Assessing the Use of BotulinumtoxinA for Hyperactive Urinary Tract Dysfunction a Decade after Approval: A Single-Blind Study to Evaluate the Reduction in Pain in OnabotulinumtoxinA Detrusor Injection Using Different Injection Needles.

Article

Author: Haberecht, Kathrin ; Schlomm, Thorsten ; Borgmann, Hendrik ; Höppner, Dirk ; Schulte-Baukloh, Heinrich ; Weiss, Catarina ; Neymeyer, Jörg ; Weinberger, Sarah

Overactive bladder (OAB) has a significant impact on the quality of life; thus, it requires treatment that can be adhered to over a long period without undue side effects. The current treatment which uses an anticholinergic or β-3 agonist may fail to improve symptoms and has side effects, leading to high discontinuation rates. OnabotulinumtoxinA (OnabotA) detrusor injection has been approved for idiopathic OAB as a second-line treatment with good effectiveness and tolerability. This study used a visual analog scale (VAS) to assess the impact of the type of needle used for OnabotA detrusor injections under local anesthesia on the pain levels after each injection. This study included 68 female patients. We used three different needles with thicknesses ranging from 22 to 27 gauge, lengths between 4 and 5 mm, and different cuts. The sensation of pain was rated at each standardized injection location. Regardless of the needle used, the patients' perceptions of pain at the beginning of the procedure were rated as being less than the subsequent injections. Most pain sensations were rated as low to moderate. The mean pain sensation on the VAS was 2.5 ± 0.3 overall, i.e., for all patients and needles used. Statistically significant differences in pain sensation were rated only at some locations of the bladder (on the back wall and the right side of the bladder). The single needles averaged the following pain scores: 2.8 ± 0.3 for needle A (20 G, 4 mm), 2.1 ± 0.3 for needle B (27 G, 5 mm), and 2.6 ± 0.4 for needle C (20 G, 4 mm, sharp cut 15°). The 27-gauge needle caused significantly less pain, and it had no negative impact due to its length, which was 1 mm longer than the other needles. Thus, the needle thickness was a decisive factor in the patients' perceptions of pain.

01 Sep 2024·Anesthesia & Analgesia

Sirtuin 3 Mediated by Spinal cMyc–Enhancer of Zeste Homology 2 Pathway Plays an Important Role in Human Immunodeficiency Virus-Related Neuropathic Pain Model

Article

Author: Toborek, Michal ; Zhu, Xun ; Gu, Jun ; Li, Heng ; Yi, Hyun ; Hao, Shuanglin ; Levitt, Roy C ; Roy, Sabita ; Pardo, Marta ; Ikegami, Daigo ; Liu, Shue ; Hayashi, Kentaro

