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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
• • 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
  • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Definitions

• Adenoviruses commonly infect the eye, respiratory and gastrointestinal tracts and can infect other organs such as the liver, urinary bladder, pancreas, central nervous system and others. There are over 50 known serotypes of Human Adenoviruses of which at least 24 have been identified as pathogens. Adenovirus has been shown to persist for months after initial infection in particular in immunosuppressed patients. Table 1 : Adenoviruses Serotypes and Disease
• Adenovirus-related disease An example of Adenovirus-related disease [0003] Adenoviruses are the most prevalent causes of acute ocular viral disease for which there is no known cure. The actual prevalence and incidence of Epidemic Keratoconjunctivitis (EKC) caused by Adenoviruses in the US and internationally are unknown, because general practitioners and optometrists see most cases and this infection does not have to be reported to any medical authority. EKC is highly contagious and has the tendency to occur in epidemics.
• EKC Epidemic Keratoconjunctivitis
• EKC is a self-limiting disease that generally resolves within 1-3 weeks, the patient may remain highly infectious for 10-14 days or more after symptoms develop (I). Symptoms of EKC include conjunctival redness, swelling or redness of the eyelid, discharge from the eye, sticking together of eyelids, pain or discomfort in the eye, photophobia, or a sensation of a foreign body in the eye. In Severe cases, membranous and pseudomembranous conjunctivitis can be seen in one third of cases, which can lead to conjunctival scarring and symblepharon formation (adherence of the bulbar and palpebral conjunctivas) (2;3).
• Both membranes and pseudomembranes can occur in EKC with a distinguishing corneal involvement that ranges from diffuse, fine, superficial keratitis to epithelial defects to subepithelial opacities (2;3). In 20-50% of cases, corneal opacities can persist for weeks to months to several years (l;3). This phenomenon can decrease visual acuity significantly and cause glare symptoms (2).
• Adenoviruses and, in particular, Adenovirus-derived keratoconjunctivitis for both therapeutic and prophylactic purposes and respiratory disease.
• the treatment for adenovirus-derived keratoconjunctivitis, whether it be for therapeutic or prophylactic purposes, can be achieved by topical administration.
• the treatment for respiratory disease may be by injection or by nasal administration, i.e., by spray or nose drops..
• the expression "therapeutic treatment” means treatment for a subject already having the disease.
• prophylactic treatment means treatment for a subject who, while not being infected by the virus, is in a situation wherein they are susceptible to or subject to the possibility of acquiring the disease, e.g., in a household where another resident is already infected.with the disease.
• CTC-96 is effective against types 1 , 2, 3, 4, 5, and 7, attesting to the effectiveness of CTC-96 against the adenovirus derived diseases outlined in Table 1.
• the word “therapeutic” means use of the inventive method to treat a subject who has already been infected with Adenovirus.
• the word “prophylactic” means use of the inventive method to protect or decrease the likelihood of a subject who may be exposed to Adenovirus from being infected with the virus.
• Compound CTC-96 has the structure:
• Ri and Rr are methyl
• R 2 and R 2' are hydrogen and R 3 and R 3 > are methyl
• X and X' are each:
• CTC-96 may be prepared by the method described in the United States
• Patent No.5,756,491 the contents of which are hereby incorporated by reference.
• this compound is administered topically in the form of an aqueous solution.
• Fig. 1 is a graph of Human Adenovirus titers following exposure to CTC-96 prior to cell infection
• Fig. 2 is a graph of virus tiers after exposure of Human Adenovirus infected cells to CTC-96;
• Fig. 3 is a graph depicting the effect of treatment of Adenovirus
• Fig 4 is a graph depicting adenovirus titers after treatment of
• Virus dilutions were prepared from the known titers of the stock viruses (4 x 10 5 pfu/ml; 4 x 10 4 /0.1 ml) of Ad1 Kmetz, Ad2 Wolf, Ad3 Holyfield, Ad4 Harris, , Ad7a Joseph, ATCC. This virus inoculation yielded a virus infection with an m.o.i. (multiplicity of infection) of approximately 1.0.
• 250, 100, 50, 10, and 0 ⁇ g/ml were prepared in culture medium according to the dilution protocol.
• Virus was adsorbed at 37°C in a 5% C0 2 water-vapor atmosphere for 1 hour.
• Viral titers were determined at each drug concentration.
• CTC-96 has considerable advantages as an anti-viral drug: a) because of its unique mode of action it Is effective against herpes and HIV virus mutants which are resistant to currently used drugs; b) because the drug acts against two different viral targets in herpes virus the development of CTC-96-resistant mutants is deemed to be extremely rare; and c) because CTC-96 has anti-inflammatory properties its use replaces the use of steroids in herpes virus and Adenovirus therapeutics. Steroids modulate the immune response in the areas where they are applied and increase tissue susceptibility to pathogens.
• CTC-96 Anti-adenovirus activity of CTC-96 was evaluated by standard cell culture using HeLa cells, a human cervical carcinoma immortalized cell line (the usual host for laboratory grade adenovirus) and anti-viral plaque-reduction assays.
• CTC-96 has an inhibitory (prophylactic) effect on growth when virus is exposed to the drug prior to cell infection.
• Fig. 1 shows Adenovirus type 5 titers following direct exposure of the virus to CTC-96 prior to HeLa cell infection.
• Fig. 1 The data graphically depicted in Fig. 1 were obtained as follows: varying concentrations of the CTC-96 were mixed with concentrated Human Adenovirus, [Adenovirus type 5 (Ad5)] and incubated at 37° C for 60 minutes. Aliquots were then diluted 500 fold into growth medium. Hela cells were exposed to
• CTC-96 also has a potentially therapeutic effect as can be seen by inhibition of viral growth in Adenovirus infected cells, which are subsequently exposed to the drug.
• Fig. 2 shows virus titers obtained after exposure of human Adenovirus type 5 (Ad5) infected HeLa cells to CTC-96. These data were obtained as follows: Adenovirus was adsorbed onto HeLa cell monolayers for 60 min at 37%; serial dilutions of CTC-96 were overlaid onto the minelayers. Monolayers were then incubated for 24 hr at 37°C and 5% C02. Monolayers were then washed, scraped, sonicated, centrifuged and the supernatant serially diluted.
• Fig. 3 shows CTC-96 treatment of Adenovirus induced keratoconjunctivitis.
• the data In Fig. 3 were obtained as follows: rabbits were infected with Human Adenovirus Type 5 by the installation 10 6 pfu adenovirus according to our protocol of conjunctival and corneal scarification for the production of Keratoconjunctivitis. On day 8 post-inoculation treatment with eye drops containing CTC-96 or placebo was initiated. Animals were examined for stromal keratitis and scored by the corneal disease scale of Wander et al.(5). The following are the Criteria For Determination Of Conjunctival Disease:

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• 2004
  • 2004-06-30 CA CA002530838A patent/CA2530838A1/en not_active Abandoned
  • 2004-06-30 EP EP04756542A patent/EP1638506A4/de not_active Withdrawn

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