Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1995-09-12
1998-02-17
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514 24, 514 45, 514275, 514311, 514380, 514564, 514592, 514636, 514646, A61K 31135, A61K 31505, A61K 3142, A61K 31155
Patent
active
057191921
DESCRIPTION:
BRIEF SUMMARY
This is a 371 of PCT/IT94/00023 filed Mar. 11, 1994.
This invention relates to a new therapeutic use for terbinafine More precisely, this invention relates to the use of terbinafine for the therapeutic treatment of Pneumocystis carinii pneumonia, or pneumocystosis.
Pneumocystis carinii pneumonia is one of the diseases most frequently encountered in new-born, undernourished children and subjects with leukaemia or lymphoma, as well as in transplant recipients or in patients subjected to immunosuppressive therapy. In addition, it is the most frequent infection and the main cause of death in patients suffering from AIDS.
Treatment is of fundamental importance because the uncured disease carries a very high mortality rate, bordering upon 100%. When promptly treated, pneumocystosis has a 25 to 20% mortality rate (first episode), but relapses are frequent (35% with 6 month, 60% within 12 month) and are associated with a 50 to 60% mortality rate. The mean life expectancy has been calculated as 12,5 months from occurrence of the first episode in U.K. and 9 months in the U.S.A.
The main anti-Pneumocystis drugs in current use are trimethoprim-sulphamethoxazole (cotrimoxazole), pentamidine isethionate, dapsone, the trimethoprim-dapsone combination, trimethotrexate, eflornithine hydrochloride and the clindamycin-primaquine combination. Other drugs can be used such as inosine analogues, dapsone derivatives and carbutamide.
Cotrimoxazole is used at dosage of 20 mg/kg/day i.v. or per os in divided doses every 8 h for 3 weeks (blood concentration 22 5/100 ng/ml). Side effects may occur due to idiosyncratic phenomena and include: skin rash, erythroderma, Stevens-Johnson syndrome, exfoliative dermatitis, fever, anaemia, leukopenia, thrombocytopenia, anorexia, nausea, vomiting, serum creatinine elevation, interstitial nephritis, etc.
Pentamidine is administered at doses of 4 mg/kg/day i.v. for 3 weeks or i.m. (the latter route may cause sterile abscesses). The main side effects are hypoglycaemia, tachycardia, arterial hypotension, shock, serum creatinine elevation, serum transaminase elevation, hallucinations, taste disorders, nausea, vomiting, diarrhoea skin rash, leukopenia and thrombocytopenia.
Pentamidine can also be used by aerosol in both the primary and secondary prophylaxis of P. carinii pneumonia. In this case, it reaches high concentrations in the alveolar spaces (>10-fold) and low blood levels (<10 ng/ml as against 600 ng/ml by the hepatic route). No haematic side effects are observed with this administration method. However, cough, bronchospasm, relapses in the upper lobes, and pneumothorax may occur. The drug is administered at the does of 300 mg every d30 days.
Other drugs which can be used for prophylactic purposes are oral cotrimoxazole (160/800 mg b.i.d.) continuously or on three consecutive days each week and Fansidar (1 tablet a week), though the results obtained to date with the latter drug are contradictory.
Other treatments are oral trimethoprim-dapsone (20/100 mg/kg/day) in a once-daily dose for 21 days. The main contraindications are glucose 6-phospate dehydrogenase deficiency and simultaneous intake of zidovudine.
Therapies which are rarely used are those based on trimethotrexate (30/60 mg/m.sup.2 i.v.)+leucovorin (20/80 mg/m.sup.2 i.m. or per os). Skin rashes or haematological abnormalities may occur. Eflornithine (100 mg/kg i.v. every 6 h) can cause reduced Hb, thrombocytopenia, skin rash and nausea.
The combination of clindamycin and primaquine (900 mg of clindamycin i.v. every 8 h+30 mg of primaquine/day) can give rise to nausea, haematological abnormalities or altered liver function parameters.
During the acute phase of pneumocystosis, corticosteroids can be administered, which are thought to exert a certain limiting action on mononuclear infiltrates and on type 2 alveolar cell hyperplasia. In addition, they are thought to inhibit the action of phospholipase A (surfactant degradation).
To date, terbinafine has been used exclusively in the treatment of superficial mycoses. The knowledge acqu
Contini Carlo
De Simone Claudio
Tzoutzoglou Sonia
Mendes s.r.l.
Spivack Phyllis G.
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