WO2010020789A2

WO2010020789A2 - Medicament and treatment for infections

Info

Publication number: WO2010020789A2
Application number: PCT/GB2009/002043
Authority: WO
Inventors: Anant Sharma
Original assignee: Anant Sharma
Priority date: 2008-08-20
Filing date: 2009-08-20
Publication date: 2010-02-25
Also published as: WO2010020789A3; GB0815179D0

Abstract

A medicament for treating neurally-transported viral infections, such as herpes simplex, herpes zoster or rabies, comprises a first active substance selected from alkaloids, anaesthetics and griseofulvin and a second active substance comprising a purine analogue or pyrimidine analogue antiviral agent. The alkaloid may comprise colchicine, vinblastine, vincristine, a cytochalasin or their derivatives. Suitable purine analogues include N- substituted guanine derivatives such as aciclovir, valaciclovir, penciclovir, famiciclovir ganciclovir, valganciclovir or pro-drugs that convert thereto in the body, and N-substituted adenine derivatives such as vindarabine. Suitable pyrimidine analogues include thymidine derivatives such as trifluorothymidine. The medicament may be orally administrable, injectable, infusible or topically applicable; a topical medicament may include a local anaesthetic. The medicament may be administered in response to a risk of infection, prior to onset of symptoms. A combination of two preparations may be used, respectively containing the first and second active substances, either administered sequentially or simultaneously.

Description

MEDICAMENT AND TREATMENT FOR INFECTIONS

The present invention relates to a medicament for use in the treatment of infections, particularly viral infections, such as herpes simplex, herpes zoster (shingles) and rabies, that are transmitted through the nervous system. The present invention also relates to a method of treatment for such infections.

A number of viral diseases are transported through the body along the nervous system, the viruses taking advantage of the elongate form of most nerve cells. A typical nerve cell comprises a cell body and an elongate axon extending away therefrom, which may easily be over a third of a meter long. The axon transports chemicals both away from the cell body (anterograde) and towards the cell body (retrograde), along structures known as microtubules. A tip of the axon distal from the respective cell body may link to a cell body of one or more further nerve cells. Viruses may thus be transported from a site of infection along a retrograde pathway along one or more axons, until they reach the central nervous system (CNS), spinal cord and brain.

In some diseases, such as rabies, the main effect of the virus is on the brain and CNS, with a very rapid onset following such retrograde transport.

Other viruses, such as herpes simplex, may once transported retrogradely lie asymptomatically dormant or latent in nerve cell bodies of the CNS. However, when reactivated, by whatever cause, these viruses are transported anterogradely along nerve cell axons to a surface of the body, where symptoms of the infection arise. A common form of herpes simplex infection lies dormant or latent in the trigeminal nerve ganglion until reactivated by any of a range of triggers, including stress and premenstrual tension. The herpes simplex virus (HSV) typically travels along trigeminal nerve axons to the lips, where it leads to symptoms such as cold sores. HSV also causes the condition genital herpes, in which the virus lies dormant in pelvic ganglia until triggered to travel along nerve axons to the genitalia. Herpes simplex infections may also take an even more serious form in which the virus travels along nerve cells to the vicinity of the eye. Here, HSV may cause symptoms such as ulceration of the cornea, with a potentially serious effect on a patient's vision.

It is estimated that up to 95% of the UK population carries antibodies to herpes simplex, and hence are presumed to be infected with latent asymptomatic HSV. A classic infection vector is believed to be transmission by lip contact from relatives, usually occurring before the age of five. No means of avoiding this has been developed, since asymptomatic carriers may still infect others, and carriers are so numerous. The current preferred treatment for herpes simplex infection is a drug, such as aciclovir, which interferes with viral replication. For cold sores, this is administered as a topical cream, while for corneal ulcers a typical prescription is administration of aciclovir, five times daily, as an ointment. In each case, aciclovir (or equivalent) is only administered once a recurrence of HSV activity is underway (e.g. aciclovir cold sore creams are indicated to be administered only reactively, once a characteristic local itch or "tingle" has warned the patient of an incipient cold sore). It would be preferable to slow or stop the HSV, before it reaches the surface of the body and starts to cause annoying or harmful symptoms. However, for chronic cases, it is known for aciclovir to be administered orally as twice daily 400mg doses over long periods.

