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

Home , Antalarmin, Benzoctamine, Bretazenil, Cartazolate, Climazolam, Emapunil

(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.

In yet another aspect, said subject is provided with at least one anxiolytic compound or sedative-hypnotic compound selected from the group consisting of bretazenil, camazepam, Chlordiazepoxide, Clotiazepam, Cloxazolam, Ethyl Loflazepate, Fludiazepam, Imidazenil, Ketazolam, Medazepam, Nordazepam, Pinazepam, Emylcamate, Mebutamate, Meprobamate (Carisoprodol, Tybamate), Phenprobamate, Procymate, Abecarnil, Adipiplon, Alpidem, CGS-8216, CGS-9896, CGS- 13767, CGS-20625, Divaplon, ELB-139, Fasiplon, GBLD-345, Gedocarnil, L- 838,417, NS-2664, NS-2710, Ocinaplon, Pagoclone, Panadiplon, Pipequaline, RWJ- 51204, SB-205,384, SL-651,498, Taniplon, TP-003, TP- 13, TPA-023, Y-23684, ZK- 93423, Cartazolate, Etazolate, ICI- 190,622, Tracazolate, Chlormezanone, Ethanol, Etifoxine, Kavalactones (Kava Kava), Gabapentin, Pregabalin, Azapirones, Flesinoxan, Naluzotan, Oxaflozane, Diphenylmethanes, Captodiame, Hydroxyzine, Brompheniramine, Chlorpheniramine, Pheniramine, Antalarmin, CP- 154, 526, Pexacerfont, Pivagabine, GR-159,897, Saredutant, ATC-0175, SNAP-94847, Eglumegad, Fenobam, DAA-1097, DAA-1106, Emapunil, FGIN-127, FGIN-143, Afobazole, Opipramol, Benzoctamine, Carbetocin, Demoxytocin, Mephenoxalone, Mepiprazole, Oxanamide, Oxytocin, Promoxolane, Tofisopam, Trimetozine, WAY- 267,464, L-tryptophan, 5-hydroxytryptophan (5-HTP), L-tyrosine, L-phenylalanine, L-arginine, L-theanine, S-Adenosylmethionine (SAM-e), Ginkgo biloba, Rhodiola, Ashwagandha (Withania somnifera), GABA, N-Acetyl Cysteine (NAC), vitamin B6, vitamin B12, vitamin D, magnesium, zinc, omega-3 fatty acids, inositol, DHEA, folic acid, Bacopa monnieri (Brahmi), Lactuca virosa (Opium Lettuce), Rhodiola rosea (Arctic Weed/Golden Root), Passiflora, Piper methysticum (Kava), Sceletium tortuosum (Kanna), Scutellaria spp. (Skullcap), Scutellaria lateriflora, Salvia splendens , Coriandrum sativum (Coriander), Myristica (Nutmeg), Salvia elegans (Pineapple Sage), Inositol, myo-inositol, fluvoxamine, Cannabidiol, Picamilon, Chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl) Melatonin, BNC210, CL-218,872, L-838,417, SL-651,498 and pharmaceutically acceptable salts, esters, hydrates, derivatives and solvates of any of these compounds.

In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises alprazolam with a total dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. In one embodiment said total dose is 0.25-0.75 mg active compound, preferably about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises lormetazepam with a total dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. In one embodiment said total dose is 0.25-0.75 mg active compound, preferably about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises bromazepam with a total dose of 0.01 - 50 mg active compound, preferably 0.05-20 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises chlordiazepoxide with a total dose of 0.01 - 200 mg active compound, preferably 0.1-50 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises clobazam with a total dose of 0.01 - 200 mg active compound, preferably 0.3-50 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises clorazepine acid with a total dose of 0.01 - 200 mg active compound, preferably 0.3-80 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises diazepam with a total dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20 mg active compound. In one embodiment said total dose is 1.0-10.0 mg active compound, preferably about 2.5 mg or about 5 mg or about 7.5 mg or about 10 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises lorazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises oxazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0-10 mg active compound. In one preferred embodiment, said total dose is about 10 mg oxazepam or about 5 mg oxazepam. In another aspect the invention provides a method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state, wherein said at least one compound comprises at least one anxiolytic compound or sedative-hypnotic compound and wherein the anxiolytic or sedative -hypnotic compound comprises prazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound.

The present invention provides a novel use for compounds that influence brain function and/or psychological state. Besides uses in brain disorders or psychological disorders, the present inventor has found that they are useful for combating symptoms of Herpes infections. Further provided is therefore a compound that influences brain function and/or psychological state for use in a method for preventing or alleviating symptoms of a Herpes simplex virus infection. Preferably, said at least one compound comprises at least one anxiolytic compound and/or at least one sedative-hypnotic compound.

Kits of parts suitable for preventing or alleviating symptoms of a Herpes simplex virus infection are also provided. Yet another aspect therefore provides a kit of parts comprising: - at least one compound that influences brain function and/or psychological state; and - at least one antiviral compound against Herpes simplex. Said at least one compound preferably comprises at least one anxiolytic compound and/or at least one sedative -hypnotic compound. In one preferred embodiment, the kit of parts comprises at least two compounds selected from anxiolytic compounds and sedative -hypnotic compounds. Hence, according to this embodiment said kit of parts comprises at least two anxiolytic compounds, or at least two sedative-hypnotic compounds, or at least one anxiolytic compound and at least one sedative -hypnotic compound. The at least one antiviral compound of a kit of parts according to the invention is preferably selected from the group consisting of acyclovir, penciclovir, famciclovir, valaciclovir, docosanol and any combination thereof.

