Title: Treatment of Herpes virus infection outbreaks using valerian

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 counteracting a Herpes simplex virus infection outbreak. In particular, methods are provided for preventing or counteracting a Herpes simplex virus infection outbreak, the methods comprising administering to a subject in need thereof at least one valerian compound. Preferably, said at least one valerian compound comprises a valerian root extract.

In a preferred embodiment, said at least one valerian compound is administered prophylactically to the subject before Herpes lesions are present on said subject. Alternatively, said at least one valerian 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 valerian compound is administered to the subject in the prodromal and/or inflammation phase. In yet another embodiment, said at least one valerian compound is administered to the subject in the pre-sore or open lesion phase.

In a preferred embodiment, the valerian 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 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 valerian compounds. In one aspect, said at least one valerian compound is administered sublabially or sublingually, preferably sublabially, to the subject. Alternatively, said at least one valerian 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 another aspect the invention provides a method for preventing or counteracting a Herpes simplex virus infection outbreak, the method comprising administering to a subject in need thereof at least one valerian compound, wherein said at least one valerian compound comprises a valerian root extract with a total dose of 0.01 - 15 g active compound, preferably 0.05-10 g active compound, more preferably 0.1 - 5 g active compound. In one embodiment said total dose is about 2 g active compound. In another embodiment, said total dose is 125-2000 mg active compound, preferably 250-2000 mg active compound or 250- 1500 mg active compound or 250- 1000 mg active compound or 500-1500 mg active compound or 500-1000 mg active compound, more preferably about 250 mg or about 375 mg or about 500 mg or about 1000 mg or about 1500 mg active compound.

In another embodiment a method according to the invention is provided wherein the subject is provided with:

- at least one valerian compound, and

- at least one anxiolytic compound and/or sedative-hypnotic compound.

The anxiolytic and/or sedative-hypnotic sedative compound is preferably 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 -HT1 A Agonists, HI 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 another embodiment, the subject is provided with at least one valerian compound, and 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 embodiment the subject is provided with at least one valerian compound and 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

The present invention provides a novel use for valerian compounds. Besides uses as a hypnotic, sedative and pain reliever, the present inventor has found that valerian compounds are useful for preventing or counteracting Herpes simplex virus infection outbreaks. Further provided is therefore a valerian compound for use in a method for preventing or counteracting a Herpes simplex virus infection outbreak. Preferably, said at least one valerian compound comprises a valerian root extract.

Kits of parts suitable for preventing or counteracting Herpes simplex virus infection outbreaks are also provided. Yet another aspect therefore provides a kit of parts comprising:

- at least one valerian compound; and

- at least one antiviral compound against Herpes simplex.

In yet another aspect, a kit of parts is provided which comprises at least one valerian compound and at least one anxiolytic compound and/or at least one sedative -hypnotic compound.

In one aspect of the invention, the at least one anxiolytic compound and/or the at least one sedative-hypnotic compound is 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-HT1 A Agonists, HI 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 another aspect of the invention, the at least one anxiolytic compound and/or the at least one sedative-hypnotic compound is selected from the group consisting of benzodiazepine compounds 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 of the invention, the anxiolytic compound or sedative- hypnotic sedative compound is 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 one embodiment a kit of parts according to the invention is provided wherein said at least one valerian compound comprises a valerian root extract, preferably in at least one unit dose of 0.01 - 15 g active compound, preferably 0.05- 10 g active compound, more preferably 0.1 - 5 g active compound. In one embodiment said kit of parts comprises a valerian root extract in at least one unit dose of about 2 g active compound. In one embodiment said kit of parts comprises a valerian root extract in at least one unit dose of 125-2000 mg active compound, preferably in at least one unit dose of 250-2000 mg active compound or 250- 1500 mg active compound or 250-1000 mg active compound or 500- 1500 mg active compound or 500- 1000 mg active compound, more preferably in at least one unit dose of about 250 mg or about 375 mg or about 500 mg or about 1000 mg or about 1500 mg active compound.

In one preferred embodiment, the kit of parts comprises at least two valerian compounds. 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.

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

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 valerian compound. A preferred example of such compound is a valerian root extract. Valerian compounds are well known in the art. Valerian (Valeriana officinalis, Valerianaceae) is a plant with rose or white flowers. The plant is also called garden valerian or garden heliotrope. Valerian has been used for centuries in pharmacology and herbal medicine as a hypnotic, sedative and pain reliever.

However, the use of valerian compounds against Herpes simplex outbreaks has not been described before.

