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WO2019243376A1 - Injection intramusculaire de toxine botulique pour le traitement de la vulvodynie - Google Patents

Injection intramusculaire de toxine botulique pour le traitement de la vulvodynie Download PDF

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Publication number
WO2019243376A1
WO2019243376A1 PCT/EP2019/066108 EP2019066108W WO2019243376A1 WO 2019243376 A1 WO2019243376 A1 WO 2019243376A1 EP 2019066108 W EP2019066108 W EP 2019066108W WO 2019243376 A1 WO2019243376 A1 WO 2019243376A1
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Prior art keywords
botulinum neurotoxin
subject
muscle
injection
administration
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English (en)
Inventor
Philippe Picaut
France CATUS
Andrew Goldstein
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Ipsen Biopharm Ltd
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Ipsen Biopharm Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
    • A61K38/4893—Botulinum neurotoxin (3.4.24.69)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/24—Metalloendopeptidases (3.4.24)
    • C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
    • G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A90/00—Technologies having an indirect contribution to adaptation to climate change
    • Y02A90/10—Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Definitions

  • the present invention relates generally to treating one of more symptoms of vulvodynia, and more particularly, to a method of treating one or more symptoms of vulvodynia using botulinum neurotoxin.
  • the invention also relates to a composition comprising botulinum neurotoxin that is useful in treating one or more symptoms of vulvodynia.
  • the invention further relates to a computer system programmed to receive information related to a subject’s response to administration of botulinum neurotoxin, store that response in a database, and transmit the response to a medical practitioner.
  • the invention additionally relates to a non-transitory computer-readable storage medium storing instructions that, when executed by a computer system, causes the computer system to perform the aforementioned steps.
  • the invention also relates to a computer-implemented method of determining a dosage regimen for the administration of botulinum neurotoxin.
  • the invention also relates to a device for use in treating one or more symptoms of vulvodynia, the device configured to administer botulinum neurotoxin to a subject in need of such treatment.
  • Vulvodynia is chronic vulvar pain in the absence of objective abnormalities such as infection or dermatoses. Harlow et al., Journal of the American Medical Women’s Association, 58:82—88, 82 (2003); Falsetta at 210. As many as 28% of women suffer from vulvodynia at some point in their lives. Pukall et al., J. Sex Med., 13:291—304, 292 (2016); Falsetta et al., British Journal of Obstetrics and Gynaegology, 124:210-218, 210 (2017).
  • Vulvodynia is often characterized as either: localized vulvodynia, which is pain localized at a particular vulvar site; or generalized vulvodynia, which involves unprovoked, diffuse vulvar pain affecting the entire vulvar area (Pukall et al. at pages 291— 292) .
  • Vestibulodynia is localized vulvodynia involving pain at the vaginal opening. In cases wherein such pain occurs only with touch or pressure, the vestibulodynia is termed provoked vestibulodynia (PVD). PVD is the most common form of vulvodynia. Vulvodynia can cause sexual dysfunction and affective disorders such as depression and anxiety.
  • botulinum neurotoxin may be effective in treating one or more symptoms of vulvodynia (Yoon et al. at page 84).
  • Botulinum neuro toxin acts on the presynaptic motor neurons and inhibits the release of acetyl choline. This leads to a reduction in muscle tone.
  • botulinum neurotoxin acts by suppressing the release of nociceptive agents and inflammatory agents, such as substance P. Yoon at 86; Falsetta at 211.
  • Botulinum neurotoxin is produced by Clostridium botulinum in the form of a large protein complex comprising botulinum neurotoxin itself complexed to a number of accessory proteins.
  • There are at present at least nine different classes of botulinum neurotoxin namely: BoNT serotypes A, B, C, D, E, F, G, H and X (known respectively as BoNT/A, BoNT/B, BoNT/C, BoNT/D, BoNT/E, BoNT/F, BoNT/G, BoNT/H and BoNT/X), all of which share similar structures and modes of action.
  • BoNT serotypes can be distinguished based on inactivation by specific neutralizing anti-sera, with such classification by serotype correlating with percentage sequence identity at the amino acid level.
  • Botulinum neurotoxin proteins of a given serotype are further divided into different subtypes on the basis of amino acid percentage sequence identity.
  • BoNT/A and BoNT/E cleave SNAP -25, serotypes /B, /D, /F and /G cleave synaptobrevin/VAMP.
  • BoNT/C cleaves SNAP -25 and syntaxin 1, syntaxin2 and syntaxin 3.
  • BoNT/X has been found to cleave SNAP-25, VAMP1, VAMP2, VAMP3, VAMP4, VAMP 5, Ykt6.
  • BoNT/A is commercially available from, eg., Ipsen (DYSPORT®, Ipsen Limited, Slough, UK), Allergan (BOTOX®, Allergan Inc., Irvine, CA, USA), Merz Pharma (XEOMIN®, Merz Pharma GmbH, Frankfurt am Main, Germany), and Medytox (CORETOX®, Medytox Inc., Seoul, South Korea), whereas botulinum neurotoxin type B is sold by Elan (NYOBLOC®/NEUROBLOC®, Solstice Neurosciences Inc., San Diego, CA, USA).
  • Topical application of anaesthetic or hormonal creams require daily administration prior to the pain-trigger event. Even then, previous placebo-controlled trials have not demonstrated any benefit to the use of treatments. Orally administered drugs, particularly antidepressants and anticonvulsants have also failed to provide any clinical benefit in placebo-controlled trials. In addition, such drugs have systemic side effects such as somnolence and fatigue which limits there clinical potential. While treatment of the symptoms of vulvodynia with botulinum neurotoxin has been described, with some positive case series and reports (Goldstein et al. J. Sex. Med.
  • the inventors have developed a method of treating symptoms of vulvodynia by the administration of a botulinum toxin.
  • the inventors have developed a comprehensive injection paradigm which targets the specific muscles involved in provoked vestibulodynia (PVD) and which can comprise multiple injections to said muscles to ensure diffusion of the botulinum neurotoxin through said muscles and hence improved treatment efficacy.
  • PVD provoked vestibulodynia
  • this reduces the potential for undesirable side effects such as incontinence of stool, flatus or urine.
  • a method for treating one or more symptoms of vulvodynia comprises administering a therapeutically-effective amount of a botulinum neurotoxin to a subject determined to be in need of such treatment, wherein the botulinum neurotoxin is administered to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/or the right deep transverse perineal muscle.
  • the botulinum toxin may be administered in an amount from about 200 to about 800 units per treatment session.
  • the subject may suffer from, for example, pain at the vaginal vestibule, chronic vulval pain, sexual dysfunction, affective disorder (eg, depression and/or anxiety), and/or provoked vestibulodynia (PVD).
  • the botulinum neurotoxin may, for example, have at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99%, preferably 80%, 90%, 95%, 97%, 98%, or 99%, sequence identity to the amino acid sequence of a botulinum neurotoxin of serotypes A, B, C, D, E, F, G, H, or X.
  • the use of recombinant, hybrid and chimeric botulinum toxins is also encompassed.
  • the botulinum neurotoxin is botulinum neurotoxin A, even more preferably the botulinum toxin is DYSPORT®.
  • botulinum neurotoxin may be administered to the bladder and/ or to the pelvic floor.
  • botulinum neurotoxin is administered to the muscles of the pelvic floor.
  • botulinum neurotoxin is administered to each of the: right and left bulbospongiosus muscles; right and left pubococcygeous muscles; right and left superficial transverse perineal muscles; and the right and left deep transverse perineal muscles. It has surprisingly been found that administration of botulinum neurotoxin to these muscles and/ or combination of muscles provides additional efficacy in treating the symptoms of vulvodynia.
  • the botulinum neurotoxin is administered in the following order: (1) to a first bulbospongiosus muscle, anterior to the hymeneal ring, (2) to a first pubococcygeous muscle, anterior to the hymeneal ring; (3) to the first bulbospongiosus muscle, posterior to the hymeneal ring; (4) to the first pubococcygeous muscle, posterior to the hymeneal ring; (5) to a second bulbospongiosus muscle, anterior to the hymeneal ring, (6) to a second pubococcygeous muscle, anterior to the hymeneal ring; (7) to the second bulbospongiosus muscle, posterior to the hymeneal ring; (8) to the second pubococcygeous muscle, posterior to the hymeneal ring; (9) to the transverse perineal muscles anterior to the hymeneal ring.
  • the amount of botulinum neurotoxin administered and/ or a dosing regimen for botulinum neurotoxin may be, at least in part, based on the severity of the vulvodynia, the weight of the subject, and/ or the subject’s previous experience with treatment with botulinum neuro toxin.
  • the subject’s response to treatment with botulinum neurotoxin is measured following an administration of botulinum neurotoxin. Exemplary methods for assessing the subject’s response to treatment are described herein. Thereafter, the amount of a subsequent administration of botulinum neurotoxin and/or a dosing regimen for botulinum neurotoxin is determined based on the subject’s response.
  • the subject’s response may be recorded, for example, onto a computer device.
  • the method for treating one or more symptoms of vulvodynia may further comprise determining a dosing regimen for botulinum neurotoxin or the amount and/ or frequency for a subsequent administration of botulinum neurotoxin based on the subject’s response to a previous administration of botulinum neurotoxin.
  • the amount of an administration of botulinum neurotoxin or a dosing regimen for botulinum neurotoxin may be determined in part by the level of pain measured following the insertion of a probe into the subject’s vagina.
  • a probe may be inserted into the subject’s vagina and, if the level of pain measured following insertion of the probe is below a threshold level, a larger sized probe is inserted and the level of pain measured and, if the level of pain measured remains below the threshold level, probe(s) of increasing size are inserted until the level of pain measured following such insertion is at or above the threshold level, and the amount of botulinum neurotoxin to administer or the dosing regimen for botulinum neurotoxin is determined based on the level of pain measured following the insertion of the final probe.
  • the method of treating one or more symptoms of vulvodynia may comprise a treatment session in which BoNT/A is administered to a female subject diagnosed with vulvodynia, the method comprising the following injection protocol: (a) injecting about 8% of the total dose of BoNT/A administered during the treatment session to the subject’s left bulbospongiosus muscle, anterior to the hymeneal ring, wherein the injection is made at about the 5 o’clock position at about 45° laterally and about 45° posteriorly, towards the hip, and at a depth of about 5 mm from the outer surface of the skin; (b) injecting about 8% of the total dose BoNT/A administered during the treatment session to the subject’s left pubococcygeous muscle, anterior to the hymeneal ring, wherein the injection is made at the same position as the first injection but at a depth of about 10 mm from the outer surface of the skin; (c) injecting about 8% of the total dose of BoNT/A administered
  • the invention also relates to a computer system programmed to perform steps of a computer-implemented method, the method comprising: receiving information related to a subject’s response to treatment with botulinum neurotoxin according to the invention; storing the response information into a database; and transmitting the response information to a medical practitioner.
  • the computer system may comprise: a first computer device that is programmed to receive the response information; a second computer device on which the database resides; and a third computer device which receives the transmitted response information. Said system may be capable of determining a subsequent dosing regimen for the administration of botulinum neurotoxin to the subject.
  • the invention further relates to a non-transitory computer-readable storage medium storing instructions that, when executed by a computer system, causes the computer system to perform steps of a computer-implemented method, the method comprising: receiving information related to a subject’s response to treatment with botulinum neurotoxin according to the present invention; storing the response information into a database; and transmitting the response information to a medical practitioner.
  • the invention further provides a computer-implemented method of determining a dosage regimen for administration of botulinum neurotoxin, the method comprising: receiving information related to a subject’s response to treatment as conducted according to a method for treating one or more symptoms of vulvodynia, the method comprising administering a therapeutically-effective amount of botulinum neuro toxin to a subject determined to be in need thereof, wherein the botulinum neurotoxin is administered to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle; receiving the response information; and determining a subsequent dosing regimen for the administration of botulinum neurotoxin to the subject based on the response information.
  • Said method may further comprise sending an instruction to administer botulinum neurotoxin accordingly.
  • the invention also provides a computer-readable medium comprising instructions which, when executed by a computer, cause the computer to carry out said method; and a data processing device comprising a processor configured to perform said method.
  • the invention further provides a device for use in treating a symptom of vulvodynia, the device configured to perform the method of the invention.
