EP0723448A1 - Use of peniclorin for the treatment of posttherapeutic neuralgia - Google Patents

Use of peniclorin for the treatment of posttherapeutic neuralgia

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Publication number
EP0723448A1
EP0723448A1 EP94929608A EP94929608A EP0723448A1 EP 0723448 A1 EP0723448 A1 EP 0723448A1 EP 94929608 A EP94929608 A EP 94929608A EP 94929608 A EP94929608 A EP 94929608A EP 0723448 A1 EP0723448 A1 EP 0723448A1
Authority
EP
European Patent Office
Prior art keywords
treatment
acyclovir
patients
composition according
pharmaceutically acceptable
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94929608A
Other languages
German (de)
French (fr)
Inventor
Ronald James Boon
David Ronald John Griffin
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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 SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP0723448A1 publication Critical patent/EP0723448A1/en
Withdrawn legal-status Critical Current

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids

Definitions

  • This invention relates to treatment of post-herpetic neuralgia, and to the use of compounds in the preparation of a medicament for use in the treatment of such conditions.
  • EP-A-308065 discloses certain amino acid esters of the purine nucleoside, acyclovir including the compound, 2-[2-amino- l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valinate, valaciclovir, as having improved oral bioavailabilty as compared with the alanine and glycine esters of acyclovir, disclosed in EP-A-99493. The properties of valaciclovir are reviewed in 'Drugs of the Future, 18, 619-628).
  • PPN Post-herpetic neuralgia
  • acyclovir given 800 mg five times daily for seven to ten days has been the only oral antiviral agent approved for treatment of acute herpes zoster. Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established, but "the effects of acyclovir on postherpetic neuralgia are less clear cut," (Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks, J. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. New Engl J Med.
  • Postherpetic neuralgia is a common severe complication of herpes zoster.
  • acyclovir herpes zoster trial McKendrick et al, Br Med J. 1989;298:431
  • no difference was shown between acyclovir and placebo in either the incidence or the duration of postherpetic neuralgia, despite enrolling only those patients most at risk of developing postherpetic neuralgia (eg, elderly).
  • two smaller trials uff et al. Am J Med. 1988;85 (Suppl 2A):84-9; Morton and Thompson, NZ Med J.
  • the present invention provides a method of treatment of PHN in humans, which method comprises the administration to the human in need of such treatment, an effective amount of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
  • a particular compound of interest is valaciclovir, the well-absorbed oral form of acyclovir (ACN).
  • the compound in particular, acyclovir or valaciclovir, may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule.
  • any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk.
  • the compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension.
  • Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups.
  • Sustained release formulations for example tablets containing an enteric coating, are also envisaged.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • An amount effective to treat the virus infection depends on the nature and severity of the infection and the weight of the mammal.
  • a suitable dosage unit might contain from 50mg to lg of active ingredient, for example 800 mg in the case of acyclovir and 1000 mg in the case of valaciclovir. Such doses may be administered up to 5 times a day, 5 times a day in the case of acyclovir and 2 or 3 times per day in the case of valaciclovir.
  • the effective dose of compound is based on administration to an adult of 70kg body weight.
  • the treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset and within 36 or 24 hours of rash onset if at all possible.
  • the treatment period is usually 7 days although it may be less or more than this, for example 5, 6, 10. 14, 21 days or for an indefinite period.
  • the treatment is particularly effective in the case of patients of greater than 50 years of age, and efficacy would be expected to be demonstrated further in patients greater than 60 years of age, especially patients of greater than 70 years of age.
  • the present invention also provides the use of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, in the preparation of a medicament for use in the treatment of PHN. Such treatment may be carried out in the manner as hereinbefore described.
  • the present invention further provides a pharmaceutical composition for use in the treatment of PHN, which comprises an effective amount of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition for use in the treatment of PHN which comprises an effective amount of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier.
  • Such compositions may be prepared in the manner as hereinafter described. The following clinical data illustrate the invention.
  • Clinical Data Patients >18 years of age with clinically diagnosed uncomplicated herpes zoster infection based on clinical judgment who gave written informed consent were eligible for study entry. Exclusion criteria included patients with zoster rash that had been present for >72 hours; complications of herpes zoster (eg, ocular or visceral involvement, disseminated zoster); presence of crusts at enrollment; patients with other serious underlying disease (eg, immunocompromised and/or HIN-infected individuals); or pregnant or lactating females.
  • diseases of herpes zoster eg, ocular or visceral involvement, disseminated zoster
  • presence of crusts at enrollment patients with other serious underlying disease (eg, immunocompromised and/or HIN-infected individuals); or pregnant or lactating females.
  • Patients were prohibited from receiving any concomitant antiviral or immunomodifying therapy and any topical medication which would be applied to zoster lesions during the course of the study. Patients were instructed to return to the clinic for lesion and pain evaluations each of the seven therapy days and every day for the next seven days following therapy. Patients with lesions that were fully crusted by day 7 were examined every other day of the week following therapy. After day 14, weekly visits were required of all patients until all lesions had lost their crusts. Patients were assessed for the presence of postherpetic neuralgia at monthly intervals following healing for an additional five months.
  • the number of papules, vesicles, ulcers, and crusts within the primary dermatome was recorded as none, mild ( ⁇ 25 lesions), moderate (25-50 lesions), or severe (>50 lesions).
  • a specimen for viral culture was taken at baseline and daily thereafter while vesicles were present. Patients were asked to rate the intensity of their pain on a scale of none, mild, moderate, or severe.
  • Time to event Timepoints at which at least 25% (Ql), 50% (Median), or 75% (Q3) of the patients no longer had pain

