Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-10-18
1998-12-29
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514110, A61K 3154, A61K 3166
Patent
active
058542400
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to pharmaceutical uses of compounds and to pharmaceutical compositions. In particular, the invention relates to the treatment or prophylaxis of encephalopathy, as may be caused by certain phosphoramide compounds.
BACKGROUND OF THE INVENTION
Ifosfamide (N,3-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide) ##STR1## is a phosphoramide compound which is a well known antineoplastic drug. It is a structural isomer of cyclophosphamide (N,N-bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide) ##STR2## which is also a phosphoramide compound and has a similar clinical utility. Although the antineoplastic activities of ifosfamide and cyclophosphamide are similar, there are sufficient differences for ifosfamide to be useful in situations which have proved refractory to cyclophosphamide therapy.
Ifosfamide is strictly speaking a pro-drug: it has to be metabolised in the liver to be active. In view of this, orally administered ifosfamide would be expected to be more active than the parenterally administered compound; and indeed it is. Oral administration of ifosfamide is desirable not only for the clinical reason of improved bio-activity of the drug but also for the economic reason that non-parenteral administration would reduce hospitalisation. Unfortunately, at least some of ifosfamide's toxic effects are also more pronounced on oral administration, again because of the effects of its metabolites. Surprisingly, until now the biochemical activities by which cyclophosphamide and in particular ifosfamide form their extremely toxic metabolites has remained illusive. It should be appreciated that the group of pharmaceuticals known as oxazaphospharines, such as ifosfamide, cyclophosphoramide and bromoifosfamide, are optically active compounds and therefore any reference made throughout this disclosure, for example, to ifosfamide, is also intended to include the R and S isomers of ifosfamide unless the context requires otherwise.
As with many effective antineoplatic drugs, the toxicity of ifosfamide is clinically a very real problem. Ifosfamide causes haemorrhagic cystitis, a severe toxicity to the bladder, (as does, to a lesser extent, cyclophosphamide) and is practically always administered in conjunction with mesna (sodium 2-mercaptoethanesulphonate), which has a uroprotective action against the effects of both ifosfamide and cyclophosphamide. Although the urinary tract toxicity can therefore now adequately be managed, the same cannot be said for other toxic effects of ifosfamide, particularly its effects on the central nervous system (CNS).
Martindale (28th Edition, 1982) reports that about 10% of patients receiving intravenous ifosfamide experience CNS side effects, especially confusion and lethargy. When ifosfamide is administered orally, the position is even worse: despite its improved efficacy against many tumour types when administered orally, the drug cannot be ethically justified for oral administration, in view of the CNS side effects. In fact, it has been reported that Asta Medica of Frankfurt, who developed ifosfamide, have ceased to sponsor clinical trials of oral formulations of the drug, largely because of the unwillingness of regulatory authorities to grant clinical trial certificates. Even when administered parenterally, the use of ifosfamide at high doses and in patients with organ dysfunction (such as renal failure) is contraindicated because of the frequent occurrence of CNS toxicity.
The CNS toxicity of ifosfamide manifests itself as encephalopathy; in other words, patients exhibit signs of cerebral irritation without any localised lesion to account for them. The cerebral irritation is apparent as cognitive, as opposed to motor or sensory dysfunction, and the symptoms experienced by patients include, in addition to the confusion and lethargy referred to above, sleep disturbance, hallucinations, psychoses and often frank coma.
To date, the only option to the clinical oncologist, if ifosfamide encephalopathy should
REFERENCES:
The Merck Index,11th Ed, p. 778, No. 4822, 1989.
Dyer, An Index of Tumor Chemotherapy, pp. 10-12 and 128, 1949.
Cerny Thomas
Kupfer Adrian
Goldberg Jerome D.
Newcastle University Ventures Limited
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