Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
• • 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
  • A61P19/00—Drugs for skeletal disorders
• • 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
• • 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

• This invention relates to treatment of zoster associated pain, and to the use of compounds in the preparation of a medicament for use in the treatment of this condition.
• 'treatment' includes prophylaxis as appropriate.
• EP-A-141927 (Beecham Group p. I.e.) discloses penciclovir, the compound of formula (A):
• the compounds of formulae (A) and (B) and salts and derivatives thereof have been described as useful in the treatment of infections caused by herpes viruses, such as herpes simplex type 1, herpes simplex type 2, varicella-zoster and Epstein-Barr viruses.
• Zoster associated pain is considered to consist of the pain associated with zoster infection and includes the acute phase pain and post-he ⁇ etic neuralgia (PHN), which is by far the most common complication of he ⁇ es zoster infection and one of the most intractable pain disorders (Strommen et al, Pharmacotherapy. 1988;8:52-68).
• PPN post-he ⁇ etic neuralgia
• 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.
• the present invention provides a method of treatment of ZAP in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (A):
• acyl derivative is used herein to include any derivative of the compounds of formula (A) in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula (A) in addition to those derivatives which are per se biologically active.
• the compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p. I.e.).
• a particular compound of formula (B) of interest is 9-(4-acetoxy-3-acetoxymethylbut-l-yl)-2-aminopurine, known as famciclovir (FCV), the well- absorbed oral form of penciclovir (PCN).
• FCV famciclovir
• PCN penciclovir
• the compound in particular, famciclovir, 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.
• Preferred parenteral formulations include aqueous formulations using sterile water or normal saline, at a pH of around 7.4 or greater, in particular, containing penciclovir sodium salt hydrate.
• compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
• a suitable dosage unit might contain from 50mg to lg of active ingredient, for example 100 to 500mg. Such doses may be administered 1 to 4 times a day or more usually 2 or 3 times a day.
• the effective dose of compound will, in general, be in the range of from 0.2 to 40mg per kilogram of body weight per day or, more usually, 10 to 20 mg/kg per day. in the case of famciclovir, the dosage unit would be 250 mg, 500 mg or 750 mg, preferably 250 mg or 500 mg.
• the treatment is preferably carried out as soon as possible after symptoms appear usually within 72 hours, preferably within 48 hours of rash onset.
• the treatment period is usually 7 days.
• 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 a compound of formula (A) 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 ZAP.
• 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 ZAP, which comprises an effective amount of a compound of formula (A) 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 ZAP which comprises an effective amount of a compound of formula (A) 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 compound of formula (A) and its prodrugs show a synergistic antiviral effect in conjunction with interferons; and treatment using combination products comprising these two components for sequential or concomitant administration, by the same or different routes, are therefore within the ambit of the present invention.
• Such products are described in EP-A-271270 (Beecham Group p.l.c).
• FCV doses were equally effective and significantly reduced the duration of VZV recovery from zoster lesions and the time to healing of zoster lesions compared with the placebo-treated group.
• a statistically significant decrease in the duration of acute phase pain was detected for famciclovir-treated patients presenting with severe rash when compared with placebo.
• the effect of famciclovir on PHN was evaluated by assessing pain at 5 monthly visits after healing.
• the duration of PHN for all age groups was significantly reduced from 128 days to 62 and 55 days following treatment with FCV 500 mg and 750 mg, respectively. There were no significant differences in the safety profiles between famciclovir and placebo.
• the median time to loss of pain from enrolment i.e. time to loss of ZAP was 21 days and 27 days for famciclovir doses of 500 mg and 750 mg respectively compared with 30 days for placebo.
• famciclovir dosed tid is an effe; ; ve and well tolerated treatment for patients with acute he ⁇ es zoster infection, significantly decreasing the time to cutaneous lesion resolution and the duration of pain measured both as PHN and as ZAP.
• ACV Acyclovir 800mg five times daily for seven days
• TLZAP Time to loss of ZAP (time to loss of pain from enrolment)

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Virology (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Molecular Biology (AREA)
• Epidemiology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Physical Education & Sports Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

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• 1993
  • 1993-12-22 GB GB939326177A patent/GB9326177D0/en active Pending
• 1994
  • 1994-12-14 CA CA002179282A patent/CA2179282A1/en not_active Abandoned
  • 1994-12-14 WO PCT/EP1994/004163 patent/WO1995017190A1/en not_active Application Discontinuation
  • 1994-12-14 EP EP95905068A patent/EP0735878A1/en not_active Withdrawn
  • 1994-12-14 CN CN94194994A patent/CN1084622C/zh not_active Expired - Lifetime
  • 1994-12-14 AU AU13834/95A patent/AU697290B2/en not_active Expired
  • 1994-12-14 JP JP7517157A patent/JPH09506883A/ja active Pending
  • 1994-12-20 ZA ZA9410113A patent/ZA9410113B/xx unknown

Non-Patent Citations (1)

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