  • Said device may be connected to a computer device which, based on information related to the subject’s response to treatment, determines a subsequent or optimal dosing regimen for the administration of botulinum neurotoxin to the subject and instructs the device to adjust its administration of botulinum neurotoxin accordingly
  • the invention relates to a composition for use in treating one or more symptoms of vulvodynia, the composition comprising a therapeutically-effective amount of botulinum neurotoxin.
  • the botulinum neurotoxin may, for example, have at least about 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% sequence identity to the amino acid sequence of a botulinum neurotoxin of serotypes A, B, C, D, E, F, G, H, or X.
  • the botulinum neurotoxin is DYSPORT®.
  • the invention provides a method for treating one or more symptoms of vulvodynia, the method comprising administering a therapeutically-effective amount of botulinum neurotoxin to a subject determined to be in need thereof, wherein the botulinum neurotoxin is administered to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle.
  • the amount of botulinum neurotoxin administered is from about 200 to about 800 units per treatment session.
  • the botulinum neurotoxin may be administered in the following order: (1) to a first bulbospongiosus muscle, anterior to the hymeneal ring, (2) to a first pubococcygeous muscle, anterior to the hymeneal ring; (3) to the first bulbospongiosus muscle, posterior to the hymeneal ring; (4) to the first pubococcygeous muscle, posterior to the hymeneal ring; (5) to a second bulbospongiosus muscle, anterior to the hymeneal ring, (6) to a second pubococcygeous muscle, anterior to the hymeneal ring; (7) to the second bulbospongiosus muscle, posterior to the hymeneal ring; (8) to the second pubococcygeous muscle, posterior to the hymeneal ring; (9) to the transverse perineal muscles anterior to the hymeneal ring.
  • the botulinum neurotoxin may have at least about 80 % sequence identity to the amino acid sequence of a botulinum neurotoxin of serotypes A, B, C, D, E, F, G, or H.
  • the botulinum neurotoxin is BoNT/A.
  • the subject may suffer from pain at the vaginal vestibule.
  • the symptom is an affective disorder.
  • the symptom is depression or anxiety.
  • the amount of botulinum neurotoxin administered may be determined based in part on the level of severity of the vulvodynia.
  • Said method may further comprises determining a dosing regimen for botulinum neurotoxin or the amount and/or frequency for a subsequent administration of botulinum neurotoxin based on the subject’s response to a previous administration of botulinum neurotoxin.
  • the amount of an administration of botulinum neurotoxin or a dosing regimen for botulinum neurotoxin may be determined in part by the level of pain measured following the insertion of a probe into the subject’s vagina.
  • a probe is inserted into the subject’s vagina and, if the level of pain measured following insertion of the probe is below a threshold level, a larger sized probe is inserted and the level of pain measured and, if the level of pain measured remains below the threshold level, probe(s) of increasing size are inserted until the level of pain measured following such insertion is at or above the threshold level, and the amount of botulinum neurotoxin to administer or the dosing regimen for botulinum neurotoxin is determined based on the level of pain measured following the insertion of the final probe.
  • Said method may further comprise recording the subject’s response to an administration of botulinum neurotoxin.
  • the method may comprise a treatment session in which BoNT/A is administered to a female subject diagnosed with vulvodynia, the method comprising the following injection protocol: injecting about 8% of the total dose of BoNT/A administered during the treatment session to the subject’s left bulbospongiosus muscle, anterior to the hymeneal ring, wherein the injection is made at about the 5 o’clock position at about 45° laterally and about 45° posteriorly, towards the hip, and at a depth of about 5 mm from the outer surface of the skin; injecting about 8% of the total dose BoNT/A administered during the treatment session to the subject’s left pubococcygeous muscle, anterior to the hymeneal ring, wherein the injection is made at the same position as the first injection but at a depth of about 10 mm from the outer surface of the skin; injecting about 8% of the total dose of BoNT/A administered during the treatment session to the subject’s left bulbospongiosus muscle, posterior to the following injection protocol: inject
  • the invention further provides a computer system programmed to perform steps of a computer-implemented method, the method comprising: receiving information related to a subject’s response to treatment as conducted according to the method of the invention; storing the response information in a database; and transmitting the response information to a medical practitioner.
  • the response information is received by the computer system from a first computer device, the database resides on a second computer device, and the response information is transmitted by the computer system to a third computer device.
  • the system is capable of determining a subsequent dosing regimen for the administration of botulinum neuro toxin to the subject.
  • the invention further provides a non-transitory computer-readable storage medium storing instructions that, when executed by a computer system, causes the computer system to perform steps of a computer-implemented method, the method comprising: receiving information related to a subject’s response to treatment as conducted according to the method of the invention; storing the response information into a database; and transmitting the response information to a medical practitioner.
  • the invention also provides a device for use in treating a symptom of vulvodynia, the device configured to perform the method of any one of the invention.
  • the device is connected to a computer device which, based on information related to the subject’s response to treatment, determines a subsequent or optimal dosing regimen for the administration of botulinum neurotoxin to the subject and instructs the device to adjust its administration of botulinum neurotoxin accordingly.
  • Figure 1 depicts injection sites for administering botulinum neurotoxin to treat one or more symptoms of vulvodynia:
  • A is a site for injecting botulinum neurotoxin to the left bulbospongiosus and left pubococcygeous muscles, anterior to the hymeneal ring;
  • B is a site for injecting botulinum neurotoxin to the left bulbospongiosus and left pubococcygeous muscles, posterior to the hymeneal ring;
  • C is a site for injecting botulinum neurotoxin to the right bulbospongiosus and right pubococcygeous muscles, anterior to the hymeneal ring;
  • D is a site for injecting botulinum neurotoxin to the right bulbospongiosus and right pubococcygeous muscles, posterior to the hymeneal ring;
  • E is a site for injecting botulinum neuro toxin to the left and
  • Described herein is a method for treating one or more symptoms of vulvodynia comprising administering a therapeutically-effective amount of botulinum neurotoxin to a subject determined to be in need of such treatment, such as a female mammal (e.g. human) diagnosed with vulvodynia.
  • a subject determined to be in need of such treatment such as a female mammal (e.g. human) diagnosed with vulvodynia.
  • Described herein is a method for treating one or more symptoms of vulvodynia in a subject determined to be in need thereof.
  • the method comprises administering to the subject a therapeutically-effective amount of botulinum neurotoxin.
  • A“subject” as used herein refers to a mammal, e.g. a primate, preferably a human, in need of such treatment.
  • a subject may be adult or juvenile.
  • the subject may be a female human patient.
  • the terms, "individual,” “patient” and “subject” are used interchangeably herein.
  • a "subject in need" of treatment for a particular condition can be a subject having that condition, diagnosed as having that condition, or at risk of developing that condition.
  • the invention provides a method for treating one or more symptoms of vulvodynia, the method comprising administering a therapeutically-effective amount of botulinum neurotoxin to a subject determined to be in need thereof, wherein the botulinum neurotoxin for administration to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle.
  • the invention also provides a botulinum neurotoxin for use in a method for treating depression and/or anxiety, the method comprising administering a therapeutically-effective amount of botulinum neurotoxin to a subject determined to be in need thereof, wherein the botulinum neurotoxin for administration to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle.
  • Said method may optionally comprise a step of assessing said subject for one or more symptom of depression and/or anxiety before treatment, after treatment or before and after treatment.
  • Any appropriate method or technique for assessing one or more symptom of depression and/ or anxiety may be used. Suitable methods/ techniques are known in the art, as non limiting examples, the Patient Health Questionnaire-9 (PHQ-9) or Beck Depression Inventory (BDI) may be used to assess one or more symptom of depression and the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), may be used to assess one or more symptom of anxiety.
  • PHQ-9 Patient Health Questionnaire-9
  • BDI Beck Depression Inventory
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders
  • any/ ll of the disclosure herein in relation to the treatment of vulvodynia using a botulinum neurotoxin applies equally and unreservedly to the treatment of depression and/or anxiety using botulinum neurotoxin.
  • any features disclosed in relation to a method of treating vulvodynia should be considered equally individualized/disclosed in the context of treating depression and/or anxiety.
  • treat means to deal with medically. It includes, for example, administering a botulinum neurotoxin according to the invention to prevent one or more symptom of vulvodynia or to lessen the severity of said symptom(s). As compared with an equivalent untreated control, “treating” or ameliorating one or more symptom of vulvodynia may reduce the severity of said symptom(s) by at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, 99% or more as measured by any standard technique. Examples of vulvodynia and pain perception assessment techniques, methods, parameters and standards are described herein.
  • botulinum neurotoxin is typically performed by a medical practitioner.
  • the term“medical practitioner” includes a clinician, physician, nurse, medical technician, or the like.
  • the subject may self-administer the botulinum neurotoxin.
  • botulinum neurotoxins are synthesised as a single-chain polypeptide that is modified post-translationally by a proteolytic cleavage event to form two polypeptide chains joined together by a disulphide bond. Cleavage occurs at a specific cleavage site, often referred to as the activation site that is located between the cysteine residues that provide the inter-chain disulphide bond. It is this di-chain form that is the active form of the toxin.
  • the two chains are termed the heavy chain (H-chain, HC), which has a molecular mass of approximately 100 kDa, and the light chain (L-chain or LC), which has a molecular mass of approximately 50 kDa.
  • the H-chain comprises an N-terminal translocation component (H N domain) and a C-terminal targeting component (H c domain).
  • the cleavage site is located between the L-chain and the translocation domain components.
  • Proteolytic activation is of botulinum neuro toxins is crucial because after receptor binding and internalisation by endocytosis, subsequent acidification of the endosome is believed to cause the a conformational change in the protein, leading to insertion of the H N domain into the endosomal membrane, formation of a translocation pore and delivery of the L-chain into the cytoplasm, where the di-sulphide bond is reduced and the L-chain released.
  • Non-cytotoxic proteases act by proteolytically cleaving intracellular transport proteins known as SNARE proteins (e.g. SNAP-25, VAMP, or Syntaxin)— see Gerald K (2002) "Cell and Molecular Biology” (4th edition) John Wiley & Sons, Inc.
  • the acronym SNARE derives from the term Soluble NSF Attachment Receptor, where NSF means N-ethylmaleimide -Sensitive Factor.
  • SNARE proteins are integral to intracellular vesicle fusion, and thus to secretion of molecules via vesicle transport from a cell.
  • the protease function is a zinc-dependent endopeptidase activity and exhibits a high substrate specificity for SNARE proteins.
  • the protease is described as non-cytotoxic, as it does not kill the cell in which it acts. Accordingly, once delivered to a desired target cell, the non- cytotoxic protease is capable of inhibiting cellular secretion from the target cell.
  • the L-chain proteases of botulinum neurotoxins are non-cytotoxic proteases that cleave SNARE proteins.
  • the botulinum neurotoxin-producing strain is preferably Clostridium botulinum, but is not limited thereto, and it will be apparent to those skilled in the art that any strain capable of producing a botulinum neurotoxin may be used in the present invention.
  • the term“botulinum neurotoxin” is meant to include not only a neurotoxin produced biologically, but also any modified, recombinant, hybrid, fusion, and chimeric botulinum neurotoxins.
  • a modified or recombinant botulinum neurotoxin may, for example, contain modifications as compared to a wild-type botulinum neurotoxin (e.g.
  • botulinum neurotoxin as used herein is meant to include any and all known botulinum neurotoxin serotypes, including serotypes A, B, C, D, E, F, G, H and X, as well as botulinum neurotoxin complexes (e.g., 300, 600 and 900 kDa complexes), and high purity botulinum neurotoxins (botulinum neurotoxins that are free from complexes with other proteins), which are all useful in the practice of the present invention.
  • the botulinum neurotoxin may be of serotypes A, B, C, D, E, F, G, H, or X.
  • the botulinum neurotoxin may be a protein containing modifications as compared to wild-type botulinum neurotoxins.
  • the botulinum neurotoxin may be a protein having an amino acid sequence that has at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% sequence identity, preferably at least 80%, 90%, 95%, 97%, 98%, or 99% sequence identity, to the amino acid sequence of a wild-type botulinum neurotoxin of serotypes A, B, C, D, E, F, G, H, or X.
  • botulinum neuro toxin may be BoNT/A.
  • a reference BoNT/A sequence is shown as SEQ ID NO: 1.
  • the botulinum neurotoxin may be BoNT/B.
  • a reference BoNT/B sequence is shown as SEQ ID NO: 2.
  • botulinum neurotoxin may be BoNT/C.
  • a reference BoNT/ sequence is shown as SEQ ID NO: 3.