In another aspect, a kit of parts according to the invention comprises 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-HT1A Agonists, H I Antagonists, CRH1 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 further preferred embodiment, a kit of parts according to the invention comprises at least one benzodiazepine compound selected from the group consisting of alprazolam, tofisopam, bromazepam, 2-keto compounds (chlorodiazepoxides, clorazepates, diazepam, ilurazepam, 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.

In yet another preferred embodiment a kit of parts according to the invention comprises at least one anxiolytic compound or sedative -hypnotic compound selected from the group consisting of bretazenil, camazepam, Chlordiazepoxide, Clotiazepam, Cloxazolam, Ethyl Loflazepate, Fludiazepam, Imidazenil, Ketazolam, Medazepam, Nordazepam, Pinazepam, Emylcamate, Mebutamate, Meprobamate (Carisoprodol, Tybamate), Phenprobamate, Procymate, Abecarnil, Adipiplon, Alpidem, CGS-8216, CGS-9896, CGS-13767, CGS-20625, Divaplon, ELB-139, Fasiplon, GBLD-345, Gedocarnil, L-838,417, NS-2664, NS- 2710, Ocinaplon, Pagoclone, Panadiplon, Pipequaline, RWJ-51204, SB-205,384, SL- 651,498, Taniplon, TP-003, TP-13, TPA-023, Y-23684, ZK-93423, Cartazolate, Etazolate, ICI- 190,622, Tracazolate, Chlormezanone, Ethanol, Etifoxine, Kavalactones (Kava Kava), Gabapentin, Pregabalin, Azapirones, Flesinoxan, Naluzotan, Oxaflozane, Diphenylmethanes, Captodiame, Hydroxyzine, Brompheniramine, Chlorpheniramine, Pheniramine, Antalarmin, CP- 154, 526, Pexacerfont, Pivagabine, GR-159,897, Saredutant, ATC-0175, SNAP-94847, Eglumegad, Fenobam, DAA-1097, DAA-1106, Emapunil, FGIN-127, FGIN-143, Afobazole, Opipramol, Benzoctamine, Carbetocin, Demoxytocin, Mephenoxalone, Mepiprazole, Oxanamide, Oxytocin, Promoxolane, Tofisopam, Trimetozine, WAY- 267,464, L-tryptophan, 5-hydroxytryptophan (5-HTP), L-tyrosine, L-phenylalanine, L-arginine, L-theanine, S-Adenosylmethionine (SAM-e), Ginkgo biloba, Rhodiola, Ashwagandha (Withania somnifera), GABA, N-Acetyl Cysteine (NAC), vitamin B6, vitamin B12, vitamin D, magnesium, zinc, omega-3 fatty acids, inositol, DHEA, folic acid, Bacopa monnieri (Brahmi), Lactuca virosa (Opium Lettuce), Rhodiola rosea (Arctic Weed/Golden Root), Passiflora, Piper methysticum (Kava), Sceletium tortuosum (Kanna), Scutellaria spp. (Skullcap), Scutellaria lateriflora, Salvia splendens , Coriandrum sativum (Coriander), Myristica (Nutmeg), Salvia elegans (Pineapple Sage), Inositol, myo-inositol, fluvoxamine, Cannabidiol, Picamilon, Chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl) Melatonin, BNC210, CL-218,872, L-838,417, SL-651,498 and pharmaceutically acceptable salts, esters, hydrates, derivatives and solvates of any of these compounds.

In a further preferred embodiment, a kit of parts according to the invention comprises alprazolam in at least one unit dose of 0.001 - 5 mg active compound, preferably of 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. In one embodiment a kit of parts according to the invention comprises alprazolam in at least one unit dose of 0.25-0.75 mg active compound, preferably in at least one unit dose of about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises lormetazepam in at least one unit dose of 0.001 - 5 mg active compound, preferably of 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. In one embodiment a kit of parts according to the invention comprises lormetazepam in at least one unit dose of 0.25-0.75 mg active compound, preferably in at least one unit dose of about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises bromazepam in at least one unit dose of 0.01 - 50 mg active compound, preferably 0.05-20 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises chloordiazepoxide in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-50 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises clobazam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.3-50 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises clorazepine acid in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.3-80 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises diazepam in at least one unit dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20 mg active compound. In one embodiment a kit of parts according to the invention comprises diazepam in at least one unit dose of 1.0-10 mg active compound, preferably in at least one unit dose of about 2.5 mg or about 5 mg or about 7.5 mg or about 10 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises lorazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises oxazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0-10 mg active compound. In one embodiment, said kit of parts comprises oxazepam in at least one unit dose of about 5 mg active compound. In another embodiment, said kit of parts comprises oxazepam in at least two unit dosages, wherein each unit dosage contains about 5 mg active compound. In a further preferred embodiment, a kit of parts according to the invention comprises prazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound.

A kit of parts according to the present invention is particularly useful for preventing or alleviating symptoms of a Herpes simplex virus infection. Further provided is, therefore, a use of a kit of parts according to the invention for preventing or alleviating symptoms of a Herpes simplex virus infection.

DETAILED DESCRIPTION The present inventor has surprisingly found that outbreaks of Herpes virus infections can be suppressed or even prevented when a subject is provided with a compound that influences brain function and/or psychological state. Preferred (but non-limiting) examples of such compounds are anxiolytic compounds and sedative- hypnotic compounds. Such compounds that influence brain function and/or psychological state are well known in the art, but their use against Herpes outbreaks has not been described before. The insight according to the present invention is, therefore, surprising, all the mere since Herpes infection is not a disease affecting brain function or psychological state.

As used herein, a symptom of a Herpes simplex virus infection means any clinical manifestation of a herpes simplex infection during an active (non-dormant) stage. Non-limiting examples of such symptoms are tingling, itching, reddening and swelling of the skin, pain, and the appearance of lesions such as papules or vesicles (follicles, blisters) or ulcers on the skin.