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pain & Pain Management (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Epidemiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Catching Or Destruction (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The use of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of post-herpetic neuralgia (PHN).

Description

SE OF PENCICLORIN FOR THE TREATMENT OF POSTTHERAPEUTIC NEURALGIA
This invention relates to treatment of post-herpetic neuralgia, and to the use of compounds in the preparation of a medicament for use in the treatment of such conditions.
When used herein, 'treatment' includes prophylaxis as appropriate. EP-A-308065 (The Wellcome Foundation Limited) discloses certain amino acid esters of the purine nucleoside, acyclovir including the compound, 2-[2-amino- l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl L-valinate, valaciclovir, as having improved oral bioavailabilty as compared with the alanine and glycine esters of acyclovir, disclosed in EP-A-99493. The properties of valaciclovir are reviewed in 'Drugs of the Future, 18, 619-628).
Post-herpetic neuralgia (PHN) is by far the most common complication of herpes zoster infection and is one of the most intractable pain disorders (Strommen et al, Pharmacotherapy. 1988;8:52-68). Patients who develop PHN suffer from a debilitating and often intractable pain which can persist for months or even years. Although rare in patients under 50 years of age, the frequency of PHN rises steeply with increasing age.
There is currently no proven therapy for preventing PHN. The pain is due to injury of the nervous system and therefore seldom responds to analgesia used to treat pain associated with tissue damage. Hence, there is a need for therapy which alleviates or shortens the duration of post-herpetic neuralgia.
For many years, acyclovir given 800 mg five times daily for seven to ten days has been the only oral antiviral agent approved for treatment of acute herpes zoster. Its effectiveness in lessening the acute signs and symptoms of herpes zoster has been established, but "the effects of acyclovir on postherpetic neuralgia are less clear cut," (Wood MJ, Johnson RW, McKendrick MW, Taylor J, Mandal BK, Crooks, J. A randomized trial of acyclovir for 7 days or 21 days with and without prednisolone for treatment of acute herpes zoster. New Engl J Med. 1994;330:896-900.) Postherpetic neuralgia is a common severe complication of herpes zoster. In the largest acyclovir herpes zoster trial (McKendrick et al, Br Med J. 1989;298:431), no difference was shown between acyclovir and placebo in either the incidence or the duration of postherpetic neuralgia, despite enrolling only those patients most at risk of developing postherpetic neuralgia (eg, elderly). However, in two smaller trials (Huff et al. Am J Med. 1988;85 (Suppl 2A):84-9; Morton and Thompson, NZ Med J. 1989;102:93-5) which enrolled both young and elderly patients in about equal proportions, some effects were seen during the first three months, but not during months 4 to 6. When one of these studies was re-analyzed (Huff et al J Med Virol. 1993;l(Suppl l):93-6), a significant effect was seen on all zoster-associated pain (ie, continuum of pain from enrollment into study until complete cessation), but postherpetic neuralgia was not addressed.
Additionally, a recent study evaluating acyclovir administered for 7 or 21 days with or without concomitant prednisolone for the treatment of acute herpes zoster revealed that although acute pain was reduced in patients treated with concomitant prednisolone or 21 days of acyclovir compared with those who had received 7 days of acyclovir treatment alone, neither the frequency of zoster-associated pain nor the time to complete cessation of pain was affected by the 14 additional days of acyclovir treatment or by concomitant prednisolone therapy (New Engl J Med. 1994;330:896- 900). No information on the duration of postherpetic neuralgia was reported from that study. Also, as this study did not include a placebo control, no conclusion can be drawn regarding the effect of acyclovir on postherpetic neuralgia.
Beutner et al in 'Abstract. American Academy of Dermatology Annual Meeting, San Francisco, USA, 30 July - 4 August 1994' report efficacy of valaciclovir in zoster associated pain.
It has now been discovered that the above compounds are effective in reducing the duration of PHN when given to the patient during the acute infection.
Accordingly, the present invention provides a method of treatment of PHN in humans, which method comprises the administration to the human in need of such treatment, an effective amount of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
Examples of bioprecursors, pharmaceutically acceptable salts and derivatives are as described in the aforementioned European Patent references, the subject matter of which are incorporated herein by reference.
A particular compound of interest is valaciclovir, the well-absorbed oral form of acyclovir (ACN).
