WO2006095178A1 - Medicament and treatment for herpes simplex - Google Patents

Medicament and treatment for herpes simplex Download PDF

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Publication number
WO2006095178A1
WO2006095178A1 PCT/GB2006/000845 GB2006000845W WO2006095178A1 WO 2006095178 A1 WO2006095178 A1 WO 2006095178A1 GB 2006000845 W GB2006000845 W GB 2006000845W WO 2006095178 A1 WO2006095178 A1 WO 2006095178A1
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WO
WIPO (PCT)
Prior art keywords
medicament
herpes simplex
infection
alkaloid
symptoms
Prior art date
Application number
PCT/GB2006/000845
Other languages
French (fr)
Inventor
Anant Sharma
Original Assignee
Anant Sharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anant Sharma filed Critical Anant Sharma
Priority to EP06726355A priority Critical patent/EP1861088A1/en
Priority to JP2008500267A priority patent/JP2008543730A/en
Publication of WO2006095178A1 publication Critical patent/WO2006095178A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention relates to a medicament for use in the treatment of viral infections, such as herpes simplex, 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), using 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.
  • Viruses such as herpes simplex, may lie asymptomatically dormant or latent in nerve cell bodies of the CNS, but when reactivated, by whatever cause, 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 nerve ganglion until reactivated by stress, premenstrual tension or a range of other triggers.
  • the herpes simplex virus typically travels along nerve axons to any part of the body, such as eyes, the nose, genitalia or most usually to the lips, where it leads to symptoms such as cold sores.
  • Herpes simplex infections may also take a more serious form in which the virus travels along nerve cells to the area of the eye socket.
  • HSV may cause symptoms such as ulceration of the cornea, with a potential serious effect on a patient's vision.
  • the current preferred treatment for herpes simplex infection is a drug, such as acyclovir, which interferes with viral replication.
  • acyclovir which interferes with viral replication.
  • cold sores this is administered as a topical cream
  • a typical prescription is administration of acyclovir, five times daily, as an ointment.
  • acyclovir (or equivalent) is only administered once a recurrence of HSV activity is underway (e.g. acyclovir cold sore creams are typically to be administered only once a "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 begins to cause annoying or harmful symptoms.
  • it may be administered orally as twice daily 400mg doses over long periods.
  • an alkaloids or griseofulvin in the manufacture of a medicament for use in the treatment of anterograde neurally transported viral infections.
  • the alkaloid comprises an antimitotic alkaloid.
  • the alkaloid may comprise colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.
  • the viral infection to be treated comprises a herpes infection, such as a herpes simplex infection.
  • the medicament is in an orally administrable form.
  • the medicament is administrable in tablet, capsule, powder or granular form.
  • 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 comprise an injectable or infusible liquid composition.
  • a method for treating a herpes simplex infection comprising the step of administering a substance capable of interfering with or blocking anterograde axonal transport.
  • the method comprises the step of administering said substance prior to the onset of symptoms of the infection.
  • the method comprises the step of administering said substance prophylactically.
  • the method preferably comprises the step of administering a composition comprising an alkaloid, advantageously an antimitotic alkaloid, such as colchicine, vinblastine or vincristine, or griseofulvin.
  • an alkaloid advantageously an antimitotic alkaloid, such as colchicine, vinblastine or vincristine, or griseofulvin.
  • a first example concerns patients with 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.
  • an ointment containing 5% w / w acyclovir 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.
  • colchicine In a treatment embodying the present invention, it is preferred to administer colchicine orally, for example in tablet or capsule form.
  • 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 takes one or more tablets containing colchicine.
  • a topical cream to a likely site of the cold sores, typically around the lips.
  • This cream comprises colchicine, together with conventional excipients, and optionally agents to encourage absorption of the colchicine through the patient's skin. It is believed that the colchicine then permeates retrogradely along the nerve axons towards 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 is believed to slow or even halt its progress along the axon. If the HSV does not reach the skin surface, it will not cause cold sores.
  • a second example concerns patients with 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 trigerminal ganglion becoming reactivated by some recognisable trigger, and travelling anterogradely down the nerve axons.
  • Acyclovir in the form of ointment is administered (five times daily) until the ulcers heal.
  • colchicine in tablet form is administered prior to an outbreak, either regularly or on recognition of a trigger event.
  • ointment or eye drops containing a solution of colchicine are administered to the patient's eyes, as soon as a likely trigger event is noticed.
  • the colchicine permeates retrogradely up the axon towards the trigerminal ganglion and interferes with or halts the progress of HSV towards the eye. Little or no HSV reaches the eye, either preventing or significantly reducing the formation of ulcers.
  • Conventional acyclovir ointment treatment may be used on any ulcers which do still occur, but since these are likely to be far less severe than would otherwise be the case, a much shorter course of treatment will be required to clear them up.

