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The Expanding Therapeutic Utility of Botulinum Neurotoxins

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      Abstract

      Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation and delivery, together with highly sensitive analytical tools, will be key for the success of next generation BoNT clinical products.

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      Most cited references 186

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      Transdermal drug delivery.

      Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.
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        Wound repair and regeneration: mechanisms, signaling, and translation.

        The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body's natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.
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          OnabotulinumtoxinA for treatment of chronic migraine: results from the double-blind, randomized, placebo-controlled phase of the PREEMPT 1 trial.

           Ronald DeGryse,  C Turkel,   (2010)
          This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine. The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U-195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24. No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (-5.2 vs. -5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.
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            Author and article information

            Affiliations
            [1 ]Ipsen Bioinnovation, 102 Park Drive, Milton Park, Abingdon, Oxfordshire OX14 4RY, UK; andrew.splevins@ 123456ipsen.com (A.S.); keith.foster@ 123456ipsen.com (K.F.)
            [2 ]Ipsen Innovation, 5 Avenue du Canada, 91940 Les Ulis, France; jacquie.maignel@ 123456ipsen.com (J.M.); stephane.lezmi@ 123456ipsen.com (S.L.); vincent.martin@ 123456ipsen.com (V.M.); mikhail.kalinichev@ 123456ipsen.com (M.K.); johannes.krupp@ 123456ipsen.com (J.K.)
            [3 ]Ipsen Biopharm Ltd., Wrexham Industrial Estate, 9 Ash Road, Wrexham LL13 9UF, UK; saif.shubber@ 123456ipsen.com
            [4 ]Ipsen Bioscience, 650 Kendall Street, Cambridge, MA 02142, USA; philippe.picaut@ 123456ipsen.com
            Author notes
            [* ]Correspondence: elena.fonfria@ 123456ipsen.com ; Tel.: +44-(0)1235-44-88-79
            Journal
            Toxins (Basel)
            Toxins (Basel)
            toxins
            Toxins
            MDPI
            2072-6651
            18 May 2018
            May 2018
            : 10
            : 5
            29783676
            5983264
            10.3390/toxins10050208
            toxins-10-00208
            © 2018 by the authors.

            Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

            Categories
            Review

            Molecular medicine

            delivery, new indications, formulation

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