Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2000-09-21
2002-03-26
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S027000, C424S401000, C424S439000, C424S440000, C426S072000, C426S541000, C426S542000, C426S546000, C426S655000, C426S658000
Reexamination Certificate
active
06362167
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method of blocking free radical processes in an animal which result in mediated pathology without accompanying deleterious pro-oxidant side reactions, and, more particularly, to administration of an extract of the fruit of the Emblica officinalis plant to effect such result.
2. Description of the Prior Art
The biomedical literature has recognized that “free radicals” and other reactive species are involved in different human diseases. These species have been implicated in over 100 disorders, ranging from rheumatoid arthritis and haemorragic shock to cardiomyopathy and cystic fibrosis to gastrointestinal ischaemia, AIDS and even male pattern baldness. Some of the clinical conditions in which the involvement of free radicals is given in Table 1 below.
TABLE 1
Category
Examples
Inflammatory/immune
Glomerulonephritis, vasculitis,
injury
Autoimmune diseases, rheumatoid arthritis,
hepatitis
Ischaemia-reflow states
Stroke, myocardial
infarction/arrythmias/angina/stunning, organ
transplantation, inflamed rheumatoid joint,
frostbite, Dupuytren's contracture, cocaine-
induced fetal damage
Iron overload (tissue
Idiopathic haemochromatosis, dietary
and plasma)
iron overload (Bantu), thalassaemia and
other chronic anaemias treated with multiple
blood transfusions, nutritional deficiencies
(kwashiorkor), alcoholism, multi-organ
failure, cardiopulmonary bypass, fulminant
hepatic failure, prematurity, alcohol-related
iron overload, cancer
chemotherapy/radiotherapy
Radiation injury
Consequences of nuclear explosions,
accidental exposure, radiotherapy or
exposure to hypoxic cell sensitizers or
radon gas; cataract
Ageing
Disorders of premature ageing, ageing
itself, age-related diseases, e.g. cancer
Red blood cells
Phenylhydrazine, primaquine and related
drugs, lead poisoning, protoporphyrin
photoxidation, malaria, sickle cell anaemia,
favism, Fanconi's anaemia, haemolytic
anaemia of prematurity, chemotherapy
Respiratory tract
Effects of cigarette smoke, snuff inhalation,
other smoke inhalation, emphysema
(COPD), hyperoxida, bronchopulmonary
dysplasia, exposure to air pollutants (03,
NO
2
, SO
2
diesel exhaust), ARDS, mineral
dust pneumoconiosis, asbestos
carcinogenicity, bleomycin toxicity, paraquat
toxicity, skatole toxicity, asthma, cystic
fibrosis
Heart and cardiovascular
Alcohol cardiomyopathy, Keshan
System
disease (selenium deficiency),
artherosclerosis, anthracycline
cardiotoxicity, cardiac iron overload
Kidney
Autoimmune nephrotic syndromes,
aminoglycoside nephrotoxicity, heavy metal
nephrotoxicity (Pb, Cd, Hg),
myoglobin/haemoglobin damage,
haemodialysis, transplant storage/rejection
Gastrointestinal tract
Betel nut-related oral cancer, liver injury
caused by endotoxins or halogenated
hydrocarbons (e.g. bromobenzene, CCI
4
),
exposure to diabetogenic agents,
pancreatitis, NSAID-induced gastrointestinal
tract lesions, oral iron poisoning
Brain
ervous system/
Hyperbaric oxygen, vitamin E
Neuromuscular disorders
deficiency, exposure to neurotoxins,
Alzheimer's disease, Parkinson's disease,
Huntington's chorea, stroke, neuronal
ceroid lipofuscinoses, allergic
encephalomyelitis, aluminium overload,
sequelae of traumatic injury, muscular
dystrophy, multiple sclerosis, amyotrophic
lateral sclerosis, Guam dementia; may also
occur during preservation of fetal dopamine-
producing cells for transplantation
Eye
Cataract, ocular haemorrhage,
degenerative retinal damage/macular
degeneration, retinopathy of prematurity
(retrolental fibroplasia), photic retinopathy,
penetration of metal objects
Skin
UV radiation, thermal injury, porphyria,
hypericin, exposure to other
photosensitizers, contact dermatitis,
baldness
Abbreviations: ARDS, adult respiratory syndrome; COPD, chromic obstructive pulmonary disease; NSAID, non-steroidal anti-inflammatory drug
