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WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T

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WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/072853 Al 21 May 2015 (21.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 45/06 (2006.01) A61K 31/5513 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/045 (2006.01) A61K 31/5517 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/522 (2006.01) A61P 31/22 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, A61K 31/551 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, PCT/NL20 14/050781 MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 13 November 2014 (13.1 1.2014) SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, 61/903,433 13 November 2013 (13. 11.2013) US TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (71) Applicant: RJG DEVELOPMENTS B.V. [NL/NL]; DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, Keizerweg 25, NL-7548 PX Enschede (NL). LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor: GAIJMANS, Reinoud Jaap; Keizerweg 25, GW, KM, ML, MR, NE, SN, TD, TG). NL-7548 PX Enschede (NL). Published: (74) Agent: JANSEN, CM.; V.O., Johan de Wittlaan 7, NL- 25 17 JR Den Haag (NL). — with international search report (Art. 21(3)) © o (54) Title: TREATMENT OF HERPES VIRUS INFECTION OUTBREAKS (57) Abstract: The invention provides means and methods for preventing or alleviating symptoms of a Herpes simplex virus infec - tion, using compounds that influence brain function and/or psychological state. Kits of parts against Herpes outbreaks are also here with provided. Title: Treatment of Herpes virus infection outbreaks The invention relates to the fields of medicine, pharmacy and biology. More particular, the invention relates to treatment and prevention of Herpes virus outbreaks. Herpes simplex infections are one of the most prevalent recurrent and chronic infections in humans. Herpes simplex is a member of the Herpesviridae. There are two types of Herpes simplex virus infection, called Herpes simplex virus type 1 (HSV-1) and Herpes simplex virus type 2 (HSV-2). The most common form of infection is oral herpes. Oral herpes, the visible symptoms of which are colloquially called cold sores or fever blisters, is an infection of the face or mouth. Most cold sores are caused by HSV-1. Herpes infection of the mouth is typically referred to as Herpes labialis. Genital herpes (Herpes genitalis) is often caused by HSV-2 but is also caused by HSV-1. It is the second most common form of herpes. Other disorders such as herpetic whitlow, herpes gladiatorum, ocular herpes, cerebral herpes infection encephalitis, Mollaret's meningitis, neonatal herpes, and possibly Bell's palsy are all caused by herpes simplex viruses. Herpes simplex infections are very common; rates of HSV infection are between 65% and 90% worldwide. In the US, 57.7% of the population is infected with HSV-1 and 16.2% is infected with HSV-2. Following an initial exposure to the Herpes simplex virus, the host develops antibodies which can maintain the virus in a latent state. A herpes infection thus typically remains dormant for some time, with no clinical signs. Such periods are alternated with episodes of clinical manifestations, which typically involve the occurrence of herpes lesions. The lesions initially appear as an area of irritation and edema, which develop into one or more small vesicles within a few hours. The vesicles ripe and subsequently rupture within one to three days to form shallow ulcerations, which grow in time to large ulcerations and may aggregate with neighboring ulcerations to one large ulcer. In the subsequent days (7-14) these ulcerations heal again. The rupturing vesicles release highly contagious fluid which may cause secondary infections and/or infect others. Currently a Herpes infection cannot be cured; once present, herpes virus cannot be eradicated from the body. Treatments aim at preventing or reducing clinical symptoms. For instance, antivirals can reduce the frequency, duration and severity of outbreaks. Well known antivirals prescribed against herpes include acyclovir, penciclovir, famciclovir and valaciclovir. Pain and fever can be suppressed with analgesics or anesthetics such as for instance ibuprofen, acetaminophen, prilocaine, lidocaine, benzocaine or tetracaine. Another kind of drug which is approved by the United States Food and Drug Administration (FDA) for herpes labialis is the saturated fatty alcohol docosanol. Further medications include lysine, zinc oxide or zinc sulfate. However, the effects of these medicaments on Herpes outbreaks are limited. If taken at a sufficient early stage, preferably before lesions become apparent, a