As used herein, the term "lesion" is used to refer to skin lesions, which encompass papules, vesicles, follicles, blisters and ulcers. A herpes outbreak is defined herein as an episode wherein the latent stage of the virus infection ends and clinical manifestations of a herpes infection become apparent. A herpes outbreak thus typically begins with the prodromal and inflammation stage and ends with the healing or post-scab stage.

According to the present invention, compounds that influence brain function and/or psychological state can suppress Herpes outbreaks, meaning that at least one symptom of a Herpes outbreak, such as the onset and growth of lesions, the swelling of the infected area, the growing of ulcerations and/or the angulations of ulcers, is reduced. Additionally, or alternatively, the duration of the outbreak is shortened. Moreover, after treatment with a method according to the present invention, the inventor has experienced that subsequent outbreaks are typically less severe and they appear to occur less often. Preferably, the occurrence of lesions is reduced, secondary infections are suppressed and/or the healing, if at all required, is shorted to only a few days. Suppressed lesions do not give distasteful appearances of the infected area. Also if lesions do not or hardly develop, they do not ripe and do not open. In that way the chance of infecting other people is strongly reduced.

A Herpes simplex infection typically has the following stages: Latent (weeks to months incident-free): The remission period; After initial infection, the viruses move to sensory nerve ganglia (Trigeminal ganglion), where they reside as lifelong, latent viruses. Asymptomatic shedding of contagious virus particles can occur during this stage. Prodromal and Inflammation (0-24 h): After an incident the recurrence of VHS is started. Virus begins reproducing and infecting cells at the end of the nerve. Symptoms typically begin with tingling (itching) of the skin. The healthy cells react to the invasion by reddening and swelling of the skin around the infected site. This stage can last from a single hour to a few days.. Pre-sore (4-24 h): This stage is defined by the appearance of tiny, hard, inflamed papules and vesicles that may itch and are painfully sensitive to touch. Pre-sore (day 2-3): In time, these fluid-filled vesicles (blisters) grow in numbers and in size and they can start to form a cluster on the lip (labial) tissue, the area between the lip and skin (vermilion border), and can occur on the nose, chin, and cheeks. Open lesion (day 3-4): This is the most painful and contagious of the stages. All the tiny vesicles break open and merge to create one big, open, weeping ulcer. Fluids are slowly discharged from blood vessels and inflamed tissue. This watery discharge is teeming with active viral particles and is highly contagious. Depending on the severity, one may develop a fever and swollen lymph glands under the jaw. Crusting (day 4-8): A honey/golden crust starts to form from the syrupy extrudate. This yellowish or brown crust or scab is not made of active virus but from blood serum containing useful proteins such as albumin and globulins. This appears as the healing process begins. The sore is still painful at this stage, but, more painful, however, is the constant cracking of the scab as one moves or stretches their lips, as in smiling or eating. Virus-filled fluid will still ooze out of the sore through any cracks. Healing (day 9-14): New skin begins to form underneath the scab as the virus retreats into latency. A series of scabs will form over the sore (called Meier Complex), each one smaller than the last. During this phase irritation, itching, and some pain are common. Post-scab (12-14 days): A reddish area may linger at the site of viral infection as the destroyed cells are regenerated. Virus shedding can still occur during this stage.

As used herein, the prodromal and inflammation stage is also referred to as the prodromal stage or prodromal phase.

In a preferred embodiment, treatment according to the present invention is started before the prodromal phase, meaning that treatment is started before the first symptoms of an outbreak become apparent. This is for instance done when a subject has experienced conditions known to cause Herpes outbreaks, such as for instance a large exposure to ultraviolet light due to sunbathing, or before the subject experiences such conditions. As shown in the Examples, treatment before a subject is subjected to such conditions reduces or even prevents a Herpes outbreak. One preferred embodiment thus provides a method according to the invention wherein said at least one compound is administered to the subject within 0-24 hours, preferably within 0-4 hours, before the prodromal phase.

When some tingling, itching, reddening or swelling of the skin is already apparent, the prodromal stage has started. This is also a very good starting point for treatment according to the invention, as shown in the Examples. Another preferred embodiment thus provides a method according to the invention wherein said at least one compound is administered to the subject in the prodromal and/or inflammation phase. Preferably, said at least one compound is administered prophylactically to the subject before Herpes lesions are present on said subject. However, even when Herpes lesions are present, a treatment according to the invention is still capable of reducing the symptoms and/or shortening the duration of the herpes outbreak. This is also demonstrated in the Examples. One aspect therefore provides a method according to the invention wherein said at least one compound is administered to the subject in the pre-sore or open lesion phase.

As used herein, a subject is preferably a human subject, such as a human adult or child. In one embodiment, for children the dosages referred to herein are lowered, for instance based on age or body weight, as is customary in the art.

The compound that influences brain function and/or psychological state is either administered as a single dose or as multiple doses. Administration of a single dose is convenient since no dosage schedule needs to be remembered. However, multiple lower dosages decrease the chance of unwanted side-effects. Preferably, when multiple dosages are used, the concentration of the compound that influences brain function and/or psychological state in the multiple doses is a factor 1.5-50, preferably a factor 2-10, lower than the concentration of said compound in a 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. These conditions are well known to cause Herpes outbreaks. It is particularly surprising that a compound influencing brain function or psychological state is capable of counteracting Herpes outbreaks due to these conditions, which have nothing to do with brain function or the psychological state of the subject.

Preferably, a method according to the invention is used in order to counteract Herpes simplex labialis, preferably HSV-1. This is the most common form of Herpes infection in humans.