BACKGROUND:Clinical data demonstrate that chronic use of opioid analgesics increases neuropathic pain in people living with human immunodeficiency virus (HIV). Therefore, it is important to elucidate the molecular mechanisms of HIV-related chronic pain. In this study, we investigated the role of the transcription factor cMyc, epigenetic writer enhancer of zeste homology 2 (EZH2), and sirtuin 3 (Sirt3) pathway in HIV glycoprotein gp120 with morphine (gp120M)-induced neuropathic pain in rats.METHODS:Neuropathic pain was induced by intrathecal administration of recombinant gp120 with morphine. Mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. Spinal expression of cMyc, EZH2, and Sirt3 were measured using Western blots. Antinociceptive effects of intrathecal administration of antisense oligodeoxynucleotide against cMyc, a selective inhibitor of EZH2, or recombinant Sirt3 were tested.RESULTS:In the spinal dorsal horn, gp120M upregulated expression of cMyc (ratio of gp120M versus control, 1.68 ± 0.08 vs 1.00 ± 0.14, P = .0132) and EZH2 (ratio of gp120M versus control, 1.76 ± 0.05 vs 1.00 ± 0.16, P = .006), and downregulated Sirt3 (ratio of control versus gp120M, 1.00 ± 0.13 vs 0.43 ± 0.10, P = .0069) compared to control. Treatment with intrathecal antisense oligodeoxynucleotide against cMyc, GSK126 (EZH2 selective inhibitor), or recombinant Sirt3 reduced mechanical allodynia and thermal hyperalgesia in this gp120M pain model. Knockdown of cMyc reduced spinal EZH2 expression in gp120M treated rats. Chromatin immunoprecipitation (ChIP) assay showed that enrichment of cMyc binding to the ezh2 gene promoter region was increased in the gp120M-treated rat spinal dorsal horn, and that intrathecal administration of antisense ODN against cMyc (AS-cMyc) reversed the increased enrichment of cMyc. Enrichment of trimethylation of histone 3 on lysine residue 27 (H3K27me3; an epigenetic mark associated with the downregulation of gene expression) binding to the sirt3 gene promoter region was upregulated in the gp120M-treated rat spinal dorsal horn; that intrathecal GSK126 reversed the increased enrichment of H3K27me3 in the sirt3 gene promoter. Luciferase reporter assay demonstrated that cMyc mediated ezh2 gene transcription at the ezh2 gene promoter region, and that H3K27me3 silenced sirt3 gene transcription at the gene promoter region.CONCLUSION:These results demonstrated that spinal Sirt3 decrease in gp120M-induced neuropathic pain was mediated by cMyc–EZH2/H3K27me3 activity in an epigenetic manner. This study provided new insight into the mechanisms of neuropathic pain in HIV patients with chronic opioids.

01 Aug 2024·International Urogynecology Journal

Posterior Tibial Nerve Stimulation With versus Without Mirabegron: A Randomized Controlled Trial

Article

Author: Stanley, Russell F ; Meyer, Isuzu ; Richter, Holly E ; Blanchard, Christina T

AbstractIntroduction and HypothesisTo compare change in urgency urinary incontinence episodes (UUIEs) in women undergoing posterior tibial nerve stimulation (PTNS) plus mirabegron versus PTNS plus placebo for the treatment of refractory urgency urinary incontinence (UUI). The primary hypothesis was that combination therapy is superior to monotherapy.MethodsA randomized controlled trial was performed in individuals identifying as female aged ≥ 18 years with UUI symptoms refractory to second-line treatment or who could not tolerate antimuscarinic medications. Both participants and providers were blinded to medication treatment allocation. Participants were randomized (1:1) to PTNS plus mirabegron or PTNS plus placebo. Participants completed a 3-day bladder diary prior to and after 12-week treatment. Validated symptom distress and impact questionnaires were obtained pre- and post-treatment. The primary outcome was change in mean number of UUIEs on a 3-day bladder diary pre- versus post-treatment between arms. Primary and secondary outcomes were analyzed via sample t tests.ResultsFifty-four subjects were randomized, mean ± SD baseline age 56.2±15.6 years and body mass index 35.0±9.4 (kg/m2); no differences were noted in any clinical–demographic characteristics. There was a significant difference between arms in mean pre- to post-treatment UUIEs, 9.4±3.9, mirabegron versus 5.3±5.5, placebo (p=0.007). Significant differences were found pre- compared with post-treatment in urinary frequency, Overactive Bladder Questionnaire Short Form Symptom Bother and Symptom Health-Related Quality of Life scores.ConclusionsIn subjects undergoing PTNS treatment for refractory UUI and OAB-wet symptoms, the addition of a β-3 agonist produced significant improvement in both objective and subjective overactive bladder symptom outcomes compared with PTNS plus placebo.

News (Medical) associated with ACU-S2

22 Jan 2024

·www.biospace.com

AIM ImmunoTech Announces that the First Subject is Enrolled in the Phase 1b/2 Study Evaluating Ampligen® in Combination with AstraZeneca’s Imfinzi® for the Treatment of Late-Stage Pancreatic Cancer