For acute infections such as rabies, a treatment to slow or stop the virus before it first reaches the CNS and brain would be extremely desirable.

While the present specification is concerned primarily with medications for treatment of viral infections of the human body, very similar considerations apply for animal viral infections. All references herein to human beings should be understood to refer equally to animals and other vertebrates unless stated otherwise.

It is hence an object of the present invention to provide a medicament to treat viral infections that are transported through the nervous system. It is also an object of the present invention to provide a method of treating such infections.

According to a first aspect of the present invention, there is provided a use of a combination of a first substance selected from a group comprising alkaloids, anaesthetics and griseofulvin - A - and a second substance comprising a purine analogue antiviral agent and/or a pyrimidine analogue antiviral agent in the manufacture of a medicament for use in the treatment of neurally transported viral infections.

Preferably, the first substance comprises an alkaloid.

Advantageously, the alkaloid comprises an antimitotic alkaloid.

The alkaloid may comprise colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.

The first substance may comprise an anaesthetic agent such as lidocaine, lignocaine, procaine, tetracaine or benzocaine.

Preferably, said purine analogue antiviral agent comprises a guanine analogue.

Advantageously, said purine analogue comprises an N-substituted guanine derivative.

Said purine analogue may comprise an ^-substituted guanine derivative.

Said purine analogue may comprise an ^-substituted guanine derivative, wherein the substituent comprises at least one hydroxyl group.

Said purine analogue may comprise an Ng-substituted guanine derivative, wherein the substituent comprises at least one group convertible in vivo to a hydroxyl group. Said purine analogue may comprise an Ng-substituted guanine derivative, wherein the substituent comprises at least one ester group, optionally at least one valyl or acetyl ester group.

Said purine analogue antiviral agent may comprise aciclovir, valaciclovir, penciclovir, famiciclovir, ganciclovir, valganciclovir, and/or a prodrug convertible in vivo thereto.

Said purine analogue antiviral agent may alternatively comprise an adenine analogue.

Advantageously, said purine analogue comprises an N-substituted adenine derivative, optionally an ^-substituted adenine derivative.

Said purine analogue antiviral agent may comprise vindarabine.

Preferably, said pyrimidine analogue antiviral agent comprises a thymidine analogue.

Advantageously, said pyrimidine analogue antiviral agent comprises trifluorothymidine.

In a preferred embodiment, the viral infection to be treated comprises a herpes infection.

The viral infection to be treated may comprise a herpes simplex infection, such as cold sores, herpes of the eye or genital herpes.

The viral infection to be treated may comprise a herpes zoster infection. Alternatively, the viral infection to be treated comprises rabies or the like.

Preferably, the medicament is in an orally administrable form.

Advantageously, the medicament is administrable in tablet, capsule, powder or granular form.

Alternatively, the medicament comprises a drinkable liquid composition.

The medicament may comprise a topically applicable composition.

The medicament may then comprise a cream, ointment, salve, eye drops, nasal spray or the like.

The medicament may then comprise a local anaesthetic, optionally lidocaine.

The medicament may comprise an injectable or infusible liquid composition.

According to a second aspect of the present invention, there is provided a method for treating a neurally transported viral infection, comprising the step of administering in combination a first substance selected from a group comprising alkaloids, anaesthetic agents and griseofulvin, and a second substance comprising a purine analogue antiviral agent and/or a pyrimidine analogue antiviral agent. Preferably, the method comprises the step of administering said substances prior to the onset of symptoms of the infection, for example in response to an event entailing a risk of infection or recurrence thereof.

Alternatively, the method comprises the step of administering said substance prophylactically.

The method may comprise administering said substances sequentially, optionally administering the first substance within a day of the administration of the second substance, possibly within an hour thereof.

The method may comprise administering said substances substantially simultaneously, optionally as a single preparation, such as a tablet, containing both substances.

Alternatively, the method may comprise administering said substances in the form of separate preparations, each containing a single said substance, administered substantially simultaneously.

The method preferably comprises the step of administering a composition comprising an antimitotic alkaloid, advantageously colchicine, vinblastine and/or vincristine.

