multiple QS laser passes results in a statistically significant increase in tattoo fading in a single office laser tattoo removal session compared to the clinical standard single-pass QS laser tattoo removal session. © 2019 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

8-(4-Methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazines: selective and centrally active corticotropin-releasing factor receptor-1 (CRF1) antagonists.

This report describes the syntheses and structure-activity relationships of 8-(4-methoxyphenyl)pyrazolo[1,5-a]-1,3,5-triazine corticotropin releasing factor receptor-1 (CRF(1)) receptor antagonists. CRF(1) receptor antagonists may be potential anxiolytic or antidepressant drugs. This research culminated in the discovery of analogue 12-3, which is a potent, selective CRF(1) antagonist (hCRF(1) IC(50) = 4.7 +/- 2.0 nM) with weak affinity for the CRF-binding protein and biogenic amine receptors. This compound also has a good pharmacokinetic profile in dogs. Analogue 12-3 is orally effective in two rat models of anxiety: the defensive withdrawal (situational anxiety) model and the elevated plus maze test. Analogue 12-3 has been advanced to clinical trials.

Design and synthesis of benzoazepinone-derived cyclic malonamides and aminoamides as potent gamma-secretase inhibitors.

We report the synthesis of benzoazepine-derived cyclic malonamides (2) and aminoamides (3) as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease. The in vitro structure-activity relationships of 2 and 3 along with dog pharmacokinetic results are described.

Interstitial temperature mapping during Prolieve transurethral microwave treatment: imaging reveals thermotherapy temperatures resulting in tissue necrosis and patent prostatic urethra.

OBJECTIVES: Temperature mapping of the prostate during transurethral microwave thermotherapy and imaging of the resultant zones of tissue necrosis have been previously performed using several commercial systems. This study was performed using the Prolieve Thermodilatation System, which simultaneously compresses the prostate with a 46F balloon circulating heated fluid and delivering microwave energy into the prostate. METHODS: Interstitial temperature mapping during Prolieve treatment was performed on 10 patients with benign prostatic hyperplasia using 24 temperature sensors arrayed throughout the prostate. Voiding cystourethrograms were performed on 3 additional patients treated without temperature mapping to document the patency of the prostatic urethra 1 hour after treatment. Gadolinium-enhanced magnetic resonance imaging studies were performed on all patients 1 week after treatment to determine the extent and pattern of tissue necrosis resulting from transurethral microwave thermotherapy. RESULTS: Interstitial temperature mapping found that the heating pattern generated by the Prolieve system created average peak temperatures of 51.8 degrees C an average of 7 mm away from the prostatic urethra. These temperatures were greater near the bladder neck and mid-gland than toward the prostatic apex. Subtherapeutic temperatures were seen adjacent to the urethra, consistent with the viable tissue seen on gadolinium-enhanced magnetic resonance imaging sequences. Magnetic resonance imaging also revealed necrotic zones that were consistent with sustained temperatures greater than 45 degrees C. Voiding cystourethrograms showed widely patent prostatic urethras 1 hour after treatment. CONCLUSIONS: Transurethral microwave thermotherapy with the Prolieve Thermodilatation System produced sustained therapeutic temperatures that resulted in tissue necrosis while maintaining viable tissue surrounding a temporarily dilated prostatic urethra.

Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors.

The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.

Anxiolytic-like effects of the corticotropin-releasing factor1 (CRF1) antagonist DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] administered acutely or chronically at doses occupying central CRF1 receptors in rats.

Corticotropin-releasing factor(1) (CRF(1)) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF(1) receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.

Interdisciplinary research: putting the methods under the microscope.

BACKGROUND: While the desirability of interdisciplinary inquiry has been widely acknowledged, indeed has become 'the mantra of science policy', the methods of interdisciplinary collaboration are opaque to outsiders and generally remain undescribed. DISCUSSION: Many have analysed interdisciplinarity, especially in relation to the creation of new disciplines and institutions. These analyses are briefly outlined. Still, there currently persists a silence about the methods of interdisciplinary collaboration itself, and the core of this paper proposes a template for such methods. SUMMARY: Breaking this silence--by making the methods of interdisciplinary projects transparent--could further invigorate interdisciplinary research.

Novel, highly potent, selective 5-HT2A/D2 receptor antagonists as potential atypical antipsychotics.

The discovery of N-substituted-pyridoindolines and their binding affinities at the 5-HT(2A), 5-HT(2C) and D(2) receptors, and in vivo efficacy as 5-HT(2A) antagonists is described. The structure-activity relationship of a series of core tetracyclic derivatives with varying butyrophenone sidechains is also discussed. This study has led to the identification of potent, orally bioavailable 5-HT(2A)/D(2) receptor dual antagonists as potential atypical antipsychotics.

Imidazo[4,5-b]pyridines as corticotropin releasing factor receptor ligands.

A series of high affinity CRF receptor ligands with an imidazo[4,5-b]pyridine core is described. Individual analogues were synthesized and tested in a rat CRF receptor binding assay. The best compounds were further tested in the dog N-in-1 pharmacokinetic model to assess plasma levels at 1mg/kg (po) and in the rat situational anxiety model to assess anxiolytic efficacy at 3mg/kg (po). The structure-activity relationships for good receptor binding affinity are described herein.

Imidazo[4,5-c]pyridines as corticotropin releasing factor receptor ligands.

A series of high affinity CRF receptor ligands with an imidazo[4,5-c]pyridine core is described. Individual analogues were synthesized and tested in vitro in rat brain receptors to determine binding affinity. The best compound was further tested in the dog N-in-1 pharmacokinetic model to assess oral bioavailability at 1 mg/kg po.

CRF ligands via Suzuki and Negishi couplings of 3-pyridyl boronic acids or halides with 2-benzyloxy-4-chloro-3-nitropyridine.

A series of imidazo[4,5-b]pyridines with a 7-(3-pyridyl) substituent is described as high affinity CRF receptor ligands. Individual analogues were synthesized from key intermediates obtained via palladium-catalyzed coupling of 3-pyridyl zinc or boronic acid organometallic intermediates with 2-benzyloxy-4-chloro-3-nitropyridine 12.

Solid-phase synthesis of alkyl aryl ethers via the Ullmann condensation.

Alkyl aryl ether formation is a frequently employed reaction in organic synthesis. Ullmann condensation is an alternative method to the widely used Mitsunobu reaction and is very useful in situations where application of the Mitsunobu reaction is limited. By application of this reaction to solid-phase synthesis of a series of alkyl aryl ethers, reaction conditions (catalyst, solvent, temperature, time, etc.) for a sterically hindered class of alcohols were investigated and optimized. A range of aryl halides was used to explore the scope of the reaction in solid phase.