  • botulinum neurotoxin may be BoNT/D.
  • a reference BoNT/D sequence is shown as SEQ ID NO: 4.
  • botulinum neurotoxin may be BoNT/E.
  • a reference BoNT/E sequence is shown as SEQ ID NO: 5.
  • the botulinum neurotoxin may be BoNT/F.
  • a reference BoNT/F sequence is shown as SEQ ID NO: 6.
  • botulinum neuro toxin may be BoNT/G.
  • a reference BoNT/ G sequence is shown as SEQ ID NO: 7.
  • the botulinum neurotoxin may be BoNT/X.
  • a reference BoNT/X sequence is shown as SEQ ID NO: 8.
  • botulinum neurotoxin As well as encompassing wild-type botulinum neuro toxins (also called native botulinum neurotoxins, unmodified botulinum neurotoxins and holotoxins), the term“botulinum neurotoxin” is also intended to embrace modified botulinum neurotoxins and derivatives thereof, including but not limited to those described below.
  • a modified botulinum neurotoxin or derivative may contain one or more amino acids that has been modified as compared to the native (unmodified) form of the botulinum neurotoxin, or may contain one or more inserted amino acids that are not present in the native (unmodified) form of the botulinum neurotoxin.
  • a modified botulinum neurotoxin may have modified amino acid sequences in one or more domains relative to the native (unmodified) botulinum neurotoxin sequence. Such modifications may modify functional aspects of the toxin, for example biological activity or persistence.
  • the botulinum neurotoxin of the invention is a modified botulinum neurotoxin, or a modified botulinum neurotoxin derivative, or a botulinum neurotoxin derivative.
  • a modified botulinum neurotoxin may have one or more modifications in the amino acid sequence of the heavy chain (such as a modified H c domain), wherein said modified heavy chain binds to target nerve cells with a higher or lower affinity than the native (unmodified) botulinum neurotoxin.
  • modifications in the H c domain can include modifying residues in the ganglioside binding site of the H c domain or in the protein (SV2 or synaptotagmin) binding site that alter binding to the ganglioside receptor and/ or the protein receptor of the target nerve cell. Examples of such modified botulinum neurotoxins are described in WO 2006/027207 and WO 2006/114308, both of which are hereby incorporated by reference in their entirety.
  • a modified botulinum neurotoxin may have one or more modifications in the amino acid sequence of the light chain, for example modifications in the substrate binding or catalytic domain which may alter or modify the SNARE protein specificity of the modified L-chain.
  • modifications in the substrate binding or catalytic domain which may alter or modify the SNARE protein specificity of the modified L-chain. Examples of such modified botulinum neurotoxins are described in WO 2010/120766 and US 2011/0318385, both of which are hereby incorporated by reference in their entirety.
  • a modified botulinum neurotoxin may comprise one or more modifications that increases or decreases the biological activity and/or the biological persistence of the modified botulinum neurotoxin.
  • a modified botulinum neurotoxin may comprise a leucine- or tyrosine- based motif, wherein said motif increases or decreases the biological activity and/ or the biological persistence of the modified botulinum neurotoxin.
  • Suitable leucine-based motifs include xDxxxLL, xExxxLL, xExxxIL, and xExxxLM (wherein x is any amino acid).
  • Suitable tyrosine-based motifs include Y-x-x-Hy (wherein Ely is a hydrophobic amino acid). Examples of modified botulinum neurotoxins comprising leucine- and tyrosine-based motifs are described in WO 2002/ 08268, which is hereby incorporated by reference in its entirety.
  • botulinum neurotoxin is intended to embrace hybrid and chimeric botulinum neurotoxins.
  • a hybrid botulinum neurotoxin comprises at least a portion of a light chain from one botulinum neurotoxin or subtype thereof, and at least a portion of a heavy chain from another botulinum neurotoxin or botulinum neurotoxin subtype.
  • the hybrid botulinum neurotoxin may contain the entire light chain of a light chain from one botulinum neurotoxin subtype and the heavy chain from another botulinum neurotoxin subtype.
  • a botulinum neurotoxin may contain a portion (e.g.
  • the therapeutic element may comprise light chain portions from different botulinum neurotoxins.
  • Such hybrid or chimeric botulinum neurotoxins are useful, for example, as a means of delivering the therapeutic benefits of such botulinum neurotoxins to patients who are immunologically resistant to a given botulinum neurotoxin subtype, to patients who may have a lower than average concentration of receptors to a given botulinum neurotoxin heavy chain binding domain, or to patients who may have a protease- resistant variant of the membrane or vesicle toxin substrate (e.g., SNAP-25, VAMP and syntaxin).
  • Hybrid and chimeric botulinum neurotoxins are described in US 8,071,110, which publication is hereby incorporated by reference in its entirety.
  • the botulinum neurotoxin of the invention is a hybrid botulinum neurotoxin, or a chimeric botulinum neurotoxin.
  • BoNT BoNT
  • H c host cell receptor binding domain
  • EGFR EGFR
  • H N LH N (LC + H N )
  • H N domain has a“belt” region that wraps around the LC— this is believed to behave as a pseudo inhibitor and have a chaperone function during LC translocation.
  • botulinum neurotoxin is also intended to encompass variants and fragments of botulinum neurotoxin, provided they retain the analgesic effect of the corresponding native botulinum neurotoxin.
  • botulinum neurotoxin may also embrace newly discovered botulinum neurotoxin protein family members expressed by non-clostridial microorganisms, such as the Enterococcus encoded toxin which has closest sequence identity to BoNT/X, the Weissella ory ⁇ ae encoded toxin called BoNT/Wo (NCBI Ref Seq: WP_027699549.1), which cleaves VAMP2 at W89- W90, the Enterococcus faecium encoded toxin (GenBank: 0T022244.1), which cleaves VAMP2 and SNAP25, and the Chryseobacterium pipero encoded toxin (NCBI Ref.Seq: WP_034687872.1).
  • non-clostridial microorganisms such as the Enterococcus encoded toxin which has closest sequence identity to BoNT/X, the Weissella ory ⁇ ae encoded toxin called BoNT/Wo (NCBI Re
  • botulinum neurotoxins are particularly suited for the treatment of vulvodynia as they can both decrease muscular overactivity (one of the causes of vulvodynia, with most patients with PVD having overactive pelvic floor muscles), and also have a direct effect on pain.
  • Botulinum neurotoxin may be obtained commercially by establishing and growing cultures of C. botulinum in a fermenter, and harvesting and purifying the fermented mixture in accordance with known techniques.
  • The“A” form of botulinum neurotoxin is currently available commercially from several sources, including Ipsen Biopharmaceuticals Limited under the tradename DYSPORT®, from Merz Pharma under the tradename XEOMIN®, from Medytox Inc. under the tradename CORETOX®, and from Allergan Inc. under the tradename BOTOX®.
  • the botulinum neurotoxin is one of these commercially- available forms.
  • the botulinum neurotoxin is abobotulinumtoxinA, even more preferably the botulinum toxin is DYSPORT®.
  • DYSPORT® is an injectable form of BoNT/A, which is isolated and purified from Clostridium bacteria producing BoNT/A.
  • Dysport® is formulated as a complex of BoNT/A with haemagglutinin (BoNT/A-HAC), a large therapeutically inert protein used to stabilise the toxin.
  • Dysport® is formulated with lactose (bulking agent) and human serum albumin, and is supplied as a lyophilised powder. It is supplied as a lyophilized powder.
  • DYSPORT® has approved therapeutic indications in the United States for the treatment of adults with Cervical Dystonia (CD), the treatment of upper and lower limb spasticity in adult patients, and the treatment of lower limb spasticity in children to improve tone and spasticity.
  • CD Cervical Dystonia
  • the medicine was first registered in the United Kingdom in 1990 for other uses and is licensed in more than 80 countries in eight different indications, with over 1,300 peer-reviewed publications.
  • the botulinum neurotoxin may be administered by any means known in the art, including parenterally, intra-muscularly, intradermally, transdermally and by instillation. Typically botulinum neurotoxin is administered parenterally, for example subcutaneously or intramuscularly. Preferably, botulinum neurotoxin is administered intramuscularly.
  • Botulinum neurotoxin may be administered to a subject’s bladder and/or pelvic floor. This has the advantage of allowing the treatment of concomitant disease (e.g. interstitial cystitis).
  • concomitant disease e.g. interstitial cystitis
  • administration may be to the muscles around the vulvar vestibule (also referred to as the vaginal vestibule or vaginal opening).
  • botulinum neurotoxin may be administered to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle, or any combination thereof. While treatment of vulvodynia with botulinum neurotoxin has been described in the art, the results have been inconsistent, with the only randomized control studies showing no effect compared with the placebo.
  • botulinum neurotoxin to the combination of all of the aforementioned muscles. It has surprisingly been found by the inventors that administration of botulinum neurotoxin to these muscles in combination provides additional efficacy in treating symptoms of vulvodynia, whilst reducing the risk of undesirable clinical side effects.
  • a method of treating one or more symptom of vulvodynia preferably comprises the administration of a botulinum toxin to each of the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and the right deep transverse perineal muscle.
  • the injection to the transverse perineal muscles may be at about 5 mm below the skin surface and/ or at about 10 mm below the skin surface.
  • botulinum neurotoxin may be administered to a subject in the following order: (1) to a first bulbospongiosus muscle, anterior to the hymeneal ring, (2) to a first pubococcygeous muscle, anterior to the hymeneal ring; (3) to the first bulbospongiosus muscle, posterior to the hymeneal ring; (4) to the first pubococcygeous muscle, posterior to the hymeneal ring; (5) to a second bulbospongiosus muscle, anterior to the hymeneal ring, (6) to a second pubococcygeous muscle, anterior to the hymeneal ring; (7) to the second bulbospongiosus muscle, posterior to the hymeneal ring; (8) to the second pubococcygeous muscle, posterior to the hymeneal ring; and (9) to the superficial and deep transverse perineal muscles (
  • the first bulbospongiosus muscle is the left or right bulbospongiosus, with the second bulbospongiosus muscle being the left bulbospongiosus if the first bulbospongiosus muscle is the right bulbospongiosus and the right bulbospongiosus if the first bulbospongiosus muscle is the left bulbospongiosus.
  • the first pubococcygeous muscle is the left or right pubococcygeous, with the second pubococcygeous muscle being the left pubococcygeous if the first pubococcygeous muscle is the right pubococcygeous and the right pubococcygeous if the first pubococcygeous muscle is the left pubococcygeous.
  • the administration may be at about the 5 o’clock position when administered to the left bulbospongiosus and pubococcygeous, at about the 7 o’clock position when administered to the right bulbospongiosus and pubococcygeous, and/or at about the 6 o’clock position when administered to the superficial and deep transverse perineal muscles (each of the left and right, superficial and deep transverse perineal muscles are administered at this position).
  • the botulinum neurotoxin can be presented as a sterile aqueous solution, for instance a pyrogen-free aqueous solution or dispersion, or as a sterile powder for reconstitution into a sterile solution or dispersion.
  • tonicity adjusting agents such as sodium chloride, glycerol and/ or various sugars can be added.
  • Stabilizers may be included if desired.
  • the formulation may be preserved by means of any suitable pharmaceutically acceptable preservative, such as a paraben.
  • the botulinum neurotoxin is formulated in unit dosage form, for example, as a sterile solution in a vial, or as a vial or sachet containing a lyophilized powder for reconstituting in a suitable carrier, such as saline, for injection.
  • a suitable carrier such as saline
  • the botulinum neurotoxin is formulated in a solution containing saline and pasteurized human serum albumin, which stabilizes the neurotoxin.
  • the solution may be sterile filtered, filled into individual vials, and then vacuum dried to give a sterile lyophilized powder.
  • the powder can be reconstituted by the addition of sterile unpreserved normal saline (sodium chloride 0.9% for injection).
  • the potency of the neurotoxin may be expressed as a multiple of the LD S0 value.
  • One LD S0 unit is the equivalent amount of neurotoxin which causes the death of 50% (one-half) of a group of test animals, such as laboratory mice.
  • Alternative methods of determining the potency of the neurotoxin may also be employed, including, for example, any method included in the European Pharmacopoeia monograph 01/2005:2113, which is hereby incorporated by reference.