These pathologies have been alleviated with antioxidants which function as blockers of such radical process. However, an antioxidant cannot distinguish between radicals that play a useful physiologic role and those that are harmful. Moreover, antioxidant compounds not only function as antioxidants, but they may have pro-oxidant action as well. Examples of antioxidants which also exhibit pro-oxidant activity are given below:
Vitamin C
Vitamin C is a hydrophilic vitamin with well-known antioxidant properties; however Vitamin C also can act as a pro-oxidant in the following manner. Specifically, the combination of Vitamin C with Fe
3−
or Fe
2+
ions causes intense oxidation of polyunsaturated fatty acids (PUFAs). The mechanism of such pro-oxidation is as follows:
The Vitamin C radical (dehydroascorbate radical anion, Vit C.), a relatively non-reactive species, can decay by disproportionation resulting in the production of Vitamin C and dehydroascorbate (DHA), thereby terminating the propagation of free radical reactions:
2Vit C.+2H
+
→Vit C+DHA
Alternately, the vitamin C radical may reduce another Fe
'+
ion:
Vit C.+Fe
3+→DHA+Fe
2+
During oxidation of Vitamin C, H
2
O
2
is also formed:
Vit C+O
2
→DHA+H
2
O
2
The reduction of Fe
3+
thus appears to be the probable cause for the pro-oxidant action of Vitamin C. The degree of ferric ion reduction may therefore determine the prevalence of Vitamin C acting either as an antioxidant or as a pro-oxidant.
Vitamin E
The propagation reaction of the oxidative breakdown of PUFAs, indicated as LH, is shown below, where K
1
is the equilibrium constant:
In which LOO
.
indicates lipid peroxyl radicals.
The lipid-soluble Vitamin E thus owes its antioxidant activity to trapping of LOO
.
, which in turn is reduced to stable LOOH (lipid hydroperoxides), as follows:
Vitamin E itself is a mixture of four lipid-soluble tocopherols (designated as &agr;, &bgr;, &ggr; and &dgr;); &agr;-tocopherol being the most active with respect to trapping of peroxyl radicals. The resonance stabilization of Vit E derived from &agr;-tocopherol renders it less reactive than LOO
.
, therefore, Vitamin E is a good antioxidant.
In contrast, Vitamin E, if present at a relatively high concentration, can induce deleterious radical formation by a side reaction with LOOH, thus functioning also as a pro-oxidant.
Vit E+LOOH→Vit E
.
+LO
.
+H
2
O
Superoxide Dismutase (SOD)
Intra-articular administration of Cu/Zn-containing SOD has been used to prevent free radical damage. However, H
2
O
2
, a reaction product of O
2
−
dismutation, can inactivate SOD. Therefore, in the presence of H
2
O
2
, SOD will act as a pro-oxidant.
Glutathione (GSH)
Thiol (SH) groups are essential in the protection against the deleterious effects of reactive oxygen species. The tripeptide GSH (&ggr;-Glu-Cys-GLY) is the pivot in various protective systems. In addition, the SH group is important for the function of many proteins. To protect the SH groups of proteins, high concentrations of the reducing GSH are required. However, it is difficult to estimate the level of GSH needed for this function since thiols may exhibit both antioxidant and pro-oxidant actions. The pro-oxidant activity of the thiol GSH can be simply explained as involving the reduction of Fe
2+
. Hence, a generally accepted antioxidant, such as GSH, may possess deleterious pro-oxidant activity under certain conditions.
Accordingly, it is an object of this invention to provide a method of blocking free radical processes which result in mediated pathology without deleterious pro-oxidant side reactions.
Another object of the present invention is to provide advantageous antioxidant activity to block free radical processes without accompanying pro-oxidant side reactions by administration of an extract of the fruit of the Emblica officinalis plant, optionally including one or more additional antioxidants.
A feature of the invention is the provision of a use formulation containing an active use level of said extract in the amount of about 0.005 to 5% by weight of said formulation.
These and oth
Katz Walter
Krass Frederick
Natreon Inc.
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