USE OF PHOSPHONOACETIC OR-FORMIC ACIDS AGAINST HUMAN HERPES VIRUS -7 (HHV-7)

Abstract: The use of a pyrophosphate analogue having activity against herpes viruses in the manufacture of a medicament for use in the treatment (including prophylaxis) of HHV-7 infection.

Description: OF PHOSPHONOACETIC OR-FORMIC ACIDS AGAINST HUMAN HERPES VIRUS -7 (HHV-7) This invention relates to treatment of infection caused by human herpesvirus 7 (HHV-7), 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. Phosphonoacetic Acid (PAA) and phosphonoformic acid (PFA, foscarnet) are pyrophosphate analogues which inhibit the replication of several viruses including members of the herpesvirus group (Oberg, Pharmacol. Ther. 19, 387-415, 1983). Human herpesvirus 7 (HHV-7) is a recently discovered member of the family Herpesviridae. The virus was first isolated in 1989 from the peripheral blood lymphocytes (PBL) of a healthy individual that were being cultured under conditions that lead to T-cell activation. Analysis of restriction endonuclease profiles of the viral DNA indicated that the new agent differed from the other known human herpesviruses. Since then, HHV-7 has been isolated from the saliva of as many as 75% of healthy adults. Antibodies to HHV-7 can be detected in serum specimens from approximately 90% of the normal population and seroconversion usually occurs during childhood after the age of 2. It is possible that HHV-7 may play a role in the activation of human immunodeficiency virus (HIV-1). It has now been discovered that the above compounds have potential activity against HHV-7. Accordingly, the present invention provides a method of treatment of HHV-7 infection in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a pyrophosphate analogue having activity against herpesviruses. The compound may be administered in the form of a bioprecursor or pharmaceutically acceptable salt. 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. If the compound is sufficiently bioavailable, it 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. 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 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. The usual dosage for foscarnet in treatment of cytomegalovirus infections are as indicated on the British product data sheet, beginning with a 30 minute infusion of 20 mg/kg body weight. The present invention also provides the use of a pyrophosphate analogue having activity against herpesviruses in the preparation of a medicament for use in the treatment of HHV-7 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 HHV-7 infection, which comprises an effective amount of a pyrophosphate analogue having activity against herpesviruses, and a pharmaceutically acceptable carrier. Such compositions may be prepared in the manner as hereinafter described. An assay method involving the inhibition of a cytopathic effect in human cord blood cells is conducted at a dose range of 0.0 lμM - lOOμM. The general procedure is as described for HHV-6, in Chapter 23 of "Human Herpesvirus; Epidemiology, Molecular Biology and Clinical Pathology - Conference Proceedings, Ablashi D. V. (Ed). Evaluation of PFA against HHV-7 in Human Cord Blood Cells* 3 Human mononuclear cells were isolated from umbilical cord blood and inoculated in triplicate with the test virus. One hour later, duplicate dilutions of the compound were added, resulting in 0, 5, 10, 50, or 100 μM final concentrations. After 3 - 6 days, cellls were removed and tested for the presence of virus by indirect immunofluorescence (IFA) using type specific monoclonal antibodies. Three fields of 100 cells each were read from each sample. a Dilutions of the compounds were added 1 hr after viral inoculation of human cord blood. The % infected cells was measured by anti-complement immunofluorescence (ACIF). AU numbers are averages of results of cord blood from 3 donors and triplicate readings were performed on each sample. Each reading represents actual counting of 3 fields.

Claims: Claims 1. A method for the treatment (including prophylaxis) of HHV-7 infection in mammals, including humans, which method comprises administering to the mammal in need of such treatment, an effective amount of a pyrophosphate analogue having activity against herpesviruses 2. The use of a pyrophosphate analogue having activity against herpesviruses in the manufacture of a medicament for use in the treatment (including prophylaxis) of HHV-7 infection. 3. A pharmaceutical composition for use in the treatment (including prophylaxis) of HHV-7 infection, which comprises a pyrophosphate analogue having activity against herpesviruses, and a pharmaceutically acceptable carrier. 4. A method, use or composition according to any one of claims 1 to 3 wherein the treatment is for HHV-7 infection in patients infected with human immunodeficiency virus. 5. A method, use or composition according to any one of claims 1 to 4 wherein the Compound is phosphonoacetic Acid (PAA) or phosphonoformic acid (PFA, foscarnet).

Inventors: FEORINO PAUL M, SCHINAZI RAYMOND F, VERE HODGE RICHARD ANTHONY, FEORINO, PAUL, M., SCHINAZI, RAYMOND, F., VERE HODGE, RICHARD, ANTHONY
Applicants: FEORINO PAUL M, SCHINAZI RAYMOND F, SMITHKLINE BEECHAM PLC, VERE HODGE RICHARD ANTHONY, FEORINO, PAUL, M., SCHINAZI, RAYMOND, F., SMITHKLINE BEECHAM P.L.C., VERE HODGE, RICHARD, ANTHONY
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61P31