  • the term“unit” refers to a unit dose of DYSPORT®, which refers to the median intraperitoneal LD S0 dose of DYSPORT® in mice. It is noted that the median intraperitoneal LD S0 dose of DYSPORT® in mice is not necessarily the same as the median intraperitoneal LD S0 dose of another botulinum neurotoxin-containing product, such as BOTOX®, as different pharmaceutical preparations are produced differendy. For example, units of BOTOX®, as described in the art, are not the same as the units of the present invention, which are units of DYSPORT®.
  • the botulinum neurotoxin is administered to the subject is a“therapeutically effective amount,” that is, an amount sufficient to reduce, ameliorate, or eliminate one or more primary or secondary symptoms of vulvodynia.
  • Primary symptoms include pain in the genital area, which can be characterized as burning, soreness, stinging, rawness, painful intercourse (dyspareunia), aching, throbbing, or itching.
  • the pain may be constant, occasional, or only when pressure is applied to the sensitive area.
  • the pain may be felt in the entire genital area (generalized) or it may be localized to a certain area, such as the opening of the vagina.
  • Genital tissue may appear normal or slighdy inflamed or swollen.
  • the subject suffers from pain at the vaginal vestibule. Accordingly, in some preferred embodiments of the invention, the subject suffers from a localized form of vulvodynia, known as vestibulodynia.
  • the vestibulodynia is general; in other embodiments, the vestibulodynia is caused by touching (known as provoked vestibulodynia or PVD), such as when the subject inserts a tampon, has a pelvic exam, or engages in sexual intercourse. Treatment of PVD is particularly preferred.
  • Secondary symptoms of vulvodynia which may be experienced by a subject to be treated by the present invention include affective disorders such as emotional distress, stress, anxiety, and depression. In some preferred embodiments, the subject to be treated by the present invention suffers from an affective disorder, preferably anxiety or depression.
  • the amount of botulinum toxin to be administered can be determined, at least in part, by the severity of the one or more symptoms of vulvodynia experienced by the subject. Any appropriate symptom, examples of which are described herein, may be used in this regard. Suitable symptoms, and methods for assessing/ quantifying their severity are known in the art and could be selected and determined by one of ordinary skill in the art, such as the attending physician.
  • severity of the symptoms of vulvodynia can be assessed, for example, by the pain felt by a subject during intercourse and/or during a dilator test.
  • One measure of the severity of the vulvodynia is the Vulvar Pain Assessment Questionnaire (VPAQ), which assesses pain as well as emotional response, cognitive response, interference with life, sexual function and self-stimulation/penetration (see, for example, Dargie et al. Pain (2016) 157:2672-2686).
  • the VPAQ includes 55 Likert-type questions and designed to capture 6 domains: pain severity, emotional response, cognitive response and interference with life, sexual function, self stimulation/penetration.
  • the score for each question ranges from 0 to 4 and a mean score is computed for each domain.
  • NRS Numerical Rating Scale
  • Non-limiting examples include: the McGill Pain Rating Index, which measures the subject’s pain over the previous month on a scale from 0 (no pain) to 3 (severe pain) (Hawker et al), ⁇ the McGill Visual Analog Scale which measures the subject’s pain intensity for the previous month, ranging from 0 (no pain) to 5 (excruciating pain) (Hawker et al); the Brief Pain Inventory (Cleeland and Ryan Ann. Acad. Med.
  • the Numerical Rating Scale can be used to assess the severity of vulvodynia.
  • Non-limiting examples of vulvodynia severity assessments/pain assessment are detailed below (also see Examples 3 to 8). Any one or more of these outcomes may be used to assess a subject’s response to treatment according to the present invention, or any combination thereof.
  • a subject may be assessed by the mean change in NRS score from baseline (prior to administration of botulinum neurotoxin) to a suitable time point (e.g. six weeks or more) post-treatment.
  • a therapeutic effect may be quantified as a significant reduction in vaginal pain, e.g.
  • a therapeutic effect may be quantified as at least a two-point, at least a three-point, at least a four-point or more decrease in vaginal pain. This decrease may be measured using any appropriate scale or index, including those disclosed herein (e.g. the NRS).
  • a therapeutic effect may be quantified as the mean change from baseline to post-treatment in maximum tolerated vaginal pain. Again, this may be measured using any appropriate scale or index, including those disclosed herein (e.g. the NRS).
  • any of the assessment techniques described herein may assess pain following insertion of a probe (e.g. a dilator). Pain may be assessed at the dilator size that provokes the maximum tolerated pain (dilator maximum testedsize, DMTS). By way of a further non-limiting example, a therapeutic effect may be quantified as the mean change from baseline to post-treatment in the composite score for vaginal pain. Such a composite score may be arrived as by a combination of dilator-induced pain and the tolerability of the dilator size. This composite score may be measured using any appropriate scale or index, including those disclosed herein (e.g. the NRS).
  • a therapeutic effect may be quantified as the mean change from baseline to post treatment in the pain suffered during intercourse. Again, this may be measured using any appropriate scale or index, including those disclosed herein (e.g. the NRS).
  • a therapeutic effect may be quantified as the mean change from baseline to post treatment in the number of instances of intercourse.
  • a therapeutic effect may be quantified as the mean change from baseline to post-treatment in the Clinical Global Impression (CGI).
  • CGI Clinical Global Impression
  • a therapeutic effect may be quantified as the mean change from baseline to post-treatment in the Patient Global Impression of change in pain (PGI-C) and/or Patient Global Impression of severity of pain (PGI- S).
  • PGI-C may be assessed by asking a patient to assess how their pain has changed compared with prior to treatment using a 7-point Likert scale (from -3: very much worse to +3: very much improved).
  • PGI-S may be conducted using a 4-point Likert scale (from 0: no pain to 3: severe pain) over a recall period of the past 1 week.
  • the severity of secondary symptoms of vulvodynia can be measured by various means, including: the Female Sexual Function Index (FSFI) (Rosen et al. J. Sex Marital Ther. (2000) 26(2):191-208); the Hamilton Depression Rating Scale (HAM-D); the Hamilton Anxiety Rating Scale (HAM-A); the Profile of Mood States; the Beck Depression Inventory; and the Pain Anxiety Symptoms Scale (PASS), which measures anxiety associated with the fear of pain.
  • FSFI Female Sexual Function Index
  • HAM-D Hamilton Depression Rating Scale
  • HAM-A Hamilton Anxiety Rating Scale
  • PASS Pain Anxiety Symptoms Scale
  • PHQ-9 Patient-Health Questionnaire 9
  • DSM Diagnostic and Statistical Manual of Mental Disorders
  • SF-36 Short Form-36
  • the Quality of Life questionnaire Short Form-36 may be used to assess a subject’s pain perception.
  • the SF-36 is a 36-item, subject-reported survey of subject health.
  • the SF-36 consists of eight scaled scores (vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, social role functioning and mental health). The higher the score recorded in the SF-36, the less disability.
  • Pelvic floor pressure (resting vaginal pressure and/or maximal sequeeze pressure) may also be assessed.
  • multi-dimensional measures of the symptoms of vulvodynia such as the Female Sexual Function Index (FSFI) (Rosen et al.), which measures sexual desire or interest, pain associated with vaginal penetration, and other factors.
  • FSFI Female Sexual Function Index
  • the FSFI is a validated self- reported multidimensional 19-item questionnaire for assessing the sexual function in women by evaluating six key domains of sexual function: desire, arousal, lubrication, orgasm, sexual satisfaction, and pain. A total score and domain scores are calculated. Every item is assessed with a score from 0 or 1 to 5, the total score being 2-36.
  • FSFI questions 17 (relating to how often pain or discomfort is experienced during vaginal penetration), 18 (relating to how often pain or discomfort is experienced after vaginal penetration) and 19 (relating to rating the level/degree of pain or discomfort during or following vaginal penetration) are particularly relevant.
  • modified forms of one or more of these assessments may be used.
  • a modified form of the VPAQ (mVPAQ) or the FSFI (mFSFI) may be used.
  • the standard VPAQ assessment as described in the art may be altered by: (i) modifying the recall period for the VPAQ subscale to the past 1 week; (ii) modifying the recall period for the VPAQ life interference subscale to over the past 1 week; (iii) altering the recall periods for the other VPAQ subscales to over the past 1 month; and/or (iv) reserving the sequence of questions for reporting distress (average/worst) on the pain severity subscale.
  • the standard FSFI assessment as described in the art may be altered by: (i) modifying the FSFI pain domain (questions 17 to 19) recall period to over the past 1 week; and/ or (ii) altering the other FSFI domains to over the past 4 weeks.
  • a therapeutically effective amount of the botulinum neurotoxin may depend upon a variety of factors, including the method of administration, the weight of the subject, the age of the subject, the size of the muscles, the location of the muscles, the severity of the subject’s vulvodynia, the severity of the subject’s symptoms of vulvodynia, the type and potency of the particular botulinum neurotoxin, the status of the subject’s recovery, the subject’s history with botulinum neurotoxin, the subject’s body mass index, contraindications, if any, and/or the judgement of the attending physician. Therefore, it is not generally practicable to specify an exact therapeutically effective amount, although these may be readily determined by one of ordinary skill.
  • a physician may increase or decrease the dose based on the efficacy and safety responses.
  • a physician may start with low dose in low weight patients, with the potential to increase the dose depending on the observed clinical response.
  • the dosage is the lowest amount of botulinum neurotoxin that is therapeutically effective.
  • the administrations may be repeated as necessary, though subsequent administrations may vary in dosage amount, administration route, frequency, muscle type, location, and/or toxin type.
  • the treatment may be continued for as long as the symptoms of vulvodynia persist. In the event treatment is terminated but the symptoms reappear, treatment can recommence.
  • the botulinum neurotoxin may be administered about every three to six months. For more severe vulvodynia, the administration interval may be decreased (i.e. the frequency of administration increased), e.g.
  • botulinum neurotoxin may be administered every month, or every two months, or at another more frequent interval as determined by the subject’s physician using routine skill.
  • the administration interval may be increased (i.e. the frequency of administration decreased), e.g. botulinum neurotoxin may be administered every six months, every eight months, or annually, or at another less frequent interval as determined by the subject’s physician using routine skill.
  • the treatment typically involves administering about 1,500 units or less of the botulinum neurotoxin DYSPORT®, for example from about 1 to about 1,500 units, about 1 to about 1,000 units, about 200 to about 800 units, about 350 to about 800 units, about 450 to about 800 units, or about 500 units per treatment session.
  • the treatment involves administering about 350 to about 600 units per treatment session, for example about 350 units, about 500 units or about 600 units per treatment session.
  • about 5 to 25% of the total dose of botulinum neurotoxin administered during a treatment session is administered to one or more of the following muscles: the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and the right deep transverse perineal muscle.
  • about 8% of the total dose of botulinum neurotoxin administered during a treatment session is administered to one or more of the following muscles: the left bulbospongiosus muscle, anterior to the hymeneal ring; the left pubococcygeous muscle, anterior to the hymeneal ring; the left bulbospongiosus muscle, posterior to the hymeneal ring; the left pubococcygeous muscle, posterior to the hymeneal ring; the right bulbospongiosus muscle, anterior to the hymeneal ring; the right pubococcygeous muscle, anterior to the hymeneal ring; the right bulbospongiosus muscle, posterior to the hymeneal ring; the right pubococcygeous muscle, posterior to the hymeneal ring.
  • about 8% of the total dose of botulinum neurotoxin administered during a treatment session is administered to each of the following muscles: the left bulbospongiosus muscle, anterior to the hymeneal ring; the left pubococcygeous muscle, anterior to the hymeneal ring; the left bulbospongiosus muscle, posterior to the hymeneal ring; the left pubococcygeous muscle, posterior to the hymeneal ring; the right bulbospongiosus muscle, anterior to the hymeneal ring; the right pubococcygeous muscle, anterior to the hymeneal ring; the right bulbospongiosus muscle, posterior to the hymeneal ring; the right pubococcygeous muscle, posterior to the hymeneal ring.
  • about 9% of the total dose of botulinum neurotoxin administered during a treatment session is administered to one or more of the following muscles: the left superficial transverse perineal muscle anterior to the hymeneal ring; the right superficial transverse perineal muscle anterior to the hymeneal ring; the left deep transverse perineal muscle anterior to the hymeneal ring; and the right deep transverse perineal muscle anterior to the hymeneal ring.
  • the total dose of botulinum toxin is split equally (as far as practicable) between the muscles to be treated.
  • Other administration protocols which allow for equal dosing of the muscles to be treated can be readily determined by one of ordinary skill in the art.