Abstract

A medicament for use in the treatment of viral infections, such as herpes simplex, that are transmitted anterogradely through the nervous system. Viruses, such as herpes simplex, may lie asymptomatically dormant or latent in nerve cell bodies of the CNS, but when reactivated, by whatever cause, 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 stress, premenstrual tension or a range of other triggers. The herpes simplex virus (HSV) typically travels along trigeminal nerve axons to the lips, where it leads to symptoms such as cold sores. Herpes simplex infections may also take a more serious form in which the virus travels along nerve cells to the area of the eye socket. Here, HSV may cause symptoms such as ulceration of the cornea, with a potential serious effect on a patient's vision. The active ingredient of the medicament is an alkaloid such as colchicine, vinblastine, vincristine, a cytochalasin or derivaties thereof.

Description

MEDICAMENT AND TREATMENT FOR HERPES SIMPLEX
The present invention relates to a medicament for use in the treatment of viral infections, such as herpes simplex, 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), using 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. Viruses, such as herpes simplex, may lie asymptomatically dormant or latent in nerve cell bodies of the CNS, but when reactivated, by whatever cause, 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 nerve ganglion until reactivated by stress, premenstrual tension or a range of other triggers. The herpes simplex virus (HSV) typically travels along nerve axons to any part of the body, such as eyes, the nose, genitalia or most usually to the lips, where it leads to symptoms such as cold sores. Herpes simplex infections may also take a more serious form in which the virus travels along nerve cells to the area of the eye socket. Here, HSV may cause symptoms such as ulceration of the cornea, with a potential 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.
The current preferred treatment for herpes simplex infection is a drug, such as acyclovir, 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 acyclovir, five times daily, as an ointment. In each case, acyclovir (or equivalent) is only administered once a recurrence of HSV activity is underway (e.g. acyclovir cold sore creams are typically to be administered only once a "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 begins to cause annoying or harmful symptoms. However, for chronic cases, it may be administered orally as twice daily 400mg doses over long periods.
While the present specification is written primarily with reference to medications for treatment of viral infections of the human body, very similar considerations apply for animal viral infections. All references to human beings should be understood to refer equally to animals unless stated otherwise.
It is hence an object of the present invention to provide a medicament to treat viral infections that are transported anterogradely 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 an use of an alkaloids or griseofulvin in the manufacture of a medicament for use in the treatment of anterograde neurally transported viral infections.
Advantageously, the alkaloid comprises an antimitotic alkaloid.
The alkaloid may comprise colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.
In a preferred embodiment, the viral infection to be treated comprises a herpes infection, such as a herpes simplex infection.
Preferably, the medicament is in an orally administrable form. - A - 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 comprise an injectable or infusible liquid composition.
According to a second aspect of the present invention, there is provided a method for treating a herpes simplex infection, comprising the step of administering a substance capable of interfering with or blocking anterograde axonal transport.
Preferably, the method comprises the step of administering said substance prior to the onset of symptoms of the infection.
Alternatively, the method comprises the step of administering said substance prophylactically.
The method preferably comprises the step of administering a composition comprising an alkaloid, advantageously an antimitotic alkaloid, such as colchicine, vinblastine or vincristine, or griseofulvin. Embodiments of the present invention will now be more particularly described, by way of example.
A first example concerns patients with 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 acyclovir 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, it is preferred to administer colchicine orally, for example in tablet or capsule form. When 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 takes one or more tablets containing colchicine.
Alternatively he or she may immediately apply a topical cream to a likely site of the cold sores, typically around the lips. This cream comprises colchicine, together with conventional excipients, and optionally agents to encourage absorption of the colchicine through the patient's skin. It is believed that the colchicine then permeates retrogradely along the nerve axons towards 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 is believed to slow or even halt its progress along the axon. If the HSV does not reach the skin surface, it will not cause cold sores.
A second example concerns patients with 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 trigerminal ganglion becoming reactivated by some recognisable trigger, and travelling anterogradely down the nerve axons.
Current treatments are in a response to the appearance of symptoms in and around the eye, by which time the patient's sight could already be at risk. Acyclovir in the form of ointment is administered (five times daily) until the ulcers heal.
In a treatment embodying the present invention, colchicine in tablet form is administered prior to an outbreak, either regularly or on recognition of a trigger event. Alternatively ointment or eye drops containing a solution of colchicine are administered to the patient's eyes, as soon as a likely trigger event is noticed. As for the first example, the colchicine permeates retrogradely up the axon towards the trigerminal ganglion and interferes with or halts the progress of HSV towards the eye. Little or no HSV reaches the eye, either preventing or significantly reducing the formation of ulcers. Conventional acyclovir ointment treatment may be used on any ulcers which do still occur, but since these are likely to be far less severe than would otherwise be the case, a much shorter course of treatment will be required to clear them up.

