Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2000-04-28
2003-07-01
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C424S773000, C424S774000, C424S775000, C424S900000, C424S777000, C424S778000, C424S779000
Reexamination Certificate
active
06586015
ABSTRACT:
The present invention relates to the use of Phyllanthus for preventing or treating connective tissue proliferations, for maintaining the level of reduced glutathione, for inhibiting the lipopolysaccharide (LPS)-induced nitric oxide synthase (NOS) and for inhibiting the expression of the cyclooxygenase (COX-2) protein.
Phyllanthus embraces a widespread group of plants native to Central and South India, Taiwan, and areas of Central and South America. The term Phyllanthus means for the purpose of this invention all representatives of the botanical family of Phyllanthus, such as Phyllanthus niruri or, in particular, Phyllanthus amarus etc. The treatment of a large number of disorders with Phyllanthus is known in Indian folk medicine. Thus, for example, the author of “Doctor K. M. Nadkarni's Indian Materia Medica (3
rd
edition; revised and enlarged by A. K. Nadkarni)” reckons in volume I that the plant is known to be deobstruent, diuretic, astringent and cooling. Likewise, compositions with Phyllanthus are described for treating jaundice, dropsy, gonorrhoea, menorrhagia and other impairments of a similar type relating to the urogenital tract. Also known are the use of the sap from the trunk mixed with oil as ophthalmologicals or administrations for ulcers, wound sites and swellings etc., as well as the leaves for treating pruritus or other skin impairments.
There is also known to be a large number of active substances which can be isolated from Phyllanthus, phyllanthin, hypophyllanthin, triacontanol, triacontanal, repandusinic acid A (see, for example, JP 03206044 A; AIDS-Res-Hum-Retroviruses (11/1992), vol. 8 (11), HIV-1 reverse transcriptase . . . ), phyllanthostatin-1, phyllanthoside, phyllanthocin, phyllanthocin acid (see, for example, EP 173 4480; U.S. Pat. No. 4,388,457), phyllamycin A, B and C, retrojusticidin B, justicidin A and B (see, for example, AIDS-Weekly, 25.9.95, AIDS Therapies Extracts . . . ), linoleic acid, linolenic acid and ricinoleic acid (see, for example, Journal of the American Oil Chemists Society edition 81.06.00, ricinoleic acid in Phyllanthus niruri . . . ), phyllamyricin D, E and F, phyllamyricoside A, B and C (see, for example, J. Nat. Prod. (11/1996), vol. 59 (11), Six lignans from . . . ), putranjivain A (see, for example, Chem. Pharm. Bull. (Tokyo), (04/1995), vol. 43 (4), Inhibitory effects of Egyptian . . . ), ursulic acid and niruriside (see, for example, J. Nat. Prod. 02/96, vol. 59 (2), Niruriside, a new HIV . . . , Rec. Trav. Chim. (06/1996), Synthesis of . . . ).
Therapeutic effects and administrations disclosed to date are an age-retarding effect (see, for example, JP 08176004), prevention and therapy of immunodeficiencies such as AIDS, influenza, colds, tuberculosis, hepatitis, cirrhoses (see, for example, U.S. Pat. No. 5,529,778; AIDS-Weekly-Plus of 05.08.96, Antiviral (Drug Development); Inhibition of HIV . . . ), antineo-plastic effect (see, for example, U.S. Pat. No. 4,388,457), therapy of HIV, HBV and/or HCV infections, especially topical treatment of Kaposi's sarcoma (see, for example, EP 1734480; U.S. Pat. No. 5,466,455), effect as protease inhibitor, elastase inhibitor and as bleach (see, for example, JP 09087136), analgesic and antiinflammatory effect, effect as tyrosinase inhibitor (see, for example, JP 08012566) and a use as disinfectant in combination with extracts from other plants. Moreover, uses in cosmetic preparations are also known. It is evident from this large number of different areas of administration and isolated active substances that Phyllanthus is a thoroughly well-known group of medicinal plants employed for a large number of indications and complaints.