As used herein, a Herpes simplex virus infection outbreak means an active (non-dormant) stage of a Herpes simplex infection. Hence, a Herpes simplex outbreak is an episode wherein the latent stage of the virus infection has ended and clinical, visual manifestations of a herpes infection, such as reddening and swelling of the skin and the appearance of lesions such as papules or vesicles (follicles, blisters) or ulcers become apparent. A Herpes simplex outbreak thus typically begins with the prodromal and inflammation stage and ends with the healing or post-scab stage.

As used herein, the term "lesion" is used to refer to skin lesions, which encompass papules, vesicles, follicles, blisters and ulcers. According to the present invention, valerian compounds can prevent or counteract Herpes simplex outbreaks, meaning that the duration of the outbreak is shorter as compared to untreated subjects, and/or that the visual symptoms of a Herpes simplex 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. 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. In preferred embodiments, the outbreak is even prevented, meaning that the above mentioned visual symptoms do not evolve.

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 simplex outbreaks, such as for instance a large exposure to ultraviolet light due to sunbathing, or before the subject experiences such conditions. One preferred embodiment thus provides a method according to the invention wherein said at least one valerian 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 valerian compound is administered to the subject in the prodromal and/or inflammation phase. Preferably, said at least one valerian 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. One aspect therefore provides a method according to the invention wherein said at least one valerian 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.

As used herein, a valerian compound is defined as a product derived from the valerian plant (Valeriana officinalis, Valerianaceae). Preferably, a valerian extract is used, most preferably a valerian root extract.. The term "valerian root extract" refers to an extract made from the ground root and/or rhizomes

(underground stems) of the valerian plant. Such extract is typically used as an oil, or integrated in dried form in capsules, pills, powders, in tea or in dietary supplements.

The valerian compound 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 during a Herpes simplex outbreak are often more efficient. Preferably, when multiple dosages are used, the concentration of the valerian compound 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 valerian compound is capable of counteracting Herpes outbreaks due to these conditions, which have nothing to do with the uses of valerian before the present invention. 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 valerian compounds 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, dietary supplement or liquid solution such as an oil or for instance valerian tea. 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. The valerian compound may also be administered effectively as a topical compound, in this way the concentration can also be considerable reduced as compared to systemic administration. Alternatively, the valerian compound is administered rectally, for instance as a suppository, or systemically, for instance via a

subcutaneous or intramuscular or intravenous or intraperitoneal injection.

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.

In yet another embodiment, a method according to the invention is provided wherein the subject is additionally provided with at least one anxiolytic compound and/or sedative -hypnotic compound. 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.

In one aspect, the subject is provided with at least one valerian compound and at least one anxiolytic and/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 -HT1 A Agonists, HI 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, 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 valerian compound and 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 another preferred embodiment said subject is provided with at least one valerian compound and at least one anxiolytic and/or sedative -hyp no tic 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, or the subject is provided with a kit of parts according to the invention comprising at least one of these compounds.

Many anxiolytic and sedative-hypnotic compounds, such as the ones listed above, 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 counteracting a Herpes simplex virus infection outbreak is, however, not described before the present invention. Further provided is a method according to the invention, comprising administering to the subject at least two valerian compounds.

Kits of parts suitable for methods according to the invention for preventing or counteracting a Herpes simplex virus infection outbreak are also provided. Yet another aspect of the invention therefore provides a kit of parts comprising:

- at least one valerian compound; and

- at least one antiviral compound against Herpes simplex. In yet another aspect, a kit of parts is provided which comprises at least one valerian compound and at least one anxiolytic compound and/or at least one sedative -hypnotic compound. Said at least one anxiolytic and/or sedative -hypnotic compound is preferably 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- HT1 A Agonists, HI 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 preferred embodiment, said benzodiazepine compound is 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 another aspect, a kit of parts according to the invention is provided wherein said anxiolytic compound and/or sedative-hypnotic sedative compound is 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), GAB A, 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.

Said at least one valerian compound of a kit according to the invention preferably comprises a valerian root extract. In one preferred embodiment, the kit of parts comprises at least two valerian 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.

In a particularly preferred embodiment, a subject in need of Herpes simplex treatment is provided with a valerian root extract with a total dose of 0.01 - 15 g active compound, preferably 0.05-10 g active compound, more preferably 0.1 - 5 g active compound. A kit of parts according to the present invention therefore also preferably comprises a valerian root extract with unit doses of 0.01 - 15 g active compound, preferably 0.05- 10 g active compound, more preferably 0.1 - 5 g active compound. In one embodiment the subject in need of Herpes simplex treatment is provided with a valerian root extract with a total dose of about 2 g active compound. In another embodiment, the subject in need of Herpes simplex treatment is provided with a valerian root extract with a total dose of 125-2000 mg active compound, preferably the subject in need of Herpes simplex treatment is provided with a valerian root extract with a total dose of 250-2000 mg active compound, or with a total dose of 250- 1500 mg active compound, or with a total dose of 250- 1000 mg active compound, or with a total dose of 500-1500 mg active compound, or with a total dose of 500- 1000 mg active compound. More preferably, said total dose is about 250 mg or about 375 mg or about 500 mg or about 1000 mg or about 1500 mg active compound.