Claims

1. The use of an alkaloid or griseofulvin in the manufacture of a medicament for use in the treatment of neurally anterogradely transported viral infections.
2. The use in the manufacture of a medicament as claimed in claim 1, wherein the alkaloid comprises colchicine, vinblastine, vincristine, a cytochalasin or derivatives thereof.
3. The use of an alkaloid in the manufacture of a medicament as claimed in either claim 1 or claim 2, wherein the viral infection to be treated comprises a herpes infection, such as a herpes simplex infection.
4. The use as claimed in any one of the preceding claims, wherein the medicament is in an orally administrable form.
5. The use as claimed in claim 4, wherein the medicament is administrable in tablet, capsule, powder or granular form.
6. The use as claimed in claim 4, wherein the medicament comprises a drinkable liquid composition.
7. The use as claimed in any one of claims 1 to 3, wherein the medicament comprises a topically applicable composition.
8. The use as claimed in any one of claims 1 to 3, wherein the medicament comprises an injectable or infusible liquid composition.
9. A method for treating a herpes simplex infection comprising the step of administering a substance capable of interfering with or blocking anterograde axonal transport.
10. A method as claimed in claim 9, comprising the step of administering said substance prior to the onset of symptoms of the infection.
11. A method as claimed claim 9, comprising the step of administering said substance prophylactically.
12. A method as claimed in claim 9, comprising the step of administering a composition comprising an alkaloid, advantageously an antimitotic alkaloid such as colchicine, vinblastine or vincristine.
PCT/GB2006/000845 2005-03-11 2006-03-10 Medicament and treatment for herpes simplex WO2006095178A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP06726355A EP1861088A1 (en) 2005-03-11 2006-03-10 Medicament and treatment for herpes simplex
JP2008500267A JP2008543730A (en) 2005-03-11 2006-03-10 Drugs and treatment for herpes simplex

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0505076.0 2005-03-11
GBGB0505076.0A GB0505076D0 (en) 2005-03-11 2005-03-11 Medicament and treatment for herpes simplex and other infections

Publications (1)

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WO2006095178A1 true WO2006095178A1 (en) 2006-09-14

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EP (1) EP1861088A1 (en)
JP (1) JP2008543730A (en)
CN (1) CN101155581A (en)
GB (1) GB0505076D0 (en)
WO (1) WO2006095178A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010020789A2 (en) * 2008-08-20 2010-02-25 Anant Sharma Medicament and treatment for infections
WO2012035321A1 (en) * 2010-09-14 2012-03-22 Ucl Business Plc Methods, compounds and compositions relating to activating a latent virus
EP3073824A4 (en) * 2013-11-25 2017-10-25 Saint Louis University Inhibitors of hsv nucleotidyl transferases and uses therefor

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994388A (en) * 1997-03-18 1999-11-30 The Children's Medical Center Corporation Cytochalasin and isoindolinone derivatives as inhibitors of angiogenesis

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US5994388A (en) * 1997-03-18 1999-11-30 The Children's Medical Center Corporation Cytochalasin and isoindolinone derivatives as inhibitors of angiogenesis

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ALARCON B ET AL: "SCREENING FOR NEW COMPOUNDS WITH ANTIHERPES ACTIVITY", ANTIVIRAL RESEARCH, ELSEVIER SCIENCE BV., AMSTERDAM, NL, vol. 4, no. 5, 1984, pages 231 - 244, XP000885848, ISSN: 0166-3542 *
EL-FIKY F K: "CYTOTOXIC AND ANTIVIRAL ACTIVITIES OF TWENTY-NINE ISOLATED NATURAL COMPOUNDS", ALEXANDRIA JOURNAL OF PHARMACEUTICAL SCIENCES, ALEXANDRIA, EG, vol. 15, no. 1, March 2001 (2001-03-01), pages 70 - 73, XP009064288, ISSN: 1110-1792 *
TAO, PEIZHEN ET AL: "Purification and characterization of herpes simplex virus type I-induced DNA polymerase and its sensitivity towards some antibiotics", KANGSHENGSU , 10(6), 336-41, 335 CODEN: KANGDS; ISSN: 0254-6116, 1985, XP009066312 *
TOKUMARU, TADASU ET AL: "Suppression of herpes simplex virus infection by antimitotic substances in the rabbit cornea", PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE , 137(1), 29-34 CODEN: PSEBAA; ISSN: 0037-9727, 1971, XP009066329 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010020789A2 (en) * 2008-08-20 2010-02-25 Anant Sharma Medicament and treatment for infections
WO2010020789A3 (en) * 2008-08-20 2010-12-09 Anant Sharma Medicament combination comprising alkaloids and a purine analog antiviral agent
WO2012035321A1 (en) * 2010-09-14 2012-03-22 Ucl Business Plc Methods, compounds and compositions relating to activating a latent virus
EP3073824A4 (en) * 2013-11-25 2017-10-25 Saint Louis University Inhibitors of hsv nucleotidyl transferases and uses therefor
US10463664B2 (en) 2013-11-25 2019-11-05 Saint Louis University Inhibitors of HSV nucleotidyl transferases and uses therefor

Also Published As

Publication number Publication date
CN101155581A (en) 2008-04-02
JP2008543730A (en) 2008-12-04
GB0505076D0 (en) 2005-04-20
EP1861088A1 (en) 2007-12-05

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