WO1998003176A1

WO1998003176A1 - Treatment of feline infections peritonitis by an antiviral

Info

Publication number: WO1998003176A1
Application number: PCT/EP1997/003882
Authority: WO
Inventors: Uschi Postl
Original assignee: Smithkline Beecham Plc
Priority date: 1996-07-18
Filing date: 1997-07-16
Publication date: 1998-01-29
Also published as: AU3768797A; GB9615111D0

Abstract

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 manufacture of a medicament for use in the treatment (including prophylaxis) of FIP infection.

Description

TREATMENT OF FELINE INFECTIONS PERITONITIS BY AN ANTTVIRAL

This invention relates to treatment of medical conditions associated with infection with feline infectious peritonitis (FIP), 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- 141927 (Beecham Group p.l.c.) discloses penciclovir, the compound of formula (A):

(A)

and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c). Penciclovir and its antiviral activity is also disclosed in Abstract P.V11-5 p.193 of 'Abstracts of Nth Int. Congress of Microbiology', Manchester, England 7-13

September 1986 (Boyd et. al.).

Orally active bioprecursors of the compound of formula (A) are of formula

(B):

(B) and salts and deπvatives thereof as defined under formula (A); wherein X is C j. alkoxy, NH2 or hydrogen. The compounds of formula (B) wherein X is C [. alkoxy or NH2 are disclosed in EP-A- 141927 and the compounds of formula (B) wherein X is hydrogen, disclosed in EP-A- 182024 (Beecham Group p.l.c.) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A- 182024, hereinafter referred to as famciclovir.

The compounds of formulae (A) and (B) and salts and deπvatives thereof have been descπbed as potentially effective in the treatment of infections caused by herpesviruses, such as herpes simplex type 1 , herpes simplex type 2, vancella-zoster, Epstein-Barr viruses, and cytomegalovirus Famciclovir, sold in the United Kingdom and the United States of America under the trademark, FΛMVIR, is used for treating herpes zoster (shingles) and genital herpes. Feline infectious pentonms (FIP) is a disease caused by a coronavirus infection. Many different strains of coronavirus are capable of infecting cats, but most do not produce senous disease. FlP-producing strains are distinguished by their ability to invade and grow in certain white blood cells The infected cells transpon the virus throughout the cat's body. An intense inflammatory reaction occurs in the ussues where these virus-infected cells locate. It is this interaction between the body's own immune system and the virus that is responsible for the disease.

Infected cats shed coronavirus in their saliva and feaces Most cats become infected by inhaling or ingesting the virus, either by direct contact with an infected cat, or by contact with virus-contaminated surfaces like clothing, bedding, feeding bowls, or toys.

Initial exposure to the FIP virus usually results in no obvious clinical disease, although some cats may experience a mild upper respiratory disease that is charactenzed by sneezing, watery eyes, and watery nasal discharge Some cats may expenence a mild intestinal disease. Most cats that undergo the pnmary infection completely recover, although some of them may become virus earners. A small percentage of exposed cats develop the lethal disease- weeks, months, or perhaps years after pnmary infection. The onset of clinical signs of lethal FIP may be sudden (especially in kittens), or the signs may gradually increase in seventy over a penod of weeks. Many cats have nonspecific signs such as intermittent lack of appetite, depression, rough hair coat, weight loss, and fever. The major forms of lethal FIP are effusive (wet) FIP, noneffusive (dry) FIP, and combinations of both. The most characteristic sign of effusive FIP is the accumulation of fluid within the abdomen and/or chest. When fluid accumulation becomes excessive, it may become difficult for the cat to breathe normally.

The onset of noneffusive FIP is usually slower. Fluid accumulation is minimal, although weight loss, depression, anemia, and fever are almost always present. Signs of kidney failure (increased water consumption and unnation), liver failure (jaundice), pancreatic disease (vomiting, diarrhoea, diabetes), neurologic disease (loss of balance, behavioural changes, paralysis, seizures), ententis (vomiting, diarrhea), or eye disease (inflammation, blindness) may be seen in vanous combinations.