The compound, in particular, acyclovir or valaciclovir, may be administered by the oral route to humans and may be compounded in the form of syrup, tablets or capsule. When in the form of a tablet, any pharmaceutical carrier suitable for formulating such solid compositions may be used, for example magnesium stearate, starch, lactose, glucose, rice, flour and chalk. The compound may also be in the form of an ingestible capsule, for example of gelatin, to contain the compound, or in the form of a syrup, a solution or a suspension. Suitable liquid pharmaceutical carriers include ethyl alcohol, glycerine, saline and water to which flavouring or colouring agents may be added to form syrups. Sustained release formulations, for example tablets containing an enteric coating, are also envisaged.
For parenteral administration, fluid unit dose forms are prepared containing the compound and a sterile vehicle. The compound depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
As is common practice, the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned. An amount effective to treat the virus infection depends on the nature and severity of the infection and the weight of the mammal.
A suitable dosage unit might contain from 50mg to lg of active ingredient, for example 800 mg in the case of acyclovir and 1000 mg in the case of valaciclovir. Such doses may be administered up to 5 times a day, 5 times a day in the case of acyclovir and 2 or 3 times per day in the case of valaciclovir. The effective dose of compound is based on administration to an adult of 70kg body weight.
The treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset and within 36 or 24 hours of rash onset if at all possible. The treatment period is usually 7 days although it may be less or more than this, for example 5, 6, 10. 14, 21 days or for an indefinite period.
The treatment is particularly effective in the case of patients of greater than 50 years of age, and efficacy would be expected to be demonstrated further in patients greater than 60 years of age, especially patients of greater than 70 years of age. The present invention also provides the use of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, in the preparation of a medicament for use in the treatment of PHN. Such treatment may be carried out in the manner as hereinbefore described.
The present invention further provides a pharmaceutical composition for use in the treatment of PHN, which comprises an effective amount of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinafter described. The following clinical data illustrate the invention.
Clinical Data Patients >18 years of age with clinically diagnosed uncomplicated herpes zoster infection based on clinical judgment who gave written informed consent were eligible for study entry. Exclusion criteria included patients with zoster rash that had been present for >72 hours; complications of herpes zoster (eg, ocular or visceral involvement, disseminated zoster); presence of crusts at enrollment; patients with other serious underlying disease (eg, immunocompromised and/or HIN-infected individuals); or pregnant or lactating females.
Patients were prohibited from receiving any concomitant antiviral or immunomodifying therapy and any topical medication which would be applied to zoster lesions during the course of the study. Patients were instructed to return to the clinic for lesion and pain evaluations each of the seven therapy days and every day for the next seven days following therapy. Patients with lesions that were fully crusted by day 7 were examined every other day of the week following therapy. After day 14, weekly visits were required of all patients until all lesions had lost their crusts. Patients were assessed for the presence of postherpetic neuralgia at monthly intervals following healing for an additional five months.
The number of papules, vesicles, ulcers, and crusts within the primary dermatome was recorded as none, mild (<25 lesions), moderate (25-50 lesions), or severe (>50 lesions). A specimen for viral culture was taken at baseline and daily thereafter while vesicles were present. Patients were asked to rate the intensity of their pain on a scale of none, mild, moderate, or severe.
The effect of treatment on resolution of pain following healing was assessed by determining the median time to pain resolution By 90 days after healing 60% of the patients had lost pain. In patients >50 years of age, median time to loss of pain following healing was 57 days.
* Five times daily by oral administration
Time to event: Timepoints at which at least 25% (Ql), 50% (Median), or 75% (Q3) of the patients no longer had pain
When the figures are compared with those for famciclovir (FCV) and placebo, the results were as follows:
The median times to loss of pain following healing in a first study were compared with those seen in a second study for all patients and in patients >50 years of age, to confirming that the speed of pain resolutions were of the same order for famciclovir, and to establish the improvement of acyclovir (ACV) over placebo.