The compounds according to the invention can be administered to the subject using any suitable route of administration. For instance, the compound is taken orally, for instance in the form of a tablet, capsule or liquid solution. In one preferred embodiment the compound is administered sublabially to the subject; the compound is dissolved under the lip (between the lip and the gingiva) as a way to speed up the effect and to increase the effect as the compound diffuses through the lip skin, in which way it is locally administered. In another embodiment the compound is administered sublingually (under the tongue). For these applications the concentration of the active compound may well be much lower than for oral or systemic administration. A lower concentration reduces the side effects of these compounds. The compound may also be administered effectively as a topical compound, in this way the risk of side effects of these compounds is also considerable reduced as compared to systemic administration. Alternatively, the compound is administered rectally, for instance as a suppository, or systemically, for instance via a subcutaneous or intramuscular or intravenous or intraperitoneal injection.

According to the invention, when a compound that influences brain function or psychological state is used against Herpes outbreaks, a lower concentration of the compound can be used as compared to the usual dosages of these compounds when used for improving brain function or psychological state. This reduces the risk of adverse side effects.

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. These antiviral compounds are well known in the art.

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.

Kits of parts suitable for methods according to the invention for preventing or alleviating symptoms of a Herpes simplex virus infection are also provided. Yet another aspect of the invention therefore provides a kit of parts comprising: - at least one compound that influences brain function and/or psychological state; and - at least one antiviral compound against Herpes simplex. Said at least one compound that influences brain function and/or psychological state preferably comprises at least one anxiolytic compound and/or at least one sedative -hypnotic compound. In one preferred embodiment, the kit of parts comprises at least two compounds selected from anxiolytic compounds and sedative -hypnotic compounds. The antiviral compound of a kit of parts according to the invention is preferably selected from the group consisting of acyclovir, penciclovir, famciclovir, valaciclovir, docosanol and any combination thereof.

An anxiolytic compound is defined as a compound that counteracts anxiety. Anxiolytic compounds typically exhibit tranquillizing effects. A sedative compound is defined as a compound that induces sedation. This means that agitation or irritability is reduced. A hypnotic compound is a compound that is capable of inducing sleep. Many anxiolytic, sedative, and hypnotic compounds are known in the art. Reference is for instance made to current pharmacopoeias and, for instance, to the Dutch "Farmacotherapeutisch Kompas". The use of such compounds for preventing or alleviating symptoms of Herpes simplex infections is, however, not described before the present invention.

In one aspect, the 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, or the subject is provided with a kit of parts according to the invention comprising at least one 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, or the subject is provided with a kit of parts according to the invention comprising at least one of these compounds. In a particularly preferred embodiment, the subject is provided with alprazolam. Preferably, a subject in need of Herpes simplex treatment is provided with alprazolam with a total dose of 0.001 - 5 mg active compound, preferably 0.01- 2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. A kit of parts according to the present invention also preferably comprises alprazolam in at least one unit dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. In one embodiment the subject in need of Herpes simplex treatment is provided with alprazolam with a total dose of 0.25-0.75 mg active compound, preferably with a total dose of about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In one embodiment a kit of parts according to the invention comprises alprazolam in at least one unit dose of 0.25-0.75 mg active compound, preferably with at least one total unit dose of about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In another particularly preferred embodiment, the subject is provided with lormetazepam. Preferably, a subject in need of Herpes simplex treatment is provided with lormetazepam with a total dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. A kit of parts according to the present invention also preferably comprises lormetazepam in at least one unit dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. In one embodiment the subject in need of Herpes simplex treatment is provided with lormetazepam with a total dose of 0.25-0.75 mg active compound, preferably with a total dose of about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In one embodiment a kit of parts according to the invention comprises lormetazepam in at least one unit dose of 0.25-0.75 mg active compound, preferably with at least one total unit dose of about 0.25 mg or about 0.5 mg or about 0.75 mg active compound. In yet another particularly preferred embodiment, the subject is provided with diazepam. Preferably, a subject in need of Herpes simplex treatment is provided with diazepam with a total dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20 mg active compound. A kit of parts according to the present invention also preferably comprises diazepam in at least one unit dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20 mg active compound. In one embodiment the subject in need of Herpes simplex treatment is provided with diazepam with a total dose of 1.0-10 mg active compound, preferably with a total dose of about 2.5 mg or about 5.0 mg or about 7.5 mg or about 10.0 mg active compound. In one embodiment a kit of parts according to the invention comprises diazepam in at least one unit dose of 1.0-10 mg active compound, preferably with at least one total unit dose of about 2.5 mg or about 5.0 mg or about 7.5 mg or about 10.0 mg active compound. In yet another particularly preferred embodiment, the subject is provided with oxazepam. Preferably, a subject in need of Herpes simplex treatment is provided with oxazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0-10 mg active compound. A kit of parts according to the present invention also preferably comprises oxazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0-10 mg active compound. In one embodiment the subject in need of Herpes simplex treatment is provided with oxazepam with a total dose of 1.0-10 mg active compound, preferably with a total dose of about 5.0 mg or about 7.5 mg or about 10.0 mg active compound. In one embodiment a kit of parts according to the invention comprises oxazepam in at least one unit dose of 1.0-10 mg active compound, preferably with at least one total unit dose of about 5.0 mg or about 7.5 mg or about 10.0 mg active compound. Preferably, said kit of parts comprises oxazepam in at least two unit dosages, wherein each unit dosage contains about 5 mg oxazepam.

All of the above mentioned compounds are well known in the art. Again, reference is made to current pharmacopoeias and, for instance, to the Dutch "Farmacotherapeutisch Kompas" and handbooks or general internet information websites such as Wikipedia.