The method preferably comprises the step of administering a composition comprising an N₉- substituted guanine derivative, advantageously aciclovir, valaciclovir, penciclovir, famiciclovir, ganciclovir, valganciclovir, and/or a prodrug convertible in vivo thereto. Said method may comprise a method for treating a herpes simplex infection.

Said method may comprise a method for treating a herpes zoster/shingles infection.

Said method may comprise a method for treating a rabies infection.

Preferably, the method then comprises the step of administering said substances prior to the onset of symptoms of the rabies infection.

The method advantageously comprises the step of administering the first and second v substances proximally of a site of presumed infection, optionally orally or possibly by injection.

According to a third aspect of the present invention, there is provided a medicament comprising a first substance selected from a group comprising alkaloids, anaesthetics and griseofulvin and a second substance comprising a purine analogue antiviral agent and/or a pyrimidine analogue antiviral agent.

Preferably, said first substance comprises an alkaloid, optionally colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.

Preferably, said second substance comprises a guanine derivative, optionally aciclovir, valaciclovir, penciclovir, famiciclovir, ganciclovir, valganciclovir and/or a prodrug convertible in vivo thereto. Advantageously, said medicament comprises an orally administrate composition.

Embodiments of the present invention will now be more particularly described, by way of example.

In a first example, a patient has a history of cold sores, brought on by a known trigger. This might for example take the form of a stressful event, such as an examination. Another common trigger is a weakened immune system as a result of another infection (for example, a cold, hence the name "cold sore"). Some women suffer regular attacks of cold sores as a premenstrual symptom. While the exact trigger(s) for each patient will vary, they are likely to recognise when they are at risk of a recurrence.

Under existing treatments, when cold sores have formed, or when an initial stage of their formation is detected (for example as a tingling sensation of the skin) an ointment containing 5%^w/_w aciclovir is applied topically, up to five times a day, until the cold sores subside. The duration of the episode may well be reduced as a result, but the patient still suffers unsightly and possibly painful cold sores for several days.

In a treatment embodying the present invention, the patient realises that some trigger event, likely to bring on his or her cold sores, has taken place or is imminent. Rather than wait for a cold sore to appear, the patient immediately takes a first tablet comprising colchicine, together with conventional excipients. The patient then takes a second tablet comprising aciclovir (or a prodrug metabolisable to aciclovir, such as valaciclovir), preferably immediately following the first, but in any case within six hours. It is believed that the colchicine permeates into the nerve axons extending from the trigeminal ganglion that is acting as a reservoir for latent herpes simplex virus. If the HSV has been activated, it will by this stage be migrating anterogradely towards the skin surface, but the colchicine and aciclovir are believed to act synergistically to prevent the virus expressing itself at the skin surface, or at least significantly to retard such expression. If the HSV does not reach the skin surface, it will not cause cold sores. Even if it is merely significantly delayed, the patient's immune system will have far longer to respond to the reactivation of the virus, producing the appropriate antibodies to attack the HSV. Thus, only a small proportion of the HSV will actually reach the skin surface, and it is likely to be dealt with rapidly by the body's own defences. The patient suffers at worst a mild and brief episode of cold sores, and frequently no episode at all.

The colchicine and/or the aciclovir may alternatively be applied topically, for example in the form of a cream.

In a second example, a patient has a history of herpes simplex infections in and around the eye. These can lead to corneal ulceration and temporary or permanent harm to the patient's sight. Again, such infections are usually the result of latent HSV in the trigeminal ganglion becoming reactivated by some recognisable trigger, and travelling anterogradely down the nerve axons.

Current treatments are in response to the appearance of symptoms in and around the eye, by which time the patient's sight could already be at risk. Typically, aciclovir in the form of ointment is administered until the ulcers heal. In a treatment embodying the present invention, as soon as a likely trigger event is noticed, the patient takes a tablet containing both colchicine (or another active alkaloid, such as vihblastine or vincristine) and aciclovir (or a prodrug metabolisable to aciclovir, such as valaciclovir). Alternatively, a first tablet containing colchicine or the like, and a second tablet containing aciclovir or the like, may be taken together. It is believed that the colchicine and aciclovir migrate to the trigeminal ganglion, and there synergistically interfere with the replication of the HSV and its progress to the axons. Any HSV that has already started to pass anterogradely towards the eye should be intercepted by colchicine and aciclovir that are also being transported along the relevant axon. Little or no HSV should reach the eye, preventing or severely reducing the formation of ulcers.