Claims

Claims
1. A method for the treatment (including prophylaxis) of PHN in mammals, including humans, which method comprises administering to the mammal in need of such treatment, an effective amount of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
2. The use of acyclovir or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing in the manufacture of a medicament for use in the treatment (including prophylaxis) of PHN.
3. A pharmaceutical composition for use in the treatment (including prophylaxis) of PHN, which comprises acyclovir, or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, and a pharmaceutically acceptable carrier.
4. A method, use or composition according to claim 1, 2 or 3 wherein the treatment is within 72 hours of herpes zoster rash onset.
5. A method, use or composition according to claim 4 wherein the treatment is within 48 hours of rash onset.
6. A method, use or composition according to any one of claims 1 to 5 where the treatment period is 7 days.
7. A method, use or composition according to any one of claims 1 to 6 wherein the treatment is carried out on patients of greater than 50 years of age.
8. A method, use or composition according to claim 7 wherein the treatment is carried out on patients of greater than 60 years of age.
9. A method, use or composition according to claim 8 wherein the treatment is carried out on patients of greater than 70 years of age.
10. A method, use or composition according to any one of claims 1 to 9 wherein the Compound is acyclovir.
11. A method, use or composition according to any one of claims 1 to 9 wherein the Compound is valaciclovir.
EP94929608A 1993-10-16 1994-10-14 Use of peniclorin for the treatment of posttherapeutic neuralgia Withdrawn EP0723448A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB939321394A GB9321394D0 (en) 1993-10-16 1993-10-16 Pharmaceuticals
GB9321394 1993-10-16
PCT/GB1994/002262 WO1995011027A1 (en) 1993-10-16 1994-10-14 Use of peniclorin for the treatment of posttherapeutic neuralgia

Publications (1)

Publication Number Publication Date
EP0723448A1 true EP0723448A1 (en) 1996-07-31

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP94929608A Withdrawn EP0723448A1 (en) 1993-10-16 1994-10-14 Use of peniclorin for the treatment of posttherapeutic neuralgia

Country Status (9)

Country Link
EP (1) EP0723448A1 (en)
JP (1) JPH09503779A (en)
AU (1) AU7860394A (en)
BE (1) BE1007586A3 (en)
CA (1) CA2174240A1 (en)
FR (1) FR2711061B1 (en)
GB (2) GB9321394D0 (en)
WO (1) WO1995011027A1 (en)
ZA (1) ZA948065B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU765246B2 (en) * 1998-07-09 2003-09-11 Warner-Lambert Company Pharmaceutical composition containing gaba analogs and an antiviral agent to treat shingles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9511027A1 *

Also Published As

Publication number Publication date
FR2711061B1 (en) 1995-12-01
AU7860394A (en) 1995-05-08
WO1995011027A1 (en) 1995-04-27
ZA948065B (en) 1996-04-10
GB9420754D0 (en) 1994-11-30
FR2711061A1 (en) 1995-04-21
GB2282759A (en) 1995-04-19
CA2174240A1 (en) 1995-04-27
GB9321394D0 (en) 1993-12-08
JPH09503779A (en) 1997-04-15
BE1007586A3 (en) 1995-08-16

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