WO1998017288A1 - Lithium containing medicament for combatting papilloma virus infections - Google Patents

Lithium containing medicament for combatting papilloma virus infections Download PDF


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WO1998017288A1 PCT/GB1997/002905 GB9702905W WO9817288A1 WO 1998017288 A1 WO1998017288 A1 WO 1998017288A1 GB 9702905 W GB9702905 W GB 9702905W WO 9817288 A1 WO9817288 A1 WO 9817288A1
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papilloma virus
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French (fr)
Simon John Arthur Gilburt
Davie Frederick Horrobin
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Scotia Holdings Plc
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Priority to GBGB9621990.2A priority Critical patent/GB9621990D0/en
Priority to GB9621990.2 priority
Application filed by Scotia Holdings Plc filed Critical Scotia Holdings Plc
Publication of WO1998017288A1 publication Critical patent/WO1998017288A1/en



    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K33/00Medicinal preparations containing inorganic active ingredients


The invention relates to the use of a physiologically tolerable lithium compound for the manufacture of a medicament for use in combatting human papilloma virus infections.


This invention relates to the use of lithium in the treatment of human papilloma virus (HPV) conditions and in the manufacture of medicaments for use in combatting, ie . treating or preventing, HPV conditions.
Papilloma viruses are DNA viruses that, in humans, cause squamous cell proliferation, ie. the production of wartlike malformations on external and internal body surfaces. These can occur on a variety of surfaces, principally the skin of the limbs and the plantar area, genital skin and mucosa and larynx and oral mucosa.
HPV replication takes place only in fully differentiated keratinocytes, particularly the cells of the upper stratum spinosum and stratum granulosum. Although the viral genome is present in epithelial cells of the basal layer, late gene expression which codes for the proteins of the viral capsid is dependent on differentiation of the squamous epithelial cells, although different HPV types vary in their specificity for different anatomical sites (see Beutner, J. Am. Acad. Dermatol. H: 114-123 (1989) and Cobb, J. Am. Acad. Dermatol. 22: 547-566 (1990)). Thus for example HPV-1 replicates in the heavily keratinized skin of the palm and sole, HPV-16 replicates preferentially in the genital areas and HPV- 11 replicates in the genital and laryngeal epithelium.
HPV papillomas are initially benign but a small percentage can progress to dysplasia or neoplasia under certain circumstances (genetic and environmental) which are not completely understood. There is moreover increasing evidence that, after initial infection, HPV may persist in a latent form and be subsequently reactivated. HPV infection can generally be diagnosed clinically but infection can be confirmed by laboratory methods including: histology; detection of virus particles by electron microscopy; DNA hybridization on tissue extracts or in situ; and polymerase chain reaction (PCR) amplification of viral DNA fragments.
The time period from acquisition of infection to manifestation of infection can seldom be ascertained but has been estimated at from a few weeks to over a year, eg. 2 years or more. One study of sexual contacts of patients with HPV genital warts indicated an incubation period of three weeks to eight months, averaging 2.8 months (see Oriel, Br. J. Vener. Dis . _ : 1-13 (1971)). Perinatally acquired HPV infection may not manifest itself as genital warts for up to two years and only 57% of cases of HPV laryngeal papilloma in children are diagnosed by two years of age (see Oriel, Br. ed. J. 96 : 1484-1485 (1988) and Bennett, Pediatr. Infect. Dis. J. £: 229-232 (1987) ) .
HPV can be extremely infectious. In a study of 97 sexual contacts of patients with HPV genital warts, two thirds developed lesions within nine months (see Oriel, Br. J. Vener. Dis. 47: 1-73 (1971)). Studies of male sexual contacts of women with genital HPV disease showed the percentage ultimately diagnosed as infected was higher still - 69% in a study by Sand et al . (Obstet. Gynaecol. «S_8: 679-681 (1986)) and 88% in a study by Sedlak et al . (Am. J. Gynecol . 15_4: 494-496 (1986)). It may therefore be concluded that any sexual contact of a patient with genital HPV infection is likely to become infected. The infectivity of other HPV forms seems however to be lower .