In one embodiment a kit of parts according to the invention comprises a valerian root extract in at least one unit dose of about 2 g active compound. In another embodiment, said kit of parts comprises a valerian root extract in at least one unit dose of 125-2000 mg active compound, preferably in at least one unit dose of 250-2000 mg active compound or in at least one unit dose of 250-1500 mg active compound or in at least one unit dose of 250-1000 mg active compound or in at least one unit dose of 500-1500 mg active compound or in at least one unit dose of 500-1000 mg active compound, more preferably in at least one unit dose of about 250 mg or about 375 mg or about 500 mg or about 1000 mg or about 1500 mg active compound.

The present invention provides a novel use for valerian compounds. Besides uses as a hypnotic, sedative and pain reliever, the present inventor has found that valerian compounds are also useful for preventing or counteracting Herpes simplex virus infection outbreaks. Further provided is therefore a valerian compound, or a kit of parts according to the invention, for use in a method for uses as a hypnotic, sedative and pain reliever, the present inventor has found that valerian compounds are useful for preventing or counteracting Herpes simplex virus infection outbreaks. Preferably, said at least one valerian compound comprises a valerian root extract.

The invention is further illustrated by the following Examples. These Examples do not limit 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

Example 2; treatment before appearance of lesions

Patient 1, 68-70 year old, had a situation which normally would result in lesions, blister and wounds. On using valerian root extract when itching on the lips was apparent but before lesions had developed, no lesion developed.

Patient 1, male 70 years old, had a stressful situation.

After eight hours some itching on the upper lip was apparent. Then two tablets of a valerian root extract (Valdispert) (125 mg/tablet) were taken and allowed to dissolve under the lips.

After 1 hour after taking the tablets the itching on the lips had largely vanished. After 12 hours some itching was noticeable again and two more tablets with valerian root extract were taken. After 24, 36, 48, 56, 64 and 72 two more tablets with valerian root extract were taken. No lesions developed.

Examples 3 and 4; treatment after appearance of closed lesions Example 3

Patient 1, male 71 years old, had six hours after sunbathing an itching on the upper lip. The upper lip was locally warm, red and swollen and 3 closed lesions, 0.3 mm in diameter, had developed. Then 1 tablet of a valerian root extract

(Valdispert) (125 mg/tablet) was taken and allowed to dissolve under the upper lip near the lesion.

After 30 min after taking the tablet the itching on the lip had largely vanished. After 24 hours the 3 closed lesions had not increased in size, not opened and had not coagulated to a large wound.

At that time 1 more tablet of a valerian root extract (Valdispert) (125 mg/tablet) was taken and allowed to dissolve under the upper lip.

After 48 hours the lesions had healed.

Example 4

Patient 1, male 71 years old, had six hours after a stressful situation an itching on the upper lip and a lesion, 0.3 mm in diameter, had developed. At that time 2 tablets of a valerian root extract (Valdispert) (125mg/tablet) were taken and allowed to dissolve under the upper lip near the lesions.

After 30 min after taking the tablet the itching on the lip had largely vanished. After 30 hours the lesion had not increased in size and had not become a large wound.

At that time 1 more tablet of a valerian root extract (Valdispert) (125mg/tablet) was taken and allowed to dissolve under the upper lip.

After 62 hours the lesion had healed.

Examples 5 and 6; treatment before appearance of lesions Example 5

Patient 1, 72 years old, had taken a sunbathing.

After 8 hours an itching on the upper lip was noticed

At that time 4 tablets valerian root extract (Valdispert) (125 mg) were taken and dissolved in the mouth between teeth and upper lip.

No lesions or cold sore lip developed. Example 6

Patient 1, 72 years old, was exposed to an open fire situation.

After 24 hours an itching on the under lip was apparent.

At that time 2 tablets valerian root extract (Valdispert) (125 mg) were taken and dissolved in the mouth between teeth and upper lip. This was repeated three times, after 2, 6 and 12 hours.

No lesions or cold sore lip developed.

Example 7; treatment after the first signs of lesion formation

Patient 1, 72 years old, had taken a sunbathing.

After 3 hours an itching on the upper lip was noticed and the first signs of lesion formation were apparent. At that time 4 tablets valerian root extract (Valdispert) (125 mg) were taken and dissolved in the mouth between teeth and upper lip. This was repeated after 9 and 15 hours.

After 3 days the lesions had healed without growing or opening. This is significant earlier than this patient normally experiences without treatment.