Young cats (less than two years of age), older cats (over ten years old), cats in poor physical condition, and cats undergoing concurrent infections or stress are more susceptible to FIP. It is a relatively uncommon disease in the general cat population, probably affecting fewer than one percent of the cats brought to a veteπnary surgeon for treatment. In multiple-cat populations such as some shelters and cattenes the disease rate can be much higher, affecnng up to 10 to 20 percent of the susceptible population over a penod of several months.

Currently, FIP is considered to be a routinely fatal disease once a positive diagnosis has been made. The basic aim of therapy is to provide supportive care and to alleviate the self- destroying inflammatory response of the disease. Some σeatments may induce short-term remissions in a small percentage of patients. A combination of corticosteroids, cytotoxic drugs, and antibiotics with maintenance of nutrient and fluid intake may be helpful in some cases

It has now been discovered that the above compounds have potential activity against FIP.

Accordingly, the present invention provides a method of treatment of FIP infection in humans, which method compnses the administration to the human in need of such treatment, an effective amount of a compound of formula (A):

(A)

or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.

The term 'acyl denvaπve' is used herein to include any deπvative of the compounds of formula (A) in which one or more acyl groups are present. Such derivauves 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.l.c).

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 formula (B) of interest ts 9-(4-acetoxy-3-acetoxymethylbut- l-yl)-2-amιnopunne, known as famciclovir (FCV), the well-absorbed oral form of penciclovir (PCV).

The compound of formula (A), bioprecursors, salts and deπvatives may be prepared as described in the aforementioned European Patent references.

The compound, in paπicular, famciclovir, 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 earner 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 flavouπng or colouπng agents may be added to form syrups.

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 stenle vehicle. Advantageously, 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.

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 seventy of the infection and the weight of the mammal.

A suitable dosage unit might contain from 50mg to 5g of active ingredient, such as lOOmg to 2g, for example 100 to 500 or 1500mg. 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 may be 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg, lOOmg, 125mg, 250 mg, 500 mg. 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 FIP infection. 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 FIP infection, 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). Combinations with other immunomodulatory compounds, such as other cytokines or cytokine inducers, or other compounds that stimulate or suppress the immune response are also within the ambit of this invention.

The following case study illustrates the invention. Case Study

The cat 'Paula' aged 18.5 months was diagnosed with FIP and showed symptoms of effusive FIP, has been treated with 1/4 of a 250mg tablet of famciclovir twice a day without interruption. After one day of treatment the condition improved and this improvement was maintained. After 3 months of treatment, tests for small amount of coronavirus antibodies in the serum showed that the titre value i.e. the highest serum dilution that still produced a positive reaction small amount of coronavirus antibodies in the serum, had decreased from 1 :300 to 1 : 1600. After 8 months of treatment the cat is still in good condition.

Claims

1. A method for the treatment (including prophylaxis) of FIP infection in domestic cats, which method comprises administering to the cat in need of such treatment, an effective amount of a compound of formula (A):

(A)

2. The use of a compound of formula (A):

(A)

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 FIP infection.

3. A pharmaceutical composition for use in the treatment (including prophylaxis) of FIP infection, which comprises a compound of formula (A):

(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.

4. A method, use, or composition according to any one of claims 1 to 3 wherein the Compound is famciclovir.

5. A method, use, or composition according to claim 4 wherein famciclovir is administered at a dose of 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 75mg, 80mg, lOOmg, 125mg, 250 mg, 500 mg, once, twice, or three times a day.

6. A method, use, or composition according to any one of claims 1 to 5 wherein the compound of formula (I) or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing, is administered in combination with an immunomodulatory agent.

7. A method, use, or composition according to claim 6 wherein the immunomodulatory agent is an interferon.