  • the transverse perineal muscles anterior to the hymeneal ring about 36% of the total dose of botulinum neurotoxin is administered to the transverse perineal muscles anterior to the hymeneal ring.
  • all four of the following muscles are administered by such a dose: the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and the right deep transverse perineal muscle. Accordingly, in certain such embodiments, each of these muscles receives about 9% of the total dose of botulinum neurotoxin.
  • the amount of botulinum neurotoxin administered to the subject may be direcdy proportional to the severity of the vulvodynia and/or the symptom(s) of vulvodynia.
  • a dosage of from about 1 to about 200 units may be administered to a subject having mild vulvodynia or mild symptom(s) of vulvodynia.
  • a dosage of from about 200 to about 800, preferably from about 350 to about 800, more preferably from about 450 to about 800 or about 350 to 600, units may be administered to a subject having moderate vulvodynia or moderate symptom(s) of vulvodynia.
  • a dosage of from about 800 to about 1,500 units may be administered to a subject having severe vulvodynia or severe symptom(s) of vulvodynia.
  • the amount of botulinum neurotoxin administered to the subject may be directly proportional to the muscle tone of the subject.
  • a lower dose of botulinum neurotoxin may be administered if the subject has exhibited adverse effects following previous treatment with botulinum neurotoxin.
  • adverse effects include: dysphagia, pneumonia, significant debility, muscle weakness, pneumopathy, urinary incontinence, and/or fecal incontinence. Examples of such a lower dose are from about 50 units to about 500 units.
  • the method of treating one or more symptom of vulvodynia may further comprise; (i) determining a dosing regimen or botulinum neurotoxin; (ii) determining the amount of botulinum neurotoxin for a subsequent administration; and / or (iii) determining the frequency for a subsequent administration of a botulinum toxin; based on the subject’s response to a previous administration of botulinum neurotoxin.
  • the subject’s response may be recorded into a software program that is configured to receive such information.
  • the program may operate on a computer device. Based on the subject’s response as measured, the program may determine an appropriate dosing regimen for a botulinum neurotoxin.
  • Also described herein is a method involving determining an appropriate dosage amount and/or an appropriate dosing regimen for botulinum neurotoxin based on an assessment of one or more of the following criteria: the subject’s weight, the severity of the vulvodynia, the severity of the symptoms of the vulvodynia, the status of the subject’s recovery following vulvodynia, the subject’s history with treatment with botulinum neurotoxin, whether the subject has previously experienced vulvodynia, the subject’s body mass index, and/or the subject’s response to a previous treatment with botulinum neurotoxin.
  • the term“dosing regimen” encompasses one or more of the amount of botulinum neurotoxin to be administered (both in total and per site or per time of administration), administration interval, frequency of administration and/or time of administration, or any combination thereof.
  • a treatment interval/ frequency of about three months may be used for subsequent administrations: (a) a treatment interval of three months may be used; or (b) a treatment interval/ frequency of more than three months may be used, with the treatment interval being decreased/treatment frequency increased following the subsequent administration if the longer treatment interval/reduced treatment frequency does not elicit or maintain the desired therapeutic response.
  • a new dosing regimen, amount of botulinum neurotoxin to be administered, administration interval, frequency of administration and/ or time of administration may be readily determined by one of ordinary skill in the art based on a subject’s response to a previous treatment with botulinum neurotoxin.
  • one of ordinary skill in the art will readily be able to determine a new dosing regimen, amount of botulinum neurotoxin to be administered, administration interval, frequency of administration and/or time of administration based on the status of the subject’s history with treatment with botulinum neurotoxin and/or whether the subject has previously experienced vulvodynia, or their recovery therefrom. It is also within the routine capabilities of one of ordinary skill in the art to determine an appropriate therapeutically effective amount of botulinum neurotoxin based on a subject’s weight and/or body mass index (BMI).
  • BMI body mass index
  • the amount of botulinum neurotoxin administered and/or the dosing regimen for botulinum neurotoxin is determined in part by the level of pain measured following the insertion of a probe ( ' e.g. , a vaginal dilator, speculum) into the subject’s vagina (use of such a probe, or a series of probes of different sizes is known in the art.
  • a probe e.g. , a vaginal dilator, speculum
  • a probe e.g. , a vaginal dilator, speculum
  • Pain may be measured using any of the means known in the art, including (but not limited to) those disclosed herein.
  • the method involves adjusting future doses or the dosing regimen based on the subject’s response to a previous treatment.
  • the quantity of neurotoxin administered and the frequency of its administration will be at the discretion of the individual(s) responsible for the treatment (eg., the medical practitioner(s) and/ or the subject), and should be commensurate with questions of safety and the effects produced by the neurotoxin.
  • the amount of a subsequent administration of botulinum neurotoxin and/or a dosing regimen for botulinum neurotoxin may be determined.
  • the amount of such subsequent administrations (s) and/or a dosing regimen may be determined based, at least in part, on the subject’s recovery following a previous treatment with botulinum neurotoxin. For example, a lower dose and/ or lower frequency of administration may be desired if the patient has exhibited significant recovery and a higher dose and/ or higher frequency of administration may be desired if the patient has exhibited a low level of recovery.
  • the status of a subject’s recovery can be measured using routine methods known to persons of ordinary skill in the art.
  • a subject’s recovery status may be measured using the Physician’s Global Assessment (PGA) of response Busner and Targum Psychiatry (2007) 4(7)28-37).
  • the PGA measures response on a scale from 1 to 7.
  • a modified PGA may be used which measures response on a scale from -4 to +4, with -4 indicating that response is markedly worse, to 0, which indicates no change, to +4 indicating that response has markedly improved.
  • a desired response may be a PGA score following administration of 1 or above, 2 or above, 3 or above, or 4.
  • the amount of a dose or dosing frequency may, for example, be increased for a subject exhibiting a PGA score of below 0, the amount of a dose or dosing frequency may, for example, be maintained for a subject exhibiting a PGA score of from 0 to 2, the amount of a dose or dosing frequency may, for example, be reduced for a subject exhibiting a level subject exhibiting a PGA score of between 2 and 4, and further treatment with botulinum neurotoxin may be terminated for a subject exhibiting a PGA score of 4 or above.
  • Another measure of the status of a subject’s response to treatment involves insertion of a vaginal dilator. Different size dilators may be used with measurement based on the dilator size that provokes the maximum tolerated pain.
  • GIS Global Response Index
  • FSFI Female Sexual Function Index
  • FSDS Female Sexual Distress Scale
  • DLQI Dermatology Life Quality Index
  • PFDI Pelvic Floor Distress Inventory
  • VAS Visual Analog Scale
  • NRS Pain Numeric Rating Scale
  • CGI Clinical Global Impression scale
  • PKI-I Patient Global Impression of Improvement scale
  • PKI-C Patient Global Impression of Change scale
  • PKI-S Patient Global Impression of Severity scale
  • QOLS Quality Of Life Scale
  • the NRS is used.
  • the information relating to a subject’s response to treatment with botulinum neurotoxin is recorded into a log or diary.
  • the response information is recorded into or by a software program that operates on a computer device and the response information is stored in a database associated with the computer device.
  • the response information is recorded into or by a software program that operates on a first computer device and the information is stored into a database on the first computer device or a second computer device that is in communication with first computer device.
  • the method may additionally comprise administering a subsequent administration of botulinum neurotoxin, wherein the subsequent administration is determined, at least in part, by the response information.
  • the method further comprises: reviewing the subject’s response information; designing a dosing regimen based, at least in part, on the subject’s response information; and administering a subsequent botulinum neurotoxin administration to the subject in accordance with the dosing regimen, wherein the botulinum neurotoxin administration is sufficient to treat or reduce the symptoms of vulvodynia.
  • the amount and/or frequency of the subsequent administration of botulinum neurotoxin and/ or a dosing regimen for botulinum neurotoxin may be determined based in part on the level of pain measured following the insertion of a probe (eg., a vaginal dilator, speculum) into the subject’s vagina following an initial administration of botulinum neurotoxin. If the level of pain measured following insertion of the probe is below a threshold level (eg.
  • a larger sized probe eg., a vagina dilator having a larger diameter
  • probe(s) of increasing size eg., vaginal dilators having larger diameters
  • the amount of botulinum neurotoxin to administer or the dosing regimen for botulinum neurotoxin is then determined based on the level of pain measured following the insertion of the final probe. The aforementioned steps may be repeated as necessary until treatment of the subject is considered satisfactory.
  • a probe may be inserted and the subject’s level of pain determined, with probes of increasing size inserted as necessary until the level of pain reaches a certain threshold.
  • the amount of the next administration of botulinum neurotoxin or a subsequent dosing regimen for botulinum neurotoxin is then determined based on the level of pain measured following insertion of the final probe.
  • botulinum neurotoxin for use in the treatment of one or more symptoms of vulvodynia, wherein said botulinum neurotoxin is for administration to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle.
  • botulinum neurotoxin in the manufacture of a medicament for use in the treatment of one or more symptoms of vulvodynia, wherein said botulinum neurotoxin-containing medicament is for administration to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle.
  • any and all disclosure herein in relation to methods of treating one or more symptom of vulvodynia applies equally and without reservation to the disclosure of botulinum neurotoxins for use in the treatment of one or more symptoms of vulvodynia.
  • any and all disclosure herein in relation to methods of treating one or more symptom of vulvodynia applies equally and without reservation to the use of a botulinum neurotoxin in the manufacture of a medicament for use in the treatment of one or more symptoms of vulvodynia.
  • the clinical management of the subject’s recovery is enhanced by virtue of the fact that information about the subject’s recovery is being recorded into a log or diary, or into a software program that is able to receive and communicate information about the subject’s recovery.
  • the software program useful in the methods described herein is capable of running on any suitable computer device.
  • Various information or data may be received by the software program, including: the time that has elapsed since the previous administration, frequency of administration, symptoms relating to vulvodynia, the effect (if any) of the administration, and/or any other comments about the administration and recovery process.
  • the software program may store that information into a database.
  • the database can reside on the same computer device used by the practitioner or on a different computer device that is able to communicate with the computer device used by the practitioner.
  • the medical practitioner reviews the response information. Using a computer device that is able to communicate with the database, a medical practitioner can access the response information. In one aspect, after reviewing the information, the medical practitioner (eg., clinician) may use this information to determine an appropriate dosing regimen, or to make or suggest an adjustment to an existing dosing regimen. In another aspect, the medical practitioner may use the response information to determine or vary the botulinum neurotoxin dosing regimen, i.e., the mode, amount, or frequency of botulinum neurotoxin administered to the subject. This determination may take into account various factors, including the response information, to arrive at an optimal dosing regimen for that subject.
  • the term“optimal dosing regimen” means the dosing regimen determined by the medical practitioner to be optimal for a particular subject based on a variety of factors, including: the subject’s age, the type of vulvodynia, the potency of the neurotoxin, and/or the subject’s symptoms relating to vulvodynia.
  • the term“computer device” refers to any electronic device for storing and processing data, typically in binary form, according to instructions given to it in a software program, and includes, for example, a desktop, laptop, or tablet personal computers;“netbooks”; mobile communication devices, such as smartphones; personal digital assistants; portable audio or video file players; portable game players; portable electronic readers; or equivalent devices.
  • the computer device can be in communication with another computer device by any suitable type of network (such as internet), and can use any suitable protocol, medium (eg., fiber optic, coaxial cable, wireless broadband, etc.), network interface, or bandwidth.
  • the computer device used by the subject can be the same as or different from the computer device used by the medical practitioner to access the response information.
  • the computer device used by the subject is the same computer device that the medical practitioner uses to access the response information.
  • the subject may enter the response information into his/her smartphone and bring that smartphone to the clinic visit to have the information viewed by the medical practitioner directly from the smartphone.
  • the computer device used to access the response information is different from the computer device used to enter the response information.
  • the response information may be entered into a website portal that is specially designed to collect this type of information and the medical practitioner uses his/her own desktop computer to access the website portal and view the information entered.
  • the computer device on which the database resides may be the same as or different from the computer device used to receive the response information and/ or the computer device used to access that information.
  • the computer device on which the database resides is different from both the computer device used to receive the response information and the computer device used by the medical practitioner to access that information.
  • the information may be entered into a website portal via a laptop computer.
  • the information is stored on a web server computer, which is then accessed by the medical practitioner on his/her own computer to view the response information.