Preferred anxiolytic and/or sedative -hypnotic compounds comprise: • alprazolam with a total dose of 0.001-5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound; • lormetazepam with a total dose of 0.001-5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound; • bromazepam with a total dose of 0.01 - 50 mg active compound, preferably 0.05-20 mg active compound; • chlordiazepoxide with a total total dose of 0.01 - 200 mg active compound, preferably 0.1-50 mg active compound; • clobazam with a total dose of 0.01 - 200 mg active compound, preferably 0.3- 50 mg active compound; · clorazepine acid with a total dose of 0.01 - 200 mg active compound, preferably 0.3-80 mg active compound; • diazepam with a total dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20.0 mg active compound; • lorazepam with a total dose of 0.01 - 200 mg active compound, preferably

0.1- 100 mg active compound; • oxazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0- 10 mg active compound; • prazepam with a total dose of 0.01 - 200 mg active compound, preferably

0.1- 100 mg active compound. Methods and kit of parts according to the invention with any of the above mentioned anxiolytic or sedative-hypnotic compounds and dosages are, therefore, preferred.

The present invention provides a novel use for compounds that influence brain function and/or psychological state. Besides uses in brain disorders or psychological disorders, the present invention have found that they are useful for combating symptoms of Herpes infections. Further provided is therefore a compound that influences brain function and/or psychological state for use in a method for preventing or alleviating symptoms of a Herpes simplex virus infection. Preferably, said at least one compound comprises at least one anxiolytic compound and/or at least one sedative-hypnotic compound.

The invention is further illustrated by the following Examples. These Examples are not limiting the invention in any way, but merely serve to clarify the invention. Examples

Patient 1, 60-68 year old, developed cold sores 7 times a year after either: a stressful situation, sunbathing, bashing of the lip (tissue trauma), exposure to open fire etc. On average in three days a wound developed and in the following 7-12 days the wound healed. The time of healing depended on the size of the wound. A typical example for this is given in example 1.

Example 1, not according to the invention

Patient 1, male 60 years old, had direct after sunbathing an itching of the lower lip. After 12 hours, 3 closed lesions were visible 0.3 mm in diameter, locally warm, red and swollen. After 24 hours, 4 closed lesions were visible 0.5 mm in diameter, locally warm, red and swollen. After 36 hours, 5 opened lesions were visible 0.6 mm in diameter, locally warm, red and swollen. After 48 hours, 5 opened lesions were visible 0.7 mm in diameter, locally warm, red and swollen. After 3 days, 1 closed wound, 6 mm in diameter was visible, locally warm, red and swollen. After 4 days, 1 closed wound, 6 mm in diameter was visible After 8 days, 1 closed wound, 4 mm in diameter was visible After 12 days, 1 closed wound, 1.5 mm in diameter was visible After 14 days, the wound had healed.

Examples 2-6; treatment after appearance of lesions

Patient 1, 68-70 year old, had several situations (stressful situations, sunbathing, exposure to open fires etc.) which normally would give respectively lesions, blister and wounds, but on using alprazolam or lormetazepam at the first hours after a lesion was visible the growth of the lesion(s) was suppressed, no coagulations of lesion(s) took place, the lesion(s) healed without opening, no wound(s) was formed and the total healing time was much shortened. This is shown in Examples 2-6. Example 2

Patient 1, male 69 years old, had a stressful situation. After 8 hours, 5 closed lesions 0.3 mm in diameter on upper lip were apparent. At that time two tablets alprazolam (0.25 mg) were taken and dissolved in the mouth. After 12 hours, 5 closed lesions 0.3 mm in diameter were visible, the lesion area was little swollen but no more itching. After 30 hours, 5 closed lesions 0.3 mm in diameter were visible, the lesion area little swollen, but little itching. At that time one more tablet alprazolam (0.25 mg) was taken. After 3 days, there were 5 closed lesions 0.1 mm in diameter were visible. After 4 days, the lesions had healed without opening. This is significantly earlier than normal.

Example 3

Patient 1, male 69 years old, without a known reason a lesion had developed on the border between inner and outer lip. After 24 hours, one tablet alprazolam 0.25 mg was taken. After 2 days the lesion was 0,6 mm in diameter, somewhat swollen but not red. After 3 days the lesion was 0,6 mm in diameter, not swollen, not red and had not increased it's size to a distasteful wound. After 9 days the lesion had healed. This is also significantly earlier than normal, although treatment had only started after 24 hours.

Example 4

Patient 1, male 70 years old, had taken a sunbathing. After 4 hours, 2 closed lesions 0.3 mm in diameter on lower lip had developed. Then one tablet alprazolam 0.25 mg was taken and dissolved in the mouth. After 48 hours, 2 closed lesions 0.3 mm in diameter were visible. After 4 days, the lesions had healed, without opening.

Example 5

Patient 1, male 70 years old, exposed to an open fire situation for some time. After 1 hour, 4 closed lesions 0.3 mm on upper lip had developed. Then one tablet alprazolam 0.25 mg was taken. After 3 days, 4 closed lesions 0.2 mm on upper lip were still visible. After 5 days, the lesions had healed.

Example 6

Patient 1, male 71 years old, had two hours after sunbathing an itching on the upper lip. Six hours after sunbathing the itching area had reddened, was slightly swollen and 2 small lesions had developed. At that time half a tablet of lormetazepam (= half of a 1 mg tablet Lormetazepam, Sandoz, resulting in 0.5 mg active compound) was taken and allowed to dissolve under the upper lip near the lesion. After 24 hours the itching had disappeared as well as the reddening and the lesion.

Examples 7-9; treatment before appearance of lesions

Patient 1, 68-70 year old, had several situations which normally would give respectively lesions, blister and wounds. On using alprazolam or diazepam when itching on the lips was apparent but before the lesions had developed, no lesion developed. This is shown in Examples 7-9.