Alternatively, the colchicine and aciclovir combination could be administered topically as eye-drops or ointment, either with both components in a single preparation, or in the form of two preparations administered together. At present, it is envisaged that oral administration is likely to prove more effective. (Of course, administration of one component topically and the other orally is not excluded).

Topical compositions also containing anaesthetics such as lidocaine may be used to slow or halt progress of HSV.

In the third example, a patient has been bitten (e.g. on the leg) by a rabid animal, and it is feared that the rabies virus is progressing up his nervous system towards his spinal column and brain. The current treatment comprises an injected dose of human rabies immune globulin (HRIG) followed by a long series of rabies vaccine injections. These are expensive, sophisticated pharmaceuticals requiring careful storage and with restricted shelf lives. They may not always be to hand when required. Although it is often recommended to wait until it is confirmed that the animal was rabid before injecting the HRIG and starting the vaccinations, this may not always be possible. There will also be concern that an infection might have progressed too far before a decision is made to administer HRIG (and/or before HRIG becomes available).

Therefore, in a treatment embodying the present invention, an oral treatment with a composition containing colchicine, vinblastine or vincristine is administered or such a composition is injected into the patient's upper leg, proximal of the bite and adjacent the major nerve axons immediately followed by an oral treatment or an injection of a composition containing aciclovir, valaciclovir or famiciclovir. This will act to slow or stop progress of the rabies virus towards the patient's brain, giving the patient's own immune system much more time to respond, and/or allowing administration of HRIG on a much less hasty timescale. It is much easier to store such compositions than to store HRIG and rabies vaccine and it is believed that the synergistic combinations described should be more effective than either component administered on its own.

In a fourth example, a patient is diagnosed as suffering from an early stage or a prodrome of shingles, or Herpes zoster (for example, the rash associated with shingles might be identified within 48 hours of its onset before it has become too severe and painful). An oral treatment is administered comprising a tablet or capsule containing colchicine and a tablet or capsule comprising aciclovir or a prodrug metabolisable to aciclovir, such as valaciclovir. Preferably, these tablets are taken together but they may be taken sequentially. In this case, it is preferable that the colchicine is taken first, but the aciclovir is then taken within an hour or two, ideally within less than an hour. For some combinations of components, it is possible that the rate of metabolisation of the two components might differ significantly. If this is the case, then it may be benefical to administer additional doses of one component, in between the above combined doses, in order to maintain active levels of both components in the body. Again, the colchicine and the aciclovir act synergistically to prevent the herpes zoster virus expressing itself at the skin surface, or at least to retard such expression significantly, reducing or preventing the formation of blisters, erythema or other lesions. It may prove possible to reduce the treatment to administration of aciclovir alone, once the shingles outbreak is in remission, but the combined treatment will be required to deal with the more severe stages of the outbreak.

Alternatively, in such a treatment, one or other of the colchicine and the aciclovir (or corresponding components) may be administered topically to the skin, optionally in a composition also comprising lidocaine.

In each case above in which oral administration is employed, administration is described in the form of two separate tablets or the like, one containing each active component of the treatment. While this is a straightforward approach for experimental testing, in practice it would be more desirable to administer the treatment in the form of a single tablet, capsule or the like containing both active components. This will ensure that both components are taken and in the correct proportions.

It is conceivable that some combinations of active components might not be stable in the long term, intimately commingled in a single tablet or the like. In such a case, it is believed that a two-compartment capsule would be appropriate, each compartment holding a preselected quantity of one of the active components. Thus, the active components would be released and would mix only once the capsule reached the stomach of the patient.

It is also envisaged that foil-sealed strips of individually-packaged tablets could be provided, for example with separate tablets containing each active component grouped in adjacent compartments of the strip and marked to indicate that the contents of such a group of compartments should be taken together. Alternatively, a common compartment could be formed to hold all the tablets, capsules, etc, making up each separate dose of the treatment. (This last option would be particularly useful where one component should preferably be administered more frequently than the other(s), for example due to differing metabolisation rates.