One pathological phenomenon which appears to be responsible for a large number of other complaints is so-called oxidative stress. By this is meant the stress on the living cell through accumulation of toxic oxidized compounds, such as lipid hydroperoxides, hydrogen peroxide, singlet oxygen and hydroxyl/superoxide anions. It is moreover possible for the stress to arise through free radicals which are produced locally or supplied from outside, especially so-called reactive oxygen species (ROS) or peroxonitrite free radicals etc. The oxidative stress can also be induced, for example, by exposure to radiation, xenobiotics, heavy metal ions or ischaemia/reperfusion (temporary interruption of the blood supply to an organ). In the latter case there is copious formation of superoxide anions by xanthine oxidase, one of the oxidases of about 300 kD and belonging to the flavoproteins, which catalyses the breakdown of purines, because its natural electron acceptor is oxygen. Under physiological conditions, these superoxide anions are deactivated by superoxide dismutase, but on reperfusion it has been demonstrated that this involves production of large amounts of oxygen free radicals.
Oxidative stress plays an important part in the development of a number of acute and, in particular, chronic disorders, for example inflammations of various types, microangiopathies, fibrosis, rheumatoid arthritis and other rheumatic disorders, arteriosclerosis (LDL oxidation), tumour development and progression, possibly Alzheimer's disease, but also drug-induced acute damage such as paracetamol damage to the liver.
The liver moreover plays, as central dynamic organ of the body, an important part in a large number of the physiological and microphysiological processes mentioned, the metabolic activities of the liver (intermediary metabolism) being of crucial importance on the one hand for supplying other organs but also, on the other hand, for the chemical conversion (biotransformation) of pharmaceutically active substances (see Pschyrembel, Klinisches Wörterbuch, de Gruyter Verlag, 1986, pp. 935-937). The phenomenon of oxidative stress which has already been described is likewise for the most part combated by the body in the liver. This contains a reservoir of diverse reduced compounds of antioxidants, for example L-ascorbic acid, carotenoids, dihydrolipoic acid, uric acid, glutathione or &agr;-tocopherol, and prevents the occurrence of reactive free radicals by means of various enzyme activities (for example superoxide dismutase, peroxidases such as glutathione peroxidase, catalase, etc.).
Oxidative stress also has in particular adverse effects on a large number of functions of liver tissue. Liver tissue frequently responds to this with connective tissue proliferation, which favours further progression of permanent liver damage, such as, for example, the development of a liver tumour. In this connection, bile acids in particular are involved in the pathogenesis of the hepatotoxic effect.
In all the above-mentioned disorders, the balance between oxidative stress and the defence systems of the cells and organs have crucial importance. It is therefore of crucial prophylactic and therapeutic importance on the one hand to protect the healthy liver from oxidative stress and, on the other hand, to strengthen the diseased liver so that it is able permanently to overcome pre-existing oxidative stress.
Compounds with a hepatoprotective activity have in some cases considerable disadvantages because they cannot be used if the liver is already diseased, because the toxicity is too high.
The present invention is therefore based on the object of providing substances which act on the liver and have both a prophylactic and a therapeutic effect.
The present invention relates to the use of Phyllanthus for preventing or treating connective tissue proliferations, in particular fibrotic changes for example of the liver, of the lung, of the kidney, of the pancreas, of the intestine, of endocrine organs, of the spleen, of the male or female urogenital tract, of the joints, for example as a consequence of chronic inflammatory processes such as, for example, rheumatoid arthritis or chronic cardiomyopathies, and of cirrhoses, an advanced stage of fibroses.
The use according to the present invention is therefore particularly preferable for fibroses and cirrhoses, preferably fibrosis of the liver and cirrh
Bahr Matthias
Buniatian Gayane Hrachia
Gebhardt Rolf
Manns Michael P.
Vollmar Angelika M.
Baker & Botts L.L.P.
Coe Susan D.
Lankford , Jr. Leon B.
Phytrix AG
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