reduction of the duration and severity of outbreaks can be achieved but this effect is often moderate. There remains, therefore, a need for further herpes therapies. It is an object of the present invention to provide additional means and methods for preventing or alleviating symptoms of Herpes simplex virus infections. It is a further object to provide alternative and/or improved medicaments against Herpes simplex virus. SUMMARY OF THE INVENTION The invention provides means and methods for preventing or alleviating symptoms of a Herpes simplex virus. In particular, methods are provided for preventing or alleviating symptoms of a Herpes simplex virus infection, the methods comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state. Preferably, said at least one compound comprises at least one anxiolytic compound and/or at least one sedative -hypnotic compound. In a preferred embodiment, said at least one compound is administered prophylactically to the subject before Herpes lesions are present on said subject. Alternatively, said at least one compound is administered to the subject within 0- 24 hours, preferably within 0-4 hours, before the prodromal phase. In another alternative embodiment, said at least one compound is administered to the subject in the prodromal and/or inflammation phase. In yet another embodiment, said at least one compound is administered to the subject in the pre-sore or open lesion phase. In a preferred embodiment, the compound that influences brain function and/or psychological state is either administered as a single dose or as a multiple dose up to the open lesion phase, wherein the concentration of said compound in the multiple doses is preferably a factor 1.5-50, preferably 2-10, lower than the concentration of said compound in said single dose. In one aspect, a method according to the invention is provided wherein said subject is suffering from, or at risk of suffering from, a Herpes simplex outbreak as a result of ultraviolet ray exposure, heat exposure, fever, dehydration, local skin trauma, a hormonal change or menstruation. In another aspect, a method according to the invention is provided wherein said Herpes simplex virus is Herpes simplex labialis, preferably HSV-1. Further provided is a method according to the invention, comprising administering to the subject at least two compounds selected from anxiolytic compounds and sedative -hypnotic compounds. Hence, according to this embodiment said subject is provided with at least two anxiolytic compounds, or with at least two sedative-hypnotic compounds, or with at least one anxiolytic compound and at least one sedative -hypnotic compound. In one aspect, at least one compound according to the invention that influences brain function and/or psychological state is administered sublabially or sublingually, preferably sublabially, to the subject. Alternatively, said at least one compound is administered topically to the subject. In one embodiment, a method according to the invention is provided wherein the subject is additionally provided with at least one antiviral compound against Herpes simplex. Said at least one antiviral compound is preferably selected from the group consisting of acyclovir, penciclovir, famciclovir, valaciclovir, docosanol, benzylammonium chloride and any combination thereof. In one aspect, said subject is provided with at least one anxiolytic compound or sedative-hypnotic compound selected from the group consisting of benzodiazepine compounds, chloralhydrates, azapirones, buspirone, tandospirone, gepirone, hydroxyzines, meprobamates, monoamine oxidase inhibitors, barbiturates, pregabalin, venlafaxine, carbamates, pyrazolopyridines, α2δ VDCC Blockers, 5-HTl A Agonists, H I Antagonists, CRHl Antagonists, NK2 Antagonists, MCH1 antagonists, mGluR2/3 Agonists, mGluR5 NAMs, TSPO agonists, ol agonists and pharmaceutically acceptable salts, esters, hydrates, derivatives and solvates of any of these compounds. In a preferred embodiment, said subject is provided with at least one benzodiazepine compound selected from the group consisting of alprazolam, tofisopam, bromazepam, 2-keto compounds (chlorodiazepoxides, clorazepates, diazepam, flurazepam, halazepam, prazepam and others), 3-hydroxy compounds (lorazepam, lormetazepam, oxazepam, temazepam and others), 7-nitro compounds (clonazepam, flunitrazepam, nimetazepam, nitrazepam and others), triazolo compounds (adinazolam, estazolam, triazolam and others), imidazo compounds (climazolam, loprazolam, midazolam and others), clobazam, etizolam, brotizolam, Zolpidem, zopiclon and pharmaceutically acceptable salts, esters, hydrates, derivatives and solvates of any of these compounds.
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