  • the computer system may be capable of determining a subsequent or optimal dosing regimen for the administration of botulinum neurotoxin to the subject. Such a determination may be made based on the response information with the appropriate adjustments in dosing amounts and frequency as discussed above.
  • the invention also provides a software product.
  • the term “software product” refers to a non-transitory computer-readable storage medium storing instructions that, when executed by a computer system, causes the computer system to perform the recited steps.
  • the software product may reside on any suitable computer-readable storage medium, such as CD-ROM, DVD, memory, hard disk, flash drive, RAM, ROM, cache, and the like.
  • the software platform for implementing the present invention can vary depending on design considerations such as user preference, cost, implementation, ease of use, machine capabilities, network limitations, etc.
  • the invention further provides a computer system.
  • the computer system is programmed to perform steps of a computer-implemented method, the method comprising: receiving information associated with the subject’s recovery; storing the information into a database; and transmitting the information to a medical practitioner.
  • the invention also provides a computer system comprising one or more computer devices that are programmed to perform the methods of the present invention.
  • the hardware platforms used by the subject, the medical practitioner, and/or any other third parties may be different, but operate together as a system.
  • the response information may be entered in one computer device, that information may be stored on a different computer device located remotely (eg., a third party web server), and the medical practitioner may use his/her own computer device to access the information.
  • these three computer devices may be considered to operate together as a system.
  • the physical and/ or functional components of the computer system may be distributed, centralized, or arranged in any suitable manner. Communications between the different physical and/or functional components may be performed in any suitable way.
  • the present invention encompasses all the various ways in which the operating work may be divided among different physical and/or functional components.
  • the response information may be received by the computer system from a first computer device, the database resides on a second computer device, and the response information is transmitted by the computer system to a third computer device.
  • the computer devices may be separate.
  • the first computer device may be in communication with the second computer device and the second computer device may be in communication with the third computer device.
  • the first computer device is programmed to receive the response information from the subject, the database resides on a second computer device, and the third computer device receives the transmitted response information.
  • a non-transitory computer-readable storage medium storing instructions is also provided.
  • the non-transitory computer-readable medium when executed by a computer system, causes the computer system to perform steps of a computer-implemented method, the method comprising: receiving information associated with the subject’s recovery; storing the response information into a database; and transmitting the response information to a medical practitioner.
  • a computer-implemented method of determining a dosage regimen for administration of botulinum neurotoxin comprising: (a) receiving information related to a subject’s response to treatment as conducted according to a method for treating one or more symptoms of vulvodynia, the method comprising administering a therapeutically-effective amount of botulinum neuro toxin to a subject determined to be in need thereof, wherein the botulinum neurotoxin is administered to the left bulbospongiosus, the right bulbospongiosus, the left pubococcygeous, the right pubococcygeous, the left superficial transverse perineal muscle, the right superficial transverse perineal muscle, the left deep transverse perineal muscle, and/ or the right deep transverse perineal muscle; (b) receiving the response information; and (c) determining a subsequent dosing regimen for the administration of botulinum neurotoxin to the subject based on the response information.
  • Said method may further comprise sending an instruction to administer botulinum neurotoxin accordingly.
  • the invention also provides a computer-readable medium comprising instructions which, when executed by a computer, cause the computer to carry out said method.
  • the invention further provides a data processing device comprising a processor configured to perform said method.
  • compositions useful in treating one of more symptoms of vulvodynia comprising a therapeutically-effective amount of botulinum neurotoxin.
  • the composition comprises a diluent, for example a sodium chloride solution.
  • the sodium chloride solution may, for example, be a 0.9% sodium chloride solution.
  • the composition comprises botulinum neurotoxin as a lyophilized powder which may be reconstituted, for example using a sodium chloride solution.
  • the botulinum neurotoxin of the composition is of serotypes A, B, C, D, E, F, G, H, or X.
  • the botulinum neurotoxin of the composition is a protein containing modifications as compared to wild-type botulinum neurotoxins.
  • the botulinum neurotoxin of the composition is a protein having an amino acid sequence that has at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, 98%, or 99% sequence identity to the amino acid sequence of a botulinum neurotoxin of serotypes A, B, C, D, E, F, G, H, or X.
  • the botulinum neurotoxin of the composition is naturally-occurring. In another embodiment, the botulinum neurotoxin of the composition is produced via recombinant means. Hybrid and chimeric botulinum toxins are also encompassed within the term“botulinum neurotoxin” according to the present invention.
  • the botulinum neurotoxin of the composition is BoNT/A, also known as botulinum neurotoxin A.
  • the botulinum neurotoxin is DYSPORT®.
  • the composition of the composition typically comprises about 50 to 700 units of DYSPORT®, for example, about 500 units of DYSPORT®.
  • the composition may be formulated for the administration of botulinum neurotoxin parenterally, intra-muscularly, intradermally, or transdermally.
  • the composition is formulated for parenteral administration, for example subcutaneous administration.
  • the composition is formulated for intramuscular administration.
  • the composition may be in the form of a liquid, a gel, or a powder.
  • the composition may comprise a lyophilized powder comprising botulinum neurotoxin, or the composition is formed by reconstituting a lyophilized powder comprising botulinum neurotoxin in a solution, for example the aforementioned sodium chloride solution. Following reconstitution, the composition may be stored under refrigeration at about 2 °C to about 8 °C and protected from light.
  • composition may be administered to a subject in need thereof in amount determined to be appropriate as described above.
  • the composition may further comprise an excipient.
  • the excipient may, for example, be a filler, a binder, a disintegrant, an anti-adherent, a solvent, a buffering agent, a preservative, or a humectant.
  • fillers include cellulose, lactose, sucrose, glucose, mannose, and sorbitol.
  • the composition may comprise, for example, 10 mg/ml lactose.
  • binders include gelatin, cellulose, polyvinyl pyrrolidone, starch, and sucrose.
  • disintegrants include polyvinyl pyrrolidone and carboxymethyl cellulose.
  • preservatives include parabens.
  • solvents examples include water, oils, glycerol, propylene glycol, and ethanol.
  • buffering agents include phosphates, carbonates, citrates, and lactates.
  • humectants include glycerol, ethylene glycol, and polyethylene glycol (PEG).
  • the device is configured to administer botulinum neuro toxin to a subject determined to be in need thereof.
  • the botulinum neurotoxin may be distributed throughout the material of the device.
  • the botulinum neurotoxin may be applied to the surface of the device.
  • the botulinum neurotoxin may be present in a reservoir within the device. Examples of such devices are described in US 2017/0105784 and WO 2018/023027, both of which are incorporated herein by reference.
  • the device may take any appropriate format.
  • the device may be an intravaginal device, which may be substantially ring-shaped with an outer edge configured to contact the vaginal wall.
  • the device may be an intravaginal device, which may be substantially ring-shaped with an outer edge configured to contact the vaginal wall.
  • the device may be a pre-filled syringe.
  • the device may be connected to a computer device.
  • the computer device may be capable of determining a subsequent or optimal dosing regimen for the administration of botulinum neurotoxin to the subject. Such a determination may be made based on the response information with the appropriate adjustments in dosing amounts and frequency as discussed above.
  • the computer device may then instruct the device to adjust its administration of botulinum neurotoxin accordingly.
  • Also described herein is a method of treating a symptom of vulvodynia, the method comprising inserting the aforementioned intravaginal device into the vagina of a subject determined to be in need of such treatment.
  • the device may remain within the vagina of the subject for as long as necessary to be effective in the treatment.
  • the subject can also have the device removed and reinserted as necessary.
  • “decrease”, “reduced”, “reduction”, or “inhibit” are all used herein to mean a decrease by a statistically significant amount.
  • “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level (e.g. the absence of a given treatment) and can include, for example, a decrease by at least about
  • “reduction” or “inhibition” does not encompass a complete inhibition or reduction as compared to a reference level.
  • “Complete inhibition” is a 100% inhibition as compared to a reference level. A decrease can be preferably down to a level accepted as within the range of normal for an individual without a given disorder.
  • the terms “increased”, “increase”, “enhance”, or “activate” are all used herein to mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance”, or “activate” can mean an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a I 00% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level.
  • an "increase" is a statistically significant
  • a "variant" botulinum neurotoxin as referred to herein is a polypeptide substantially homologous to a native or reference polypeptide, but which has an amino acid sequence different from that of the native or reference polypeptide because of one or a plurality of deletions, insertions or substitutions.
  • Polypeptide-encoding DNA sequences encompass sequences that comprise one or more additions, deletions, or substitutions of nucleotides when compared to a native or reference DNA sequence, but that encode a variant protein or fragment thereof that retains the relevant biological activity relative to the reference protein, e.g., at least 50% of the wildtype reference protein.
  • amino acid sequences one of skill will recognize that individual substitutions, deletions or additions to a nucleic acid, peptide, polypeptide, or protein sequence which alters a single amino acid or a small percentage, (i.e. 5% or fewer, e.g. 4% or fewer, or 3% or fewer, or 1 % or fewer) of amino acids in the encoded sequence is a "conservatively modified variant" where the alteration results in the substitution of an amino acid with a chemically similar amino acid. It is contemplated that some changes can potentially improve the relevant activity, such that a variant, whether conservative or not, has more than 100% of the activity of wild-type, e.g. 110%, 125%, 150%, 175%, 200%, 500%, 1000% or more.
  • a given amino acid can be replaced by a residue having similar physiochemical characteristics, e.g., substituting one aliphatic residue for another (such as lie, Val, Leu, or Ala for one another), or substitution of one polar residue for another (such as between Lys and Arg; Glu and Asp; or Gin and Asn).
  • Other such conservative substitutions e.g., substitutions of entire regions having similar hydrophobicity characteristics, are known.
  • Polypeptides comprising conservative amino acid substitutions can be tested in any one of the assays described herein to confirm that a desired activity of a native or reference polypeptide is retained.
  • Conservative substitution tables providing functionally similar amino acids are well known in the art.
  • conservatively modified variants are in addition to and do not exclude polymorphic variants, interspecies homologs, and alleles consistent with the disclosure.
  • conservative substitutions for one another include: 1) Alanine (A), Glycine (G); 2) Aspartic acid (D), Glutamic acid (E); 3) Asparagine (N), Glutamine (Q); 4) Arginine (R), Lysine (K); 5) Isoleucine (L), Leucine (L ), Methionine (M), Valine (V); 6) Phenylalanine (F), Tyrosine (Y), Tryptophan (W); 7) Serine (S), Threonine (T); and 8) Cysteine (C), Methionine (M) (see, e.g., Creighton, Proteins (1984)).
  • cysteine residues not involved in maintaining the proper conformation of the polypeptide also can be substituted, generally with serine, to improve the oxidative stability of the molecule and prevent aberrant crosslinking.
  • cysteine bond(s) can be added to the polypeptide to improve its stability or facilitate oligomerization.
  • fragment when used in relation to a protein, particularly a botulinum neurotoxin, means a peptide having at least 10, at least 20, at least 50, at least 100, at least 150, at least 200, at least 250, at least 300, at least 400, at least 500, at least 600, at least 700 or more, amino acid residues of the protein in question, but not containing the full-length protein sequence, and which fragment thereof retains the relevant biological activity relative to the reference protein.
  • compositions, methods, and respective component(s) thereof that are essential to the method or composition, yet open to the inclusion of unspecified elements, whether essential or not.
  • consisting of' refers to compositions, methods, and respective components thereof as described herein, which are exclusive of any element not recited in that description of the embodiment.
  • the term "consisting essentially of' refers to those elements required for a given embodiment. The term permits the presence of elements that do not materially affect the basic and novel or functional characteristic(s) of that embodiment.
  • the term“equivalent” as used herein may mean that the two or more values being compared are not statistically significantly different.
  • the term“equivalent” as used herein means that the two or more values are identical.
  • nucleic acid sequences are written left to right in 5' to 3' orientation; amino acid sequences are written left to right in amino to carboxy orientation, respectively.
  • Amino acids are referred to herein using the name of the amino acid, the three letter abbreviation or the single letter abbreviation.
  • the term“protein”, as used herein, includes proteins, polypeptides, and peptides.
  • the term“amino acid sequence” is synonymous with the term“polypeptide” and/ or the term“protein”.
  • the term“amino acid sequence” is synonymous with the term“peptide”.
  • the term“amino acid sequence” is synonymous with the term “enzyme”.
  • the terms "protein” and "polypeptide” are used interchangeably herein. In the present disclosure and claims, the conventional one-letter and three- letter codes for amino acid residues may be used.
