Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2000-01-05
2002-01-29
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C514S365000
Reexamination Certificate
active
06342490
ABSTRACT:
This invention relates to a composition comprising the cardenolide glycoside uscharin.
Plants of the family Asclepidaceae are known to be extremely poisonous. Such plants have a history of use in folk medicines in those areas where they occur naturally, for example in South East Asia and Africa. Two of the best known representatives of the Asclepiadaceae are
Calotropis gigantea
and
Calotropis procera.
Extracts from
Calotropis procera
plants have traditionally been used as an abortifacient, for infanticide, for rheumatic pain and to produce a purgative.
The stems, flowers and leaves of plants from the family Asclepiadaceae (including
Calotropis gigantea
and
Calotropis procera
) are known to contain certain compounds known as cardenolides. In several species substantial amounts of cardenolides have been found to be concentrated in the latex (Roeske et al, in Biochemical Interactions Between Plants and Insects published in Volume 10 of Recent Advances in Phytochemistry, Plenum Press, New York (ed. Wallace), Seiber et al, Phytochemistry 21:2343 (1982), Seiber et al, in Isopentoids in Plants, Academic Press (ed Nes, 1984) and Seiber et al, in J. Chem. Ecol. 6:321 (1980)). The natural production of carcenolides in
Ascelopias curassavia
has been reported by Groeneveld et al in Phytochemistry 29(11):3479-3438 (1990). Examples of carcenolide glycosides found in
C. procera
are voruscharin, uscharin, uscharidin, calotropin, calactin, calotoxin, and caletropagenin Formula I shows the chemical structure of these carcenolides.
R
1
R
2
(95)
H
(96)
H
C
(97)
H
(98)
H
&agr;-OH, &bgr;-H
(99)
H
&agr;-H, &bgr;-CH
(100)
CH
&agr;-OH, &bgr;-OH
It has now been found that the cardenolide uscharin is particularly useful for medical purposes. Whilst uscharin has been isolated and its chemical structure determined, no utility for this compound has previously been reported.
The present invention thus provides a composition comprising uscharin, the analogues and salts thereof as active ingredient together with a pharmaceutically acceptable carrier or excipient.
Further, the present invention also provides the use of uscharin, the analogues and salts thereof for medical (including veterinary) purposes.
Previously, certain cardenolide glycosides such as calotropin and uzarigenin have been noted to have cytotoxic activity against primate tumour cells. Certain cardenolide glycosides from the Asclepiadaceae family share structural and pharmacological similarities with the Digitalis cardiac glycosides. Whilst we do not wish to be bound by theoretical considerations it is believed that the cytotoxicity of some cardenolide glycosides is related to the inhibition of the plasma membrane bound Na
+
/K
+
ATPase (ie analogous to the manner in which Digitalis cardiac glycosides exert their toxic effects). However, it has also been shown that whilst some cardenolide glycosides are cytotoxic to cell cultures they have no in vivo tumour-inhibiting activity. This is true of calotropin and uzarigenin.
It has never previously been proposed that uscharin would be useful for medical applications. The inventors' results have shown that at 1 mg/ml a primary extract of
Calotropis gigantea
known as CGE-1 does have tumour inhibiting activity in rats (weighing about 200 g) and does not lead to the death of the test animals.
Typically, the use of uscharin according to the present invention is to combat cell proliferation for example in the treatment of cancer, Thus administration of uscharin may kill or reduce the growth rate of cancer cells and may also be of application in other medical conditions presenting symptoms of excessive or uncontrolled cell proliferation.
The word “combat” is used herein to refer to treatment of an existing condition so as to alleviate or reverse the symptoms of the condition in an affected human or animal and to prevent such a condition in a healthy human or animal.
The composition according to the present invention may be administered by any convenient route and mention may be made of enteral, parenteral, topical administration and the composition will be formulated accordingly. Conveniently, the composition may be administered locally to the affected site, generally by means of injection. Thus the uscharin will be suitably dissolved and/or suspended in a pharmaceutically acceptable liquid carrier medium, which will generally be aqueous-based, for example an isotonic solution. Alternatively, the composition according to the invention may be taken orally.
Formulations for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemoraneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
The dose will depend on a number of factors known to the skilled physician including the severity of the conditions, the identity of the recipient; and also the is efficacy and toxicity of the particular composition which is being administered. Generally doses in the range 0.1-100 mg/kg body weight may be used, particularly 1-10 mg/kg. The frequency of administration will vary depending on the rate of metabolism or excretion of the administered compound, but may be repeated daily, optionally as two or more sub-doses. Unit doses of 20 to 500 mg, preferably 100 to 400 mg may be used.
A single dosage may be given daily or smaller quantities or dosage units may be given at intervals throughout a 24 hour period, for example dosage units given 2, 3 or 4 times throughout the day.
Any type of cancer or condition involving cell proliferation may be treated by the present invention. Uscharin is especially useful for the treatment of cancers such as leukaemia, non-small cell lung cancer, small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostrate cancer, and breast cancer. However the invention is not limited to treatment of these specific conditions since uscharin is believed to be of general effect.
Cancers where uscharin is particularly efficacious include ovarian cancer and skin cancer.
Uscharin may by produced by any convenient method, for example by chemical synthesis. Alternatively the uscharin may be conveniently extracted and purified from organisms (for example plants of the family Asclepiadacaeae) which produce uscharin naturally. It is also envisaged that uscharin may be manufactured using genetically engineered micro-organisms, plants or animals or may be made using cell-culture or other biotechnological techniques.
Further, the present invention also provides the use of a composition as described above for medical purposes, for example to combat conditions in which cell proliferation is undesirable (eg cancer).
In another aspect, the present invention provides the use of uscharin in the manufacture of a medicament. Generally such medicament would be of use to combat cancer and other conditions where cell proliferation is undesirable.
In a further aspect, the present invention provides a method of treatment of a human or non-human animal body, said method comprising administering to said body a composition as described above.
REFERENCES:
patent: 92/09295 (1992-06-01), None
Hussein et al., J. Chem. Ecol., 20(1), 135-40 Abstract Only 1994.*
Parsons et al., “Cat assay for the emetic action of digitalis and related glycosides”, Br. J. Pharmacol., vol. 42, No. 1, 1971, pp. 143-152.
Kiuchi et al., “Cytotoxic Principles of a Bangladeshi Crude Drug, Akond Mul (Roots of Calotropis gigantea
Anand Chaman Lal
Gray Alexander Irvine
Stimson William Howard
Goldberg Jerome D.
Phyto Corporation Limited
Ratner & Prestia
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