It is believed that, in the later stages of such treatments, the most important aspect of the treatment is likely to become dealing with the effects of any viral material that has managed to reach a body surface, despite the inhibitory effect on axonal transport of the administration of the combination of colchicines plus aciclovir (or equivalent). As the axonal transport of viral material to the body surface falls away naturally, the course of treatment may then gradually shift towards administration of aciclovir (or equivalent) alone, in order to deal with any symptoms arising from the restricted amount of surviving viral material that might possibly have reached the body surface. The levels of colchicine (or equivalent) would thus be tapered off from an initial large dose, probably over the course of two weeks, while aciclovir continued to be administered at regular intervals at its original level.

It would thus be beneficial to provide a pre-packaged course of treatment, comprising a series of individual tablets, capsules, etc, having the desired sequence of dosages for each active component, or comprising a sequence of groups of tablets to be taken together, making up the correct dosage combination at each stage.

A suitable dosage level for orally-administrable compositions containing aciclovir, of the types described above, would probably be in the region of 800mg acyclovir per dose, five times per day, over the course of one to two weeks. Depending on the exact condition to be treated, total daily aciclovir dosages of between lOOmg and 10 grams may be appropriate; for higher total dosages, the number of separate doses taken per day would usually be higher, and vice versa.

Where famiciclovir is used in place of aciclovir, a suitable total daily dosage would probably be in the region of 750mg, either once per day or split into several individual doses as convenient. Depending on the exact condition to be treated, total daily famiciclovir dosages of between lOOmg and 2 grams may be appropriate.

Where colchicine is the alkaloid of choice, a suitable dosage is probably in the region of 2mg per day, which could be taken as a single daily dose, or as a single daily controlled-release administration, or split into multiple doses to correspond to the administration of aciclovir or other antiviral (e.g. as combination tablets). For many conditions, 0.5mg per day may be sufficient. Where treatment has begun at 2mg per day, the colchicine level may be reduced to 0.5mg per day at an intermediate stage of treatment, or may even be tapered off to zero over the course of the treatment. Depending on the exact condition to be treated, doses of colchicine amounting to between 0.1 mg and lOmg per day may be effective. (Clearly, where possible rabies infection is concerned, the highest doses would be employed, since possible side-effects would be of lesser concern). It is envisaged that one or both active components of the treatment (particularly the colchicine or other alkaloid) may be administered in the form of a transdermal patch or other controlled-release device. It is also believed that tablets designed to be held in the mouth (e.g. under the tongue) for slow dissolution and release of one or both active components, may well be of use.

The present invention thus provides a more reliable and effective approach to the treatment of several medical conditions, particularly viral conditions involving axonal transport such as Herpes zoster (shingles), Herpes simplex (cold sores, herpes of the eye and/or genital herpes) and rabies. The compositions and methods of the present invention may be used as a rapid response to the first onset of symptons, or may be used to prevent recurrence of repeated attacks. They may also be used to slow the course of viral infections such as rabies so as to provide more time for a specific treatment, such as a vaccine, to be obtained and administered. In each case, the combinations of drugs described should have a much greater effect than would either of the individual drugs if administered alone.

Claims

1. A medicament comprising a first substance selected from a group comprising alkaloids, anaesthetics and griseofulvin and a second substance comprising a purine analogue antiviral agent and/or a pyrimidine analogue antiviral agent.

2. A medicament as claimed in claim 1, wherein said first substance comprises an alkaloid.

3. A medicament as claimed in claim 2, wherein said alkaloid comprises an antimitotic alkaloid.

4. A medicament as claimed in either claim 2 or claim 3, wherein said alkaloid comprises colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.

5. A medicament as claimed in any one of the preceding claims, wherein said purine analogue antiviral agent comprises a guanine analogue.

6. A medicament as claimed in any one of the preceding claims, wherein said purine analogue antiviral agent comprises an Ncrsubstituted guanine derivative.

7. A medicament as claimed in any one of the preceding claims, wherein the second substance comprises aciclovir, valaciclovir, penciclovir, famiciclovir, ganciclovir, valganciclovir and/or a prodrug convertible in vivo thereto.

8. A medicament as claimed in any one of claims 1 to 4, wherein said purine analogue antiviral agent comprises an adenine analogue.

9. A medicament as claimed in any one of claims 1 to 4, wherein said purine analogue antiviral agent comprises an Ncrsubstituted adenine derivative.