Example 7

Patient 1, male 70 years old, exposed to an open fire situation, like in example 4. Direct after this situation some itching on upper lip (no lesion yet) was apparent. Than one tablet alprazolam 0.25 mg was taken and allowed to dissolved under the lips. No lesions developed.

Example 8

Patient 1, male 70 years old, exposed to an open fire situation, like in example 4. After 6 hours some itching on upper lip (no lesion yet) was apparent. Than one tablet alprazolam 0.25 mg was taken and allowed to dissolved under the lips. No lesions developed. Example 9

Patient 1, male 71 years old, had four hours after sunbathing an itching on the under lip and the itching area had reddened. At that time half a tablet of diazepam (= half of a 10 mg tablet Valium 10, Roche, resulting in 5 mg active compound) was taken and allowed to dissolve under the under lip. After 18 hours the itching had disappeared, the reddening had largely vanished and no lesion had developed.

Examples 10-11; treatment before Herpes outbreak inducing situations Patient 1, 70 years old, had several situations which normally would give in succession lesions, blister and wounds, but on using alprazolam a short time (1-4 hours) before such a situation, no lesions developed. This is shown in Examples 10- 11.

Example 10

Patient 1, male 70 years old, was exposed to an open fire situation, like in example 4. Before this situation was taking place 1 tablet alprazolam 0.25 mg was taken and no lesions developed.

Example 11

Patient 1, male 70 years old, was expecting within one hour of a stressful situation which normally would result in: lesion-forming, the growth of lesions, the swelling of the infected area, the growing of the ulcerations and the angulations of the ulcers. One tablet alprazolam 0.25 mg was taken before this stressful situation and allowed to dissolve in the mouth. After the stressful time had passed no lesions had developed.

Example 12: treatment with oxazepam after appearance of lesions

Patient 1, male 71 years old, had taken a sunbathing. After 8 hours, 4 closed lesions 0.3 mm in diameter on the upper lip had developed. Then half a tablet of oxazepam (Seresta) (= half of a 10 mg tablet, thus containing 5 mg oxazepam) was taken and dissolved in the mouth between teeth and upper lip. After 16 hours, the closed lesions had not grown, but the upper lip was still itching. At that time a second half of a 10 mg tablet of oxazepam (thus containing 5 mg oxazepam) was taken and dissolved in the mouth between teeth and upper lip. After that the closed lesions did not grow, did not open and no blister wound was formed. After four days the lesions had healed without opening. This is significantly earlier than this patient normally experiences without treatment. Claims

1. A method for preventing or alleviating symptoms of a Herpes simplex virus infection, the method comprising administering to a subject in need thereof at least one compound that influences brain function and/or psychological state.