HPV infection is spread by direct or indirect contact. Impairment of the epithelial barrier function by trauma (including mild abrasions) , maceration or both greatly predisposes to inoculation of HPV and may be required for infection of fully keratinized skin. Thus plantar HPV warts are commonly acquired from swimming pool or shower-room floors whose rough surfaces abrade moistened keratin from infected feet and help inoculate the virus into the softened skin of others . HPV warts on the other hand may spread widely round the nails or periungual skin in those who bite their finger nails, over habitually sucked fingers in young children, and to the lips and surrounding skin areas in both cases. Shaving may facilitate the spread of HPV infection over the beard area. Occupational handlers of meat, fish and poultry have high incidences of HPV hand warts ; this may be attributable to cutaneous injury and prolonged contact with wet flesh and water. Genital warts, as indicated above, have high infectivity. The thinner mucosal surface is presumably more susceptible to HPV viral inoculation than thicker keratinized skin. Moreover lesions have been noted to occur most commonly in both sexes in sites subject to the greatest coital friction (see Oriel, Br. J. Vener. Dis. .47: 1-13 (1971) ) .
The characteristic histological feature of HPV warts is vacuolation in cells in and below the granular layer, often with basophilic inclusion bodies composed of viral particles and eosinophilic inclusions representing abnormal keratin. Genital HPV warts show extreme acanthosis and papillomatosis, but the horny layer is parakeratoic and not much thickened. There may be many vacuolated cells in the upper Malpighian layer but these may be limited in distribution. The epidermal processes are wide and rounded, with a well defined lower border. The connective tissue is frequently very oedematous and the capillaries tortuous and increased. The term condyloma acuminatum is frequently used to denote HPV anogenital warts as well as associated HPV type infections in the extragenital sites, eg. the mouth .
HPV anogenital warts are often asymptomatic, but may cause discomfort, discharge and bleeding. The typical anogenital wart is soft, pink, elongated and sometimes filiform or peduculated. The lesions are usually multiple, especially on moist surfaces and their growth may be enhanced during pregnancy or in the presence of other local infections. Large malodorous masses may form on vulvar or perianal skin. This classical "acuminate" (sometimes called papillomatous or hyperplastic) form constitutes about two thirds of anogenital warts. The commonest sites, the areas of frenulum, corona and glans in men, and the posterior introitus in women, correspond to the likely sites of greatest coital friction. Most other lesions are flat and some of these, generally on non-mucosal surfaces such as the penile shaft, pubic skin, perianal skin and groin, are pigmented.
Occasionally vulvar HPV warts are so large in pregnancy as to obstruct vaginal delivery and require Caesarian section.
The duration of anogenital warts varies from a few weeks to many years with recurrences experienced in about 25% of cases at an interval of from 2 months to 23 years. HPV DNA has been found in normal skin adjacent to warts and intrapithelial neoplasia and this latency has been found to correlate well with recurrence after clinical cure (see Ferenczy, New Engl . J. Med. 313 : 784-788 (1985)) .
HPV infection, like other viral infections, is not responsive to anti-viral agents in general and a range of different treatments has been developed and are now used. These for the most part depend on local destruction of the infected tissue and not on an antiviral action. They can be very harsh and locally toxic.
A preparation containing salicylic and lactic acids in a quick drying base (such as collodion/pyroxylin paint or gel) is the treatment of first choice for common and plantar warts .
These preparations however are not suitable for treatment of anogenital warts. Thus they can be particularly irritant on facial skin and other sensitive skin areas. Collodion moreover may cause allergic contact dermatitis.
Podophyllin, a plant-derived resin containing several cytotoxic compounds including podophyllotoxin, has been used in the treatment of anogenital warts as has purified podophyllotoxin. Nonetheless this treatment is problematic. Application of podophyllin to large or bleeding areas has been followed by intra-uterine death, vomiting, diarrhoea, liver damage, renal damage, coma, peripheral neuropathy, bone marrow suppression and death (due to presumed systemic absorption) . Oral ingestion has similar effects and can be fatal. In animal studies podophyllin has been found to be an abortifacient .
Podophyllin must therefore not be used on large or bleeding surfaces and its use during pregnancy is generally contra-indicated.
After podophyllin application, some local irritation is expected and, histologically, epidermal intra- and intercellular oedema, mitoses and necrosis are seen. Podophyllin is generally applied only under professional supervision.