10. A medicament as claimed in any one of claims 1 to 4, wherein the second substance comprises vindarabine.

11. A medicament as claimed in any one of claims 1 to 4, wherein said pyrimidine analogue antiviral agent comprises a thymidine analogue.

12. A medicament as claimed in any one of claims 1 to 4, wherein the second substance comprises trifluorothymidine.

13. A medicament as claimed in any one of the preceding claims, comprising an orally administrable composition.

14. A medicament as claimed in any one of claims 1 to 12, comprising a topically applicable composition, such as a cream, ointment, salve, eye drops or nasal spray.

15. A medicament as claimed in claim 14, adapted for administration in transdermal patch form.

16. A medicament as claimed in either claim 14 or claim 15, comprising a local anaesthetic, optionally lidocaine.

17. A medicament as claimed in any one of claims 1 to 12, comprising an injectable or infusible liquid composition.

18. The use in the manufacture of a medicament for use in the treatment of neurally transported viral infections of a combination of a first substance selected from a group comprising alkaloids, anaesthetics and griseofulvin and a second substance comprising a purine analogue antiviral agent and/or a pyrimidine analogue antiviral agent.

19. The use of a combination of substances as claimed in claim 18, wherein the first substance comprises an alkaloid.

20. The use of a combination of substances as claimed in claim 19, wherein said alkaloid comprises an antimitotic alkaloid.

21. The use of a combination of substances as claimed in either claim 19 or claim 20, wherein said alkaloid comprises colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.

22. The use of a combination of substances as claimed in any one of claims 18 to 21, wherein said purine analogue antiviral agent comprises a guanine analogue.

23. The use of a combination of substances as claimed in any one of claims 18 to 22, wherein said purine analogue antiviral agent comprises an ^-substituted guanine derivative.

24. The use of a combination of substances as claimed in any one of claims 18 to 23, wherein said purine analogue antiviral agent comprises aciclovir, valaciclovir, penciclovir, famciclovir, ganciclovir, valganciclovir, and/or a prodrug convertible in vivo thereto.

25. The use of a combination of substances as claimed in any one of claims 18 to 21, wherein said purine analogue antiviral agent comprises an adenine analogue.

26. The use of a combination of substances as claimed in claim 25, wherein said purine analogue antiviral agent comprises an Ncrsubstituted adenine derivative.

27. The use of a combination of substances as claimed in either claim 25 or claim 26, wherein said purine analogue antiviral agent comprises vindarabine.

28. The use of a combination of substances as claimed in any one of claims 18 to 21, wherein said pyrimidine analogue antiviral agent comprises a thymidine analogue.

29. The use of a combination of substances as claimed in claim 28, wherein said pyrimidine analogue antiviral agent comprises trifluorothymidine?

30. The use of a combination of substances in the manufacture of a medicament for treatment of neurally transported viral infections, as claimed in any one of claims 18 to 29, wherein the viral infection to be treated comprises a herpes infection.

31. The use of a combination of substances in the manufacture of a medicament for treatment of neurally transported viral infections, as claimed in any one of claims 18 to 29, wherein the viral infection to be treated comprises rabies.

32. The use of a combination of substances in the manufacture of a medicament for the treatment of neurally transported viral infections, as claimed in any one of claims 18 to 31 , wherein the medicament is in the form of a single administrable preparation comprising each of the substances of the combination.

33. The use of a combination of substances in the manufacture of a medicament for the treatment of neurally transported viral infections, as claimed in any one of claims 18 to 31 , wherein the medicament comprises a plurality of preparations each comprising one of the substances of the combination, optionally with said plurality of preparations being so packaged as to define a desired dosage regime.

34. A method for treating a neurally transported viral infection, comprising the step of administering in combination a first substance selected from a group comprising alkaloids, anaesthetic agents and griseofulvin, and a second substance comprising a purine analogue antiviral agent and/or a pyrimidine analogue antiviral agent.

35. A method for treating a neurally transported viral infection as claimed in claim 34, wherein said first and second substances are administered simultaneously, optionally in the form of a single preparation.

35. A method for treating neurally transported viral infection as claimed in claim 34, wherein said first and second substances are administered sequentially.