  • sequence alignment methods can be used to determine percent identity, including, without limitation, global methods, local methods and hybrid methods, such as, e.g., segment approach methods. Protocols to determine percent identity are routine procedures within the scope of one skilled in the art. Global methods align sequences from the beginning to the end of the molecule and determine the best alignment by adding up scores of individual residue pairs and by imposing gap penalties. Non-limiting methods include, e.g., CLUSTAL W, see, e.g., Julie D.
  • Non-limiting methods include, e.g., Match-box, see, e.g., Eric Depiereux and Ernest Feytmans, Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences, 8(5) CABIOS 501 -509 (1992); Gibbs sampling, see, e.g., C. E.
  • percent sequence identity is determined by conventional methods. See, for example,
  • Substantially homologous polypeptides are characterized as having one or more amino acid substitutions, deletions or additions. These changes are preferably of a minor nature, that is conservative amino acid substitutions (see below) and other substitutions that do not significantly affect the folding or activity of the polypeptide; small deletions, typically of one to about 30 amino acids; and small amino- or carboxyl-terminal extensions, such as an amino-terminal methionine residue, a small linker peptide of up to about 20-25 residues, or an affinity tag.
  • Aromatic phenylalanine
  • non-standard amino acids such as 4- hydroxyproline, 6-N-methyl lysine, 2-aminoisobutyric acid, isovaline and a -methyl serine
  • a limited number of non-conservative amino acids, amino acids that are not encoded by the genetic code, and unnatural amino acids may be substituted for botulinum polypeptide amino acid residues.
  • the polypeptides of the present invention can also comprise non-naturally occurring amino acid residues.
  • Non-naturally occurring amino acids include, without limitation, trans-3-methylproline, 2,4- methano-proline, cis-4-hydroxyproline, trans-4-hydroxy-proline, N-methylglycine, allothreonine, methyl-threonine, hydroxy-ethylcysteine, hydroxyethylhomo-cysteine, nitroglutamine, homoglutamine, pipecolic acid, tert-leucine, norvaline, 2-azaphenylalanine, 3- azaphenyl-alanine, 4-azaphenyl-alanine, and 4-fluorophenylalanine.
  • Several methods are known in the art for incorporating non-naturally occurring amino acid residues into proteins.
  • an in vitro system can be employed wherein nonsense mutations are suppressed using chemically aminoacylated suppressor tRNAs.
  • Methods for synthesizing amino acids and aminoacylating tRNA are known in the art. Transcription and translation of plasmids containing nonsense mutations is carried out in a cell free system comprising an E. coli S30 extract and commercially available enzymes and other reagents. Proteins are purified by chromatography. See, for example, Robertson et ak, J. Am. Chem. Soc. 113:2722, 1991; Ellman et ak, Methods Enzymol.
  • E.coli cells are cultured in the absence of a natural amino acid that is to be replaced (e.g., phenylalanine) and in the presence of the desired non-naturally occurring amino acid(s) (e.g., 2-azaphenylalanine, 3- azaphenylalanine, 4-azaphenylalanine, or 4-fluorophenylalanine ).
  • a natural amino acid that is to be replaced e.g., phenylalanine
  • the desired non-naturally occurring amino acid(s) e.g., 2-azaphenylalanine, 3- azaphenylalanine, 4-azaphenylalanine, or 4-fluorophenylalanine
  • the non-naturally occurring amino acid is incorporated into the polypeptide in place of its natural counterpart. See, Koide et ah, Biochem. 33:7470-6, 1994.
  • Naturally occurring amino acid residues can be converted to non-naturally occurring species by in vitro chemical modification.
  • Essential amino acids in the polypeptides of the present invention can be identified according to procedures known in the art, such as site-directed mutagenesis or alanine scanning mutagenesis (Cunningham and Wells, Science 244: 1081 -5, 1989). Sites of biological interaction can also be determined by physical analysis of structure, as determined by such techniques as nuclear magnetic resonance, crystallography, electron diffraction or photoaffinity labelling, in conjunction with mutation of putative contact site amino acids. See, for example, de Vos et al., Science 255:306- 12, 1992; Smith et al, J. Mol. Biol. 224:899-904, 1992; Wlodaver et al., FEBS Lett. 309:59-64, 1992. The identities of essential amino acids can also be inferred from analysis of homologies with related components (e.g. the translocation or protease components) of the polypeptides of the present invention.
  • related components e.g. the translocation or protease components
  • residue/codon may be optional.
  • TSSFWKFISRDPGWVE SEP ID NO: 5 iBoNT/E - UniProt 000496.2
  • 0.5 mL of the reconstituted DYSPORT® is drawn up without inverting the vial.
  • This 0.5 mL solution is then combined with 2.0 mL of preservative-free 0.9% sodium chloride solution.
  • This can be accomplished, for example, by drawing 2.0 mL of preservative-free 0.9% sodium chloride solution into a syringe, connecting that syringe to the syringe containing the 0.5 mL solution of reconstituted DYSPORT®, and using the plunger of the latter syringe to pull 2.0 mL of preservative-free 0.9% sodium chloride solution.
  • This will result in a syringe having 2.5 mL of preservative-free 0.9% sodium chloride solution containing 100 units of DYSPORT®.
  • a“first” 1 mL syringe is connected to the syringe containing the DYSPORT® solution.
  • the plunger of the first 1 mL syringe is pulled to transfer 0.8 mL of the DYSPORT® solution into the first 1 mL syringe.
  • the syringe is removed and capped.
  • This first 1 mL syringe contains about 32 units of DYSPORT®.
  • a“second” 1 mL syringe is connected to the syringe containing the DYSPORT® solution.
  • the plunger of the second 1 mL syringe is pulled to transfer 0.8 mL of the DYSPORT® solution into the second 1 mL syringe.
  • the syringe is removed and capped.
  • This second 1 mL syringe contains about 32 units of DYSPORT®.
  • a“third” 1 mL syringe is connected to the syringe containing the DYSPORT® solution.
  • the plunger of the third 1 mL syringe is pulled to transfer 0.9 mL of the DYSPORT® solution into the third 1 mL syringe.
  • the syringe is removed and capped.
  • This third 1 mL syringe contains about 36 units of DYSPORT®.
  • Botulinum neurotoxin is administered by intramuscular injection to a subject determined to have vulvodynia on day 1 of each testing cycle.
  • the administration paradigm is as follows:
  • the first 1 mL syringe containing 0.8 mL of DYSPORT® as reconstituted according to Example 1 is used to inject 0.2 mL of DYSPORT® (about 8 units) to the subject’s left bulbospongiosus, anterior to the hymeneal ring. This is accomplished by injecting at about the 5 o’clock position (with the front of the patient facing the 12 o’clock position) at about 45° laterally and about 45° posteriorly (towards the hip) and at a depth of about 5 mm from the outer the surface of the skin.
  • the same syringe is then used to inject a further 0.2 mL of DYSPORT® (about 8 units) to the subject’s left pubococcygeous, anterior to the hymeneal ring, by injecting at the same position but at a depth of about 10 mm from the outer surface of the skin.
  • the same syringe is then used to inject 0.2 mL of DYSPORT® (about 8 units) to the subject’s left bulbospongiosus muscle, posterior to the hymeneal ring. This is accomplished by injecting at about the 5 o’clock position at about 45° laterally and about 45° posteriorly (towards the hip) and at a depth of about 5 mm from the outer the surface of the skin.
  • the same syringe is then used to inject the final 0.2 mL of DYSPORT® (about 8 units) to the subject’s left pubococcygeous muscle, posterior to the hymeneal ring, by injecting at the same position but at a depth of about 10 mm from the outer surface of the skin.
  • the second 1 mL syringe containing 0.8 mL of DYSPORT® as reconstituted according to Example 1 is used to inject 0.2 mL of DYSPORT® (about 8 units) to the subject’s right bulbospongiosus, anterior to the hymeneal ring. This is accomplished by injecting at about the 7 o’clock position (with the front of the patient facing the 12 o’clock position) at about 45° laterally and about 45° posteriorly (towards the hip) and at a depth of about 5 mm from the outer the surface of the skin.
  • the same syringe is then used to inject a further 0.2 mL of DYSPORT® (about 8 units) to the subject’s right pubococcygeous, anterior to the hymeneal ring, by injecting at the same position but at a depth of about 10 mm from the outer surface of the skin.
  • the same syringe is then used to inject 0.2 mL of DYSPORT® (about 8 units) to the subject’s right bulbospongiosus muscle, posterior to the hymeneal ring. This is accomplished by injecting at about the 5 o’clock position at about 45° laterally and about 45° posteriorly (towards the hip) and at a depth of about 5 mm from the outer the surface of the skin.
  • the same syringe is then used to inject the final 0.2 mL of DYSPORT® (about 8 units) to the subject’s right pubococcygeous muscle, posterior to the hymeneal ring, by injecting at the same position but at a depth of about 10 mm from the outer surface of the skin.
  • the third syringe containing 0.9 mL of DYSPORT® (as reconstituted according to Example 1) is used to inject 0.45 mL of DYSPORT® (about 18 units) to the subject’s superficial and deep transverse perineal muscles anterior to the hymeneal ring.
  • the same syringe is then used to inject the final 0.45 mL of DYSPORT® (about 18 units) to the superficial and deep transverse perineal muscles, anterior to the hymeneal ring, by injecting at the same position but at a depth of about 10 mm from the outer surface of the skin (both left and right, superficial and deep transverse perineal muscles are administered to with this injection).
  • DYSPORT® about 18 units
  • the injection sites are depicted in Figure 1. A total of approximately 500 units of DYSPORT ® is administered to the subject.
  • a 36 year old woman with PVD presents with symptom duration of 14 months and a baseline score of 6 on the NRS scale when tested with the 0.75 inch dilator - the size that provokes the maximum tolerated pain (dilator maximum tested size, DMTS). She receives a course of DYSPORT ® injections according to Example 2. Within 6 weeks her pain perception as recorded on the NRS scale drops to 4 using the baseline DMTS (0.75 inches).
  • the treatment is repeated 12 weeks later and three months later the patient reports no return of PVD symptoms.
  • Example 4 Use of DYSPORT ® to treat vulvodynia
  • a 23 year old woman with vuvlodynia presents with symptom duration of 8 months and a baseline score of 9 on the NRS scale when tested with the 0.5 inch dilator (DMTS). She receives a course of DYSPORT ® injections according to Example 2. Within 6 weeks her pain perception as recorded on the NRS scale drops to 6 using the baseline DMTS (0.5 inches).
  • DMTS 0.5 inch dilator
  • Example 5 Use of DYSPQRT ® to treat vestibulodynia
  • a 42 year old woman with vestibulodynia presents with symptom duration of 3 years and a baseline score of 6 on the NRS scale when tested with the 0.5 inch dilator (DMTS) and has bilateral provoked pain at the posterior vestibule on a cotton-bud test, with pain at positions 5, 6 and 7 o’clock. She receives a course of DYSPORT ® injections according to Example 2. Within 6 weeks the DMTS increases from the 0.5 inch dilator to the 0.75 inch dilator and her pain perception as recorded on the NRS scale drops to 4 using the baseline DMTS (0.5 inches). Thus, her compositie score (combination of pain perception measured by NRS and the DMTS) significantly improves.
  • the treatment is repeated 24 weeks later and four months later the patient reports no return of vestibulodynia symptoms.
  • a 30 year old woman with PVD presents with symptom duration of 2 years and a baseline score of 8 on the NRS scale when tested with the 0.75 inch dilator (DMTS). She receives a course of DYSPORT ® injections according to Example 2. Within 6 weeks her mean CGI (as assessed by her attending physician) significandy improves.
  • the treatment is repeated twice at 12 week intervals and four months after the last treatment the patient reports no return of PVD symptoms.
  • Example 7 Use of DYSPORT ® to treat PVD
  • a 38 year old woman with PVD presents with symptom duration of 10 months and a baseline score of 5 on the NRS scale when tested with the 0.5 inch dilator (DMTS). She receives a course of DYSPORT ® injections according to Example 2. Within 6 weeks her mean PGG-C (as assessed by the patient) significantly improves.
  • Example 8 Use of DYSPQRT ® to treat vestibulodynia
  • a 19 year old woman with vestibulodynia presents with symptom duration of 11 months and a baseline score of 10 on the NRS scale when tested with the 0.75 inch dilator (DMTS). She receives a course of DYSPORT ® injections according to Example 2. Within 6 weeks her mean PGG-S (as assessed by the patient) significantly improves.