OCALA, Fla., Jan. 22, 2024 (GLOBE NEWSWIRE) -- AIM ImmunoTech Inc. (NYSE American: AIM) (“AIM” or the “Company”) today announced that the first subject has been enrolled at Erasmus Medical Center (“Erasmus MC”) in a Phase 1b/2 clinical trial combining AIM’s Ampligen® (rintatolimod) with AstraZeneca’s anti-PD-L1 immune checkpoint inhibitor Imfinzi® (durvalumab) for the treatment of late-stage pancreatic cancer (the “DURIPANC Study”). Data strongly suggests Ampligen has therapeutic synergy when combined with checkpoint inhibitors — potentially increasing cancer treatment efficacy and subject survival rates. A successful DURIPANC Study could make AIM an especially attractive partnership or buyout target for Big Pharma. Data already strongly suggests that Ampligen synergistically enhances anti-PD-1 therapy. Strong positive clinical data from the DURIPANC study would also support our belief that Ampligen could synergistically enhance anti-PD-L1 therapies. Such broad-spectrum success could create value. AIM recently took an important step to secure potential stockholder value when it received a U.S. patent for the use of Ampligen as part of a combination therapy with an anti-PD-L1 antibody, which is an immune checkpoint inhibitor that helps the body attack tumor cells. The DURIPANC Study is an investigator-initiated, exploratory, open-label, single-center study with the full name “Combining anti-PD-L1 immune checkpoint inhibitor durvalumab with TLR-3 agonist rintatolimod in patients with metastatic pancreatic ductal adenocarcinoma for therapy effect.” The primary objective of the Phase 1b portion is to determine the safety of combination therapy with Imfinzi and Ampligen. The primary objective of the Phase 2 portion is to determine the clinical benefit rate of the combination therapy. “We expect to complete the Phase 1b portion of the study within six months,” states Prof. Casper H.J. van Eijck, MD, PhD, the DURIPANC Study’s Coordinating Investigator. See ClinicalTrials.gov: NCT05927142 for more information. AIM CEO Thomas K. Equels stated: “Ampligen’s potential as part of a combination therapy is a relatively simple equation. One, elevated PD-L1 expression — which is known to occur in pancreatic cancer — has been associated with increased exhaustion of peripheral and intra-tumoral cytotoxic T cells, commonly called ‘killer’ T cells. Two, data indicate that Ampligen has the potential to mitigate T cell exhaustion. Three, Ampligen can increase the number and activity of immune cells in the blood and tumor. And four, Imfinzi inhibits PD-L1 activity, thereby making those activated immune cells in the tumor microenvironment more effective at fighting the cancerous tumor. Data from our Dutch Early Access Program strongly supports Ampligen’s potential to increase progression-free survival and overall survival. Our hope for the DURIPANC trial is that at a minimum we see an even longer period of stable disease, also called progression-free survival. However, we also believe this combination of drugs has the potential to decrease tumor size or even to cure the cancer, which is defined as being tumor free for at least five years. That would be a dramatic breakthrough in the treatment of a highly lethal and treatment-resistant human cancer.” The study is expected to enroll up to 18 subjects in its Phase 1b portion and up to 25 subjects in its Phase 2 portion. Subjects will start with Ampligen 200 mg via IV infusion twice per week for a total of 6 weeks (12 doses). Ampligen dose will be escalated to 400 mg according to a 3+3 DLT design. The first dose of Ampligen will be administered preferably 4-6 weeks after the last chemotherapy FOLFIRINOX dose. After two doses of Ampligen, the first dose of durvalumab 1500 mg via IV infusion will be introduced in week 2. Patients will continue to receive 1500 mg durvalumab via IV infusion every 4 weeks for up to a maximum of 48 weeks (up to 12 doses/cycles) with the last administration on week 48 or until confirmed disease progression according to Response Evaluation Criteria in solid Tumors (RECIST 1.1), unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. About AIM ImmunoTech Inc. AIM ImmunoTech Inc. is an immuno-pharma company focused on the research and development of therapeutics to treat multiple types of cancers, immune disorders and viral diseases, including COVID-19. The Company’s lead product is a first-in-class investigational drug called Ampligen® (rintatolimod), a dsRNA and highly selective TLR3 agonist immuno-modulator with broad spectrum activity in clinical trials for globally important cancers, viral diseases and disorders of the immune system. For more information, please visit aimimmuno.com and connect with the Company on Twitter, LinkedIn, and Facebook. Cautionary Statement This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 (the “PSLRA”). Words such as “may,” “will,” “expect,” “plan,” “anticipate,” “continue,” “believe,” “potential,” “upcoming” and other variations thereon and similar expressions (as well as other words or expressions referencing future events or circumstances) are intended to identify forward-looking statements. Many of these forward-looking statements involve a number of risks and uncertainties. The Company urges investors to consider specifically the various risk factors identified in its most recent Form 10-K, and any risk factors or cautionary statements included in any subsequent Form 10-Q or Form 8-K, filed with the U.S. Securities and Exchange Commission (the “SEC”). You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date of this press release. Among other things, for those statements, the Company claims the protection of the safe harbor for forward-looking statements contained in the PSLRA. The Company does not undertake to update any of these forward-looking statements to reflect events or circumstances that occur after the date hereof. Investor Contact: JTC Team, LLC Jenene Thomas (833) 475-8247 AIM@jtcir.com A photo accompanying this announcement is available at Erasmus Medical Center Erasmus Medical Center