Podophyllin is generally ineffective against warts of other types but has been used in treatment of plantar warts. In this treatment the keratin is pared down, the podophyllin preparation is applied and the wart is then covered by adhesive plaster. The dressing is removed after about one week and the treatment is repeated if the wart persists. Acute pain may occur, due to formation of a sterile abscess.
An alternative approach is cryotherapy. In hospital practice, liquid nitrogen is commonly used for this. The main disadvantage of this technique however is pain. This can be unpredictable and surprisingly variable between patients, but in some cases, especially with longer freezing times, the pain may be severe and persist for many hours or even a few days. Occasionally freezing may cause damage to underlying tissues and depigmentation may occur. Depigmentation may of course be a significant cosmetic disadvantage to certain patients. In areas of sensitive skin, eg. in the genital area, cryotherapy is not a preferred technique.
Surgical excision (and analogous techniques such as curettage and electrocoagulation) of HPV warts is also possible although it is generally to be avoided since scarring is inevitable and recurrences of the wart in the scar are frequent. Again, in areas of sensitive skin such techniques are preferably avoided.
Cytotoxic agents, such as bleomycin, have been used to combat HPV warts, generally by injection directly into the lesion by a physician. Injections are painful and local anaesthesia may be required for sensitive sites. Various interferons have been tried in attempts to deal with refractory warts. However the results are not always conclusive. In one study, of 28 patients with refractory anogenital warts given intramuscular human gamma-interferon only two were cleared with thirteen showing some improvement .
A further known treatment for HPV infection is topical application of 5-fluorouracil . If used periungually however, 5-fluorouracil may cause onycholysis and topical application of 5-fluorouracil ointment has resulted in a high incidence of hyperpigmentation as well as erythema and erosion.
There is thus a need for a simple safe and effective means of treating HPV infection, in particular of sensitive skin areas and of HPV anogenital warts.
It has now surprisingly been found that lithium therapy is effective in this regard.
Thus viewed from one aspect the invention provides the use of a physiologically tolerable lithium compound (eg. a lithium salt which acts as a source of bioavailable lithium ions and has a physiologically tolerable counterion) for the manufacture of a medicament for use in combatting human papilloma virus infections, particularly anogenital warts .
Viewed from a further aspect the invention provides a method of treatment of a human subject to combat human papilloma virus infection, said method comprising administering to said subject (eg. a person infected with HPV or at risk of HPV infection due to exposure to HPV infected individuals, for example as a result of sexual contact, birth or repeated exposure to environments where HPV transmission is frequent (such as communal swimming pools, changing rooms and the like)) an effective amount of a physiologically tolerable lithium compound.
While lithium is known to be effective in the treatment of depression, alcoholism, herpes infections, and seborrhoeic dermatitis, its utility in the treatment of HPV disease is surprising and hitherto has not been suggested. Other agents effective in treating herpes infections, such as acyclovir, are ineffective in treating HPV infections. Orally administered lithium moreover is widely acknowledged to have toxic side effects and the margin between therapeutic efficacy and toxicity for its major indication (treatment of manic depressive illness) is narrow. Accordingly in the absence of a strong positive indication of a beneficial activity against a given condition, lithium is not a drug which would routinely be administered.
Lithium thus was not an obvious candidate in the search for a treatment for HPV infection. Its efficacy is unpredictable and surprising since a positive effect on one viral infection cannot readily be extrapolated to a prediction of a similar effect on another, as noted for acyclovir above .
Lithium may be administered according to the invention in any form which will effectively deliver it to the infected area, although inorganic and organic salts are generally preferred. Suitable examples of organic and inorganic salts include lithium succinate, lithium chloride, lithium carbonate and lithium orotate, lithium succinate being generally preferred.
It may also be useful in certain circumstances to administer the lithium in the form of a salt with a polyunsaturated fatty acid, preferably a C18_22