2. A method according to claim 1, wherein said at least one compound comprises at least one anxiolytic compound.

3. A method according to claim 1, wherein said at least one compound comprises at least one sedative-hypnotic compound. 4. A method according to any one of claims 1-3, wherein said at least one compound is administered prophylactically to the subject before Herpes lesions are present on said subject. 5. A method according to any one of claims 1-3, wherein said at least one compound is administered to the subject within 0-24 hours, preferably within 0-4 hours, before the prodromal phase. 6. A method according to any one of claims 1-3, wherein said at least one compound is administered to the subject in the prodromal and/or inflammation phase. 7. A method according to any one of claims 1-3, wherein said at least one compound is administered to the subject in the pre-sore or open lesion phase. 8. A method according to any of claim 1-7, wherein the at least one compound 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 a factor 1.5-50, preferably 2-10, lower than the concentration of said compound in said single dose. 9. A method according to any one of claims 1-8, 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. 10. A method according to any one of claims 1-9, wherein said Herpes simplex virus is Herpes simplex labialis, preferably HSV-1. 11. A method according to any one of claims 1-10, comprising administering to the subject at least two compounds selected from anxiolytic compounds and sedative -hypnotic compounds. 12. A method according to any one of claims 1-11, wherein said at least one compound is administered sublabially or sublingually, preferably sublabially, to the subject. 13. A method according to any one of claims 1-11, wherein said at least one compound is administered topically to the subject. 14. A method according to any one of claims 1-13, further comprising administering to the subject at least one antiviral compound against Herpes simplex. 15. A method according to claim 14, wherein said at least one antiviral compound is selected from the group consisting of acyclovir, penciclovir, famciclovir, valaciclovir, docosanol, benzylammonium chloride and any combination thereof. 16. A method according to any one of claims 1-15, wherein 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-HT1A Agonists, H I Antagonists, CRH1 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. 17. A method according to any one of claims 1-16, wherein 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. 18. A method according to any one of claims 1-17, wherein said subject is provided with at least one anxiolytic compound or sedative-hypnotic compound selected from the group consisting of bretazenil, camazepam, Chlordiazepoxide, Clotiazepam, Cloxazolam, Ethyl Loflazepate, Fludiazepam, Imidazenil, Ketazolam, Medazepam, Nordazepam, Pinazepam, Emylcamate, Mebutamate, Meprobamate (Carisoprodol, Tybamate), Phenprobamate, Procymate, Abecarnil, Adipiplon, Alpidem, CGS-8216, CGS-9896, CGS-13767, CGS-20625, Divaplon, ELB-139, Fasiplon, GBLD-345, Gedocarnil, L-838,417, NS-2664, NS-2710, Ocinaplon, Pagoclone, Panadiplon, Pipequaline, RWJ-51204, SB-205,384, SL-651,498, Taniplon, TP-003, TP- 13, TPA-023, Y-23684, ZK-93423, Cartazolate, Etazolate, ICI- 190,622, Tracazolate, Chlormezanone, Ethanol, Etifoxine, Kavalactones (Kava Kava), Gabapentin, Pregabalin, Azapirones, Flesinoxan, Naluzotan, Oxaflozane, Diphenylmethanes, Captodiame, Hydroxyzine, Brompheniramine, Chlorpheniramine, Pheniramine, Antalarmin, CP- 154,526, Pexacerfont, Pivagabine, GR-159,897, Saredutant, ATC-0175, SNAP-94847, Eglumegad, Fenobam, DAA-1097, DAA-1106, Emapunil, FGIN-127, FGIN-143, Afobazole, Opipramol, Benzoctamine, Carbetocin, Demoxytocin, Mephenoxalone, Mepiprazole, Oxanamide, Oxytocin, Promoxolane, Tofisopam, Trimetozine, WAY-267,464, L- tryptophan, 5-hydroxytryptophan (5-HTP), L-tyrosine, L-phenylalanine, L- arginine, L-theanine, S-Adenosylmethionine (SAM-e), Ginkgo biloba, Rhodiola, Ashwagandha (Withania somnifera), GABA, N-Acetyl Cysteine (NAC), vitamin B6, vitamin B12, vitamin D, magnesium, zinc, omega-3 fatty acids, inositol, DHEA, folic acid, Bacopa monnieri (Brahmi), Lactuca virosa (Opium Lettuce), Rhodiola rosea (Arctic Weed/Golden Root), Passiflora, Piper methysticum (Kava), Sceletium tortuosum (Kanna), Scutellaria spp. (Skullcap), Scutellaria lateriflora, Salvia splendens , Coriandrum sativum (Coriander), Myristica (Nutmeg), Salvia elegans (Pineapple Sage), Inositol, myo-inositol, fluvoxamine, Cannabidiol, Picamilon, Chlorpheniramine (Chlor-Trimeton), diphenhydramine (Benadryl) Melatonin, BNC210, CL-218,872, L-838,417, SL-651,498 and pharmaceutically acceptable salts, esters, hydrates, derivatives and solvates of any of these compounds. 19. A method according to any one of claims 2-18, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises alprazolam with a total dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. 20. A method according to any one of claims 2-19, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises lormetazepam with a total dose of 0.001 - 5 mg active compound, preferably 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. 21. A method according to any one of claims 2-20, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises bromazepam with a total dose of 0.01 - 50 mg active compound, preferably 0.05-20 mg active compound. 22. A method according to any one of claims 2-21, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises chlordiazepoxide with a total total dose of 0.01 - 200 mg active compound, preferably 0.1-50 mg active compound. 23. A method according to any one of claims 2-22, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises clobazam with a total dose of 0.01 - 200 mg active compound, preferably 0.3-50 mg active compound. 24. A method according to any one of claims 2-23, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises clorazepine acid with a total dose of 0.01 - 200 mg active compound, preferably 0.3-80 mg active compound. 25. A method according to any one of claims 2-24, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises diazepam with a total dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20 mg active compound. 26. A method according to any one of claims 2-25, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises lorazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound. 27. A method according to any one of claims 2-26, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises oxazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0-10 mg active compound. 28. A method according to any one of claims 2-27, wherein said at least one anxiolytic compound or sedative-hypnotic compound comprises prazepam with a total dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound. 29. A compound that influences brain function and/or psychological state for use in a method for preventing or alleviating symptoms of a Herpes simplex virus infection. 30. A compound for use according to claim 29, wherein said compound comprises at least one anxiolytic compound. 31. A compound for use according to claim 29 or 30, wherein said compound comprises at least one sedative-hypnotic compound. 32. A kit of parts comprising: - at least one compound that influences brain function and/or psychological state; and - at least one antiviral compound against Herpes simplex. 33. A kit of parts according to claim 32, wherein said at least one compound comprises at least one anxiolytic compound. 34. A kit of parts according to claim 32 or 33, wherein said at least one compound comprises at least one sedative-hypnotic compound. 35. A kit of parts according to any one of claims 32-34, comprising at least two compounds selected from anxiolytic compounds and sedative-hypnotic compounds. 36. A kit of parts according to any one of claims 32-35, wherein said antiviral compound is selected from the group consisting of acyclovir, penciclovir, famciclovir, valaciclovir, docosanol and any combination thereof. 37. A kit of parts according to any one of claims 32-36, comprising 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-HT1A Agonists, H I Antagonists, CRH1 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. 38. A kit of parts according to any one of claims 32-37, comprising 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. 39. A kit of parts according to any one of claims 32-38, comprising at least one anxiolytic compound or sedative-hypnotic compound selected from the group consisting of bretaze nil, camazepam, Chlordiazepoxide, Clotiazepam, Cloxazolam, Ethyl Loflazepate, Fludiazepam, Imidazenil, Ketazolam, Medazepam, Nordazepam, Pinazepam, Emylcamate, Mebutamate, Meprobamate (Carisoprodol, Tybamate), Phenprobamate, Procymate, Abecarnil, Adipiplon, Alpidem, CGS-8216, CGS-9896, CGS- 13767, CGS-20625, Divaplon, ELB-139, Fasiplon, GBLD-345, Gedocarnil, L-838,417, NS-2664, NS-2710, Ocinaplon, Pagoclone, Panadiplon, Pipequaline, RWJ-51204, SB-205,384, SL-651,498, Taniplon, TP-003, TP-13, TPA- 023, Y-23684, ZK-93423, Cartazolate, Etazolate, ICI- 190,622, Tracazolate, Chlormezanone, Ethanol, Etifoxine, Kavalactones (Kava Kava), Gabapentin, Pregabalin, Azapirones, Flesinoxan, Naluzotan, Oxaflozane, Diphenylmethanes, Captodiame, Hydroxyzine, Brompheniramine, Chlorpheniramine, Pheniramine, Antalarmin, CP-154,526, Pexacerfont, Pivagabine, GR-159,897, Saredutant, ATC- 0175, SNAP-94847, Eglumegad, Fenobam, A A-1097, BAA- 1106, Emapunil, FGIN-127, FGIN-143, Afobazole, Opipramol, Benzoctamine, Carbetocin, Demoxytocin, Mephenoxalone, Mepiprazole, Oxanamide, Oxytocin, Promoxolane, Tofisopam, Trimetozine, WAY-267,464, L-tryptophan, 5-hydroxytryptophan (5- HTP), L-tyrosine, L-phenylalanine, L-arginine, L-theanine, S-Adenosylmethionine (SAM-e), Ginkgo biloba, Rhodiola, Ashwagandha (Withania somnifera), GABA, N- Acetyl Cysteine (NAC), vitamin B6, vitamin B12, vitamin D, magnesium, zinc, omega-3 fatty acids, inositol, DHEA, folic acid, Bacopa monnieri (Brahmi), Lactuca virosa (Opium Lettuce), Rhodiola rosea (Arctic Weed/Golden Root), Passiflora, Piper methysticum (Kava), Sceletium tortuosum (Kanna), Scutellaria spp. (Skullcap), Scutellaria lateriflora, Salvia splendens , Coriandrum sativum (Coriander), Myristica (Nutmeg), Salvia elegans (Pineapple Sage), Inositol, myo-inositol, fluvoxamine, Cannabidiol, Picamilon, Chlorpheniramine (Chlor- Trimeton), diphenhydramine (Benadryl) Melatonin, BNC210, CL-218,872, L-838,417, SL-651,498 and pharmaceutically acceptable salts, esters, hydrates, derivatives and solvates of any of these compounds. 40. A kit of parts according to any one of claims 32-39, comprising alprazolam in at least one unit dose of 0.001 - 5 mg active compound, preferably of 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. 41. A kit of parts according to any one of claims 32-40, comprising lormetazepam in at least one unit dose of 0.001 - 5 mg active compound, preferably of 0.01-2.0 mg active compound, or more preferably 0.1-1.0 mg active compound. 42. A kit of parts according to any one of claims 32-41, comprising bromazepam in at least one unit dose of 0.01 - 50 mg active compound, preferably 0.05-20 mg active compound. 43. A kit of parts according to any one of claims 32-42, comprising chloordiazepoxide in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-50 mg active compound. 44. A kit of parts according to any one of claims 32-43, comprising clobazam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.3-50 mg active compound. 45. A kit of parts according to any one of claims 32-44, comprising clorazepine acid in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.3-80 mg active compound. 46. A kit of parts according to any one of claims 32-45, comprising diazepam in at least one unit dose of 0.01 - 100 mg active compound, preferably 0.1-20 mg active compound, or more preferably 1.0-20 mg active compound. 47. A kit of parts according to any one of claims 32-46, comprising lorazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound. 48. A kit of parts according to any one of claims 32-47, comprising oxazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound, or more preferably 1.0-20 mg active compound or 1.0-10 mg active compound. 49. A kit of parts according to any one of claims 32-48, comprising prazepam in at least one unit dose of 0.01 - 200 mg active compound, preferably 0.1-100 mg active compound. 50. Use of a kit of parts according to any one of claims 32-49 for preventing or alleviating symptoms of a Herpes simplex virus infection. International application No PCT/NL2014/05Q781