ImmunotherapyPhase 2Phase 1

06 Jul 2023

·www.prnewswire.com

The Estée Lauder Companies Shares New Preclinical and Clinical Findings at World Congress of Dermatology Spanning Emerging Research Areas that Support Skin Health and Longevity

Findings indicate sirtuins, or longevity proteins, are instrumental in regulating the mechanobiology of the skin and promoting youthful skin properties and function First-of-its-kind study confirms impact of regular use of moisturizer to mitigate skin aging Topical treatment proven as viable alternative to dermatological procedure NEW YORK, July 6, 2023 /PRNewswire/ -- The Estée Lauder Companies Inc. (ELC) (NYSE: EL) today announced that the company and several of its brands presented a range of novel preclinical and clinical findings at the 25th World Congress of Dermatology, held this week in Singapore. The poster and satellite symposium presentations reflect a strong portfolio of prestige beauty and skin care brands effectively translating biological learnings and progressive research efforts into meaningful innovation, including better methods to care for and protect skin. "For over 75 years, innovation in skin science has been our north star. With rapidly emerging knowledge and advancements from the dermatologic and scientific communities, the science of skin care has never been more important," said Lisa Napolione, Senior Vice President, Global Research & Development (R&D). "As we live longer, research on health span and longevity will only accelerate. To meet these innovation challenges, we are thinking differently, and in a manner enabled by novel science across all our global laboratories and clinics." Additional poster details highlighting key data are as follows. Title: The benefits of regular use of moisturizer to skin aging prevention: a six-month evaluator blinded, randomized, and controlled clinical study Presenter: Hao Ouyang, PhD, Executive Director, Clinical Sciences Key Takeaways: Moisturizers are routinely used to treat dry skin conditions and are considered the basis of skin care, but the long-term standalone benefits of consistent application have not been fully demonstrated with randomized controlled trial clinical studies. This evaluator-blinded, randomized, 6-month longitudinal study evaluated 160 women, aged 35-65, with dry skin, mild to moderate crow's feet wrinkles, and a low frequency of skin care regimen. Participants were split into two groups: one using moisturizer regularly and the other continuing at a low frequency. Results revealed that regular application of a potent moisturizer can not only treat skin dryness, but also improve the dry skin stratum corneum (the outermost layer of the epidermis) cohesion to reduce the appearance of facial aging. Title: The effect of a multi-ingredient facial cream on skin structure, function, and appearance: evidence from ex vivo and clinical studies Presenter: Jaime Emmetsberger, PhD, La Mer's Max Huber Research Labs Lead Scientist Key Takeaways: La Mer scientists evaluated a topical cream formulation containing Macrocystis pyrifera ferment and other ingredients in clinical studies with participants with a range of skin tones. In in vivo experiments, the cream improved skin barrier recovery and resilience, mitigated visible redness (erythema) in addition to irritation and demonstrated a reduction in hallmark signs of aged skin in U.S.- and Asia-based populations. Histological assessment of ex vivo human skin explants suggested that topical application enhanced key extracellular matrix proteins and hyaluronic acid, corroborating in vivo results. Findings suggest the facial cream provides an effective treatment for improving barrier integrity and strength as well as signs of aging parameters and skin appearance with regular daily use. Title: The importance of Sirt2 in regulating mechanobiology of the skin Presenter: Nadine Pernodet, PhD, Senior Vice President, Bioscience and Lead Scientist Estée Lauder Research Laboratories Key Takeaways: Estée Lauder researchers