  • the treatment is repeated twice at 12 week intervals and four months after the last treatment the patient reports no return of vestibulodynia symptoms.

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Abstract

L'invention concerne une méthode de traitement d'un ou de plusieurs symptômes de vulvodynie chez un sujet, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace de neurotoxine botulique. L'invention concerne également une composition destinée à être utilisée dans le traitement d'un ou de plusieurs symptômes de vulvodynie chez un sujet comprenant une neurotoxine botulique. Un système informatique est programmé pour recevoir des informations relatives à la réponse d'un sujet à l'administration de neurotoxine botulique, pour mémoriser cette réponse dans une base de données et pour transmettre la réponse à un médecin. Un support d'enregistrement lisible par ordinateur non transitoire mémorise des instructions qui, lorsqu'elles sont exécutées par un système informatique, amènent le système informatique à effectuer les étapes susmentionnées. L'invention concerne un dispositif intravaginal destiné à être utilisé dans le traitement d'un ou de plusieurs symptômes de vulvodynie, le dispositif étant configuré pour administrer une neurotoxine botulique à un sujet ayant besoin d'un tel traitement.
PCT/EP2019/066108 2018-06-18 2019-06-18 Injection intramusculaire de toxine botulique pour le traitement de la vulvodynie Ceased WO2019243376A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11286473B2 (en) * 2016-07-08 2022-03-29 Children's Medical Center Corporation Botulinum neurotoxin and its derivatives

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006204A1 (fr) 1990-09-28 1992-04-16 Ixsys, Inc. Banques de recepteurs heteromeres a expression en surface
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
WO2002008268A2 (fr) 2000-07-21 2002-01-31 Allergan, Inc. Motif a base de leucine et neurotoxines clostridiales
WO2006027207A1 (fr) 2004-09-06 2006-03-16 Toxogen Gmbh Proteine de transport pour l'introduction de composes chimiques dans des cellules nerveuses
WO2006114308A2 (fr) 2005-04-26 2006-11-02 Toxogen Gmbh Porteur destine a cibler des cellules nerveuses
WO2010120766A1 (fr) 2009-04-14 2010-10-21 Mcw Research Foundation, Inc. Neurotoxine botulinique remaniée
US8071110B2 (en) 1999-08-25 2011-12-06 Allergan, Inc. Activatable clostridial toxins
US20110318385A1 (en) 2010-06-23 2011-12-29 Wisconsin Alumni Research Foundation Engineered botulinum neurotoxin c1 with selective substrate specificity
US20170105784A1 (en) 2015-10-16 2017-04-20 Medtronic, Inc. Therapy to treat pelvic floor dysfunction and/or pain
WO2018023027A1 (fr) 2016-07-28 2018-02-01 Lumileds Llc Boîtier de dispositif électroluminescent à revêtement latéral réfléchissant

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5223409A (en) 1988-09-02 1993-06-29 Protein Engineering Corp. Directed evolution of novel binding proteins
WO1992006204A1 (fr) 1990-09-28 1992-04-16 Ixsys, Inc. Banques de recepteurs heteromeres a expression en surface
US8071110B2 (en) 1999-08-25 2011-12-06 Allergan, Inc. Activatable clostridial toxins
WO2002008268A2 (fr) 2000-07-21 2002-01-31 Allergan, Inc. Motif a base de leucine et neurotoxines clostridiales
WO2006027207A1 (fr) 2004-09-06 2006-03-16 Toxogen Gmbh Proteine de transport pour l'introduction de composes chimiques dans des cellules nerveuses
WO2006114308A2 (fr) 2005-04-26 2006-11-02 Toxogen Gmbh Porteur destine a cibler des cellules nerveuses
WO2010120766A1 (fr) 2009-04-14 2010-10-21 Mcw Research Foundation, Inc. Neurotoxine botulinique remaniée
US20110318385A1 (en) 2010-06-23 2011-12-29 Wisconsin Alumni Research Foundation Engineered botulinum neurotoxin c1 with selective substrate specificity
US20170105784A1 (en) 2015-10-16 2017-04-20 Medtronic, Inc. Therapy to treat pelvic floor dysfunction and/or pain
WO2018023027A1 (fr) 2016-07-28 2018-02-01 Lumileds Llc Boîtier de dispositif électroluminescent à revêtement latéral réfléchissant

Non-Patent Citations (49)

* Cited by examiner, † Cited by third party
Title
"GenBank", Database accession no. OT022244.1
"NCBI", Database accession no. WP_034687872.1
ALTSCHUL ET AL., BULL. MATH. BIO., vol. 48, 1986, pages 603 - 16
ANONYMOUS: "Long-term assessment of effectiveness and quality of life of OnabotulinumtoxinA injections in provoked vestibulodynia - Pelletier - 2016 - Journal of the European Academy of Dermatology and Venereology - Wiley Online Library", 22 October 2015 (2015-10-22), XP055624576, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/epdf/10.1111/jdv.13437> [retrieved on 20190920] *
BOWIESAUER, PROC. NATL. ACAD. SCI. USA, vol. 86, 1989, pages 2152 - 6
C. E. LAWRENCE ET AL.: "Detecting Subtle Sequence Signals: A Gibbs Sampling Strategy for Multiple Alignment", SCIENCE, vol. 262, no. 5131, 1993, pages 208 - 214, XP001152872, DOI: doi:10.1126/science.8211139
CHUNG ET AL., PROC. NATL. ACAD. SCI. USA, vol. 90, 1993, pages 10145 - 9
CHUNG ET AL., SCIENCE, vol. 259, 1993, pages 806 - 9
CLEELANDRYAN, ANN. ACAD. MED., vol. 23, 1994, pages 129 - 138
CUNNINGHAMWELLS, SCIENCE, vol. 244, 1989, pages 1081 - 5
DARGIE ET AL., PAIN, vol. 157, 2016, pages 2672 - 2686
DE VOS ET AL., SCIENCE, vol. 255, 1992, pages 306 - 12
DERBYSHIRE ET AL., GENE, vol. 46, 1986, pages 145
DIOMANDE ET AL., ARCH. GYNECOL. OBSTET., vol. 299, no. 4, 2019, pages 993 - 1000
DYKSTRA DENNIS D ET AL: "Botulinum toxin type A for the treatment of provoked vestibulodynia: an open-label, pilot study.", THE JOURNAL OF REPRODUCTIVE MEDICINE JUN 2006, vol. 51, no. 6, June 2006 (2006-06-01), pages 467 - 470, XP009516176, ISSN: 0024-7758 *
ELLMAN ET AL., METHODS ENZYMOL., vol. 202, 1991, pages 301
ERIC DEPIEREUXERNEST FEYTMANS: "Match-Box: A Fundamentally New Algorithm for the Simultaneous Alignment of Several Protein Sequences", CABIOS, vol. 8, no. 5, 1992, pages 501 - 509
FALSETTA ET AL., BRITISH JOURNAL OF OBSTETRICS AND GYNAEGOLOGY, vol. 124, 2017, pages 210 - 218
GERALD K: "Cell and Molecular Biology", 2002, JOHN WILRY & SONS, INC
GOLDSTEIN ET AL., J. SEX. MED., vol. 13, 2016, pages 575 - 590
HARLOW ET AL., JOURNAL OF THE AMERICAN MEDICAL WOMEN'S ASSOCIATION, vol. 58, 2003, pages 82 - 88
HAWKER ET AL., ARTHRITIS CARE RES., vol. 63, no. S11, 2011, pages S240 - S252
HENIKOFFHENIKOFF, PROC. NAD. ACAD. SCI. USA, vol. 89, 1992, pages 10915 - 19
HUNG-JEN WANG ET AL: "Neurotoxin Use for Voiding Dysfunction", CURRENT BLADDER DYSFUNCTION REPORTS, CURRENT SCIENCE INC, NEW YORK, vol. 6, no. 3, 7 June 2011 (2011-06-07), pages 182 - 189, XP019941232, ISSN: 1931-7220, DOI: 10.1007/S11884-011-0096-5 *
IVO VAN WALLE ET AL.: "Align-M - A New Algorithm for Multiple Alignment of Highly Divergent Sequences", BIOINFORMATICS, vol. 20, no. 9, 2004, pages 1428 - 1435
JARVIS SHERIN K ET AL: "Pilot study of botulinum toxin type A in the treatment of chronic pelvic pain associated with spasm of the levator ani muscles.", THE AUSTRALIAN & NEW ZEALAND JOURNAL OF OBSTETRICS & GYNAECOLOGY FEB 2004, vol. 44, no. 1, February 2004 (2004-02-01), pages 46 - 50, XP002794435, ISSN: 0004-8666 *
JULIE D. THOMPSON ET AL.: "CLUSTAL W: Improving the Sensitivity of Progressive Multiple Sequence Alignment Through Sequence Weighting", POSITION- SPECIFIC GAP PENALTIES AND WEIGHT MATRIX CHOICE, vol. 22, no. 22, XP002956304
KARP BARBARA ILLOWSKY ET AL: "Methodological approaches to botulinum toxin for the treatment of chronic pelvic pain, vaginismus, and vulvar pain disorders", INTERNATIONAL UROGYNECOLOGY JOURNAL, SPRINGER INTERNATIONAL, LONDON, GB, vol. 30, no. 7, 7 January 2019 (2019-01-07), pages 1071 - 1081, XP036816006, ISSN: 0937-3462, [retrieved on 20190107], DOI: 10.1007/S00192-018-3831-Z *
KOIDE ET AL., BIOCHEM., vol. 33, 1994, pages 7470 - 6
LOWMAN ET AL., BIOCHEM., vol. 30, 1991, pages 10832 - 7
MELZACK PAIN, vol. 30, 1990, pages 191 - 197
NANCY PHILLIPS ET AL: "Relationship between nongenital tender point tenderness and intravaginal muscle pain intensity: ratings in women with provoked vestibulodynia and implications for treatment", AMERICAN JOURNAL OF OBSTETRICS & GYNECOLOGY, vol. 215, no. 6, 1 December 2016 (2016-12-01), US, pages 751.e1 - 751.e5, XP055624586, ISSN: 0002-9378, DOI: 10.1016/j.ajog.2016.06.047 *
NER ET AL., DNA, vol. 7, 1988, pages 127
NUCLEIC ACIDS RESEARCH, 1994, pages 4673 - 4680
OSAMU GOTOH: "Significant Improvement in Accuracy of Multiple Protein. Sequence Alignments by Iterative Refinement as Assessed by Reference to Structural Alignments", J. MOL. BIOL., vol. 264, no. 4, 1996, pages 823 - 838
PACIK, P, FEMALE PELVIC MEDICINE & RECONSTRUCTIVE SURGERY, vol. 19, 2013, pages S45 - S195
PELLETIER, BR. J. DERMATOLOGY, vol. 164, 2011, pages 617 - 622
PETERSEN ET AL., J. SEX. MED., vol. 6, 2009, pages 2523 - 2537
PHYSICIAN'S GLOBAL ASSESSMENT (PGA) OF RESPONSE BUSNER AND TARGUM PSYCHIATRY, vol. 4, no. 7, 2007, pages 28 - 37
PUKALL ET AL., J. SEX MED., vol. 13, 2016, pages 291 - 304
REIDHAAR-OLSONSAUER, SCIENCE, vol. 241, 1988, pages 53 - 7
REISSING ET AL., PSYCHOSOM. OBSTET. GYNAECOL., vol. 26, 2005, pages 107 - 113
ROBERTSON ET AL., J. AM. CHEM. SOC., vol. 113, 1991, pages 2722
ROSEN ET AL., J. SEX MARITAL THER, vol. 26, no. 2, 2000, pages 191 - 208
SMITH ET AL., J. MOL. BIOL., vol. 224, 1992, pages 899 - 904
TURCATTI ET AL., J. BIOL. CHEM., vol. 271, 1996, pages 19991 - 8
WLODAVER ET AL., FEBS LETT, vol. 309, 1992, pages 59 - 64
WYNNRICHARDS, PROTEIN SCI, vol. 2, 1993, pages 395 - 403
YOON ET AL., INTERNATIONAL JOURNAL OF IMPOTENCE RESEARCH, vol. 19, 2007, pages 84 - 87

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US11286473B2 (en) * 2016-07-08 2022-03-29 Children's Medical Center Corporation Botulinum neurotoxin and its derivatives

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