A. CLASSIFICATION O F SUBJECT MATTER INV. A61K45/06 A61K31/045 A61K31/522 A61K31/551 A61K31/5513 A61K31/5517 A61P31/22 ADD. According to International Patent Classification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61K A61P

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)

EPO-Internal , BIOSIS, EMBASE, SCISEARCH, WPI Data

C. DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

US 7 862 838 Bl (ZENG QING SI [US] ) 1-3, 10, 4 January 2011 (2011-01-04) 11 , 16-18, 25 ,29-31 col umns 1-7; claims; examples 1-50

UA 26 239 U (SELEZNEVA LUDMYLA 1-3, 11 , VOLODYMYRIVN [UA] ; SELEZNEVA HALYNA 29-31 OLEKSANDRIVNA [U) 10 September 2007 (2007-09-10) c l aims; exampl es

0 2011/148257 Al (L0GI ROBERTO [IT] ) 1-50 1 December 2011 (2011-12-01) c l aims; f i gures 7-9; example 2

US 5 248 503 A (EMANUEL-KING R0SALBA [US] ) 1-50 28 September 1993 (1993-09-28) col umns 1-2; claims

□ Further documents are listed in the continuation of Box C. See patent family annex. * Special categories of cited documents : "T" later document published after the international filing date or priority date and not in conflict with the application but cited to understand "A" document defining the general state of the art which is not considered the principle or theory underlying the invention to be of particular relevance "E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive "L" document which may throw doubts on priority claim(s) orwhich is step when the document is taken alone cited to establish the publication date of another citation or other " document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is "O" document referring to a n oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art "P" document published prior to the international filing date but later than the priority date claimed "&" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report

12 December 2014 22/12/2014

Name and mailing address of the ISA/ Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 Vent i i , Francesca International application No Information on patent family members PCT/NL2014/05Q781

Patent document Publication Patent family Publication cited in search report date member(s) date

US 7862838 B l 04-01-2011 NONE

UA 26239 U 10-09-2007 NONE

WO 2011148257 A l 01-12-2011 AU 2011256942 A l 13-12 2012 CA 2799457 A l 01-12 2011 CN 102917719 A 06-02 2013 EA 201291176 A l 30-09 2013 EP 2575840 A l 10-04 2013 JP 2013527193 A 27-06 2013 KR 20130120375 A 04-11 2013 US 2013071427 A l 21-03 2013 W0 2011148257 A l 01-12 2011

US 5248503 28-09-1993 NONE