examined the role of sirtuins (SIRTs) or "longevity proteins" – a class of enzymes synchronized to circadian rhythms that regulate protein expression – in promoting youthful skin properties. The findings build on the team's previous results that showed SIRT activity in skin cells is linked to environmental stressors, including UV and ozone. Treatment with SIRT 1, 2, 3, and 6 activators helped to rebuild protein structure and increased collagen production in mature skin cells, while the combination of SIRT 1 and 3 activators increased elastin and fibrillin production in ex vivo skin samples. Activation of SIRT2 also increased skin cell area – a hallmark feature typical of younger skin cells. Taken together, all four activators exerted different effects to preserve the mechanical properties of young skin. Title: Anti-glycation and anti-sallowness effects of certain materials in 3D skin equivalent models Presenter: Tom Mammone, PhD, Vice President, Advanced Technologies, Bioscience Key Takeaways: One cause of skin aging and a sallow complexion is glycation – a chemical modification that occurs on sugar molecules and leads to the formation of advanced glycation end products (AGEs). AGEs can be detected using measurements of auto-fluorescence at different excitation/emission wavelengths within the UV and blue spectrum. Using 3D skin models, researchers studied the anti-glycation properties of 6 compounds to determine their capacities to reduce auto-fluorescence in 3D skin models. The compounds were tested topically in a dose-response study over 7 days, revealing that GlcNAc, DE, vitamin C and E were most effective in demonstrating significant reduction of AGE auto-fluorescence compared to skin models treated with glycation agent methylglyoxal alone. These results reveal that the anti-glycation capacity of compounds used in skin care formulations may be associated with the reduced appearance of skin sallowness. Title: A topical cosmetic serum with a targeted, triple action approach provides anti-aging benefits equal to a single laser treatment Presenter: Kristine Schmalenberg, PhD, Executive Director, Clinical Sciences Key Takeaways: A Clinique-led clinical trial evaluated a combination of ingredients that supported natural skin repair versus a single laser treatment in a population of 42 women with moderate facial photodamage. The efficacy and tolerability of the topical product versus a single ablative laser treatment was assessed over 16 weeks. While no statistically significant differences in tolerability were observed, treatment with the cosmetic topical product achieved a statistically significant improvement in all measured parameters compared to a single laser treatment, thereby showing parity on those parameters. The topical product improved the appearance of global lines, wrinkles, and hyperpigmentation, as well as skin tone evenness, texture, smoothness, and firmness – suggesting efficacy in combatting visible signs of skin aging. About The Estée Lauder Companies The Estée Lauder Companies Inc. is one of the world's leading manufacturers, marketers, and sellers of quality skin care, makeup, fragrance, and hair care products, and is a steward of outstanding luxury and prestige brands globally. The company's products are sold in approximately 150 countries and territories under brand names including: Estée Lauder, Aramis, Clinique, Lab Series, Origins, M·A·C, La Mer, Bobbi Brown Cosmetics, Aveda, Jo Malone London, Bumble and bumble, Darphin Paris, TOM FORD, Smashbox, AERIN Beauty, Le Labo, Editions de Parfums Frédéric Malle, GLAMGLOW, KILIAN PARIS, Too Faced, Dr.Jart+, and the DECIEM family of brands, including The Ordinary and NIOD. SOURCE The Estée Lauder Companies

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100 Deals associated with ACU-S2

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Indication	Highest Phase	Country/Location	Organization	Date
Scleroderma, Systemic	Preclinical	US	Accuitis, Inc.	-

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