Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1999-03-29
2001-05-08
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S405000, C426S648000, C426S655000
Reexamination Certificate
active
06228366
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a purified and standardized water-soluble fraction obtained from the leaves of a cultivated variety of
Phlebodium decumanum,
identified as EXPLY-37, to formulations containing it and to their use as nutritional supplements of general application and particularly, in patients suffering from general weakness and cachectic syndrome, as AIDS and cancer patients. Such formulations can also be used in combination with anti-retroviral drugs in AIDS patients and with conventional anticancer treatments (surgery and/or radio-and chemotherapy) in order to improve the efficacy and to reduce the undesired effects of such treatments. The formulations are also useful in the recovery of patients under those treatments.
BACKGROUND OF THE INVENTION
Cachexia is a complex syndrome characterized by appetite and body weight loss, general weakness, anemia and asthenia. This syndrome is associated to a metabolic dysbalance and shown by weight loss and generalized wasting: the organism is unable to maintain the adequate energy supply and spends its own lipid store and muscle protein.
It is accepted that a high percentage (50-90%) of HIV infected patients suffer from some kind of malnutrition. This disturbance can be attributed to alterations in the intake, absorption and metabolism of foods [C. Fields-Gardner, Nutr.Clin. Pract. 1995, 10(5), 167-176.] Severe weight loss is closely related to the mortality increase in AIDS patients. It may be related, on the other hand, to some kind of gastrointestinal pathology, anorexia, systemic infections and can appear in patients with advanced disease and CD4+ count lower than 100 [D. P. Kotler, AIDS Res. Hum. Retroviruses 1994, 10(8), 930-934]
Wasting syndrome associated to HIV infection is characterized by progressive weight loss and increasing weakness, frequently associated to fever and diarrhea. The causes of these alterations are complexes, multifactorial and seem to be related to inadequate diets, malabsorption phenomena, metabolic dysbalance and activity of some cytokines such as tumor necrosis factor (TNF), IL-1, IL-6 and &agr;-IFN [S. E. Weinroth et al. Infect. Agents Dis. 1995, 4,76-94]. P. Kelly et al. [Q.S. Med. 1996, 89 (II), 831-837] found a relationship between the severity of cachexia in a group of African males and the high cytokine activity, specially high concentrations of sTNF55, although no correlation could be established with either oesophagic candidiasis or any intestinal opportunistic infection.
The relationship between wasting syndrome and low blood levels of testosterone has been demonstrated in male AIDS patients. Special diets, testosterone, nandrolone [J. Gold et al. 1996, 10 (7), 108-112] and growth hormone [M. Shambelan et al. Ann. Inter. Med. 1996, 125 (11), 873-882] have been used for the treatment of cachexia in AIDS patients.
The relationships between nutrition, HIV infection and immune system [J. M. Hoyt et al., II. Assoc. Nurses AIDS care 1991, 2 (3), 16-28,] and the role of certain cytokines in the wasting syndrome in AIDS patients, can be considered as the basis for new treatments involving the use of immunomodulators. The use of thalidomide, an immunomodulating drug, in the treatment of the wasting syndrome associated to AIDS has recently been published [G. Reyes-Teran et al., AIDS, 1996, 10, 1501-1507].
On the other hand, cachexia is also associated to the high mortality rate in cancer patients, this rate being estimated by some authors as 30-70%. Many cancer patients die after continuous weight loss and generalized weakness. Oncology patients with associated cachexia have a negative prognostic as the possibilities of effective chemoterapeutic treatments are substantially reduced. Consequently, an effective treatment of cachexia should improve the general condition of the patient: more effective chemotherapy, better quality of life and more favorable prognosis of the disease could be achieved.
However, all the approaches for slowing down or reverting cachexia have been focused on the improvement of nutritional supply through special diets and regimen without positive results.
Recent publications are now stressing the relationships between the high levels of certain pro-inflammatory citokynes and cancer cachexia: TNF&agr;, IL-1, IL-6 and IFN gamma [P. Elliot et al., Drug &. Market Development 1989, 9, 26-18.] This dysfunction of the immune system, together with reduction in the NK cell activity and plasma levels of cystine and glutamine, accompanied of urea overproduction, shown in different pathologies, is extremely important in the induction and progression of cachexia in cancer patients. Although the induction mechanism by such cytokines is unknown, antagonizing their effects by using inmunomodulators is one of the most updated approaches to revert cachexia.
It is obviously necessary to develop new ways to stop or revert the cachetic syndrome in order to improve the quality of life and to enhance the efficacy of basic treatments.
The fern known for years as
Polypodium leucotomos
has historically been used by the Honduran natives, as infusions of leaves and rhizomes, for the treatment of malign tumors, rheumatoid arthritis and psoriasis. Horvath et al. [Nature, 1967, 214, 1256-1258] showed both the in vitro and in vivo antitumor effect of an aqueous extract of the fern. Later, a water soluble fraction from the leaves of
Polypodium leucotomos
has been widely studied. Its inmunomodulator/inmunosuppresor profile and its antioxidant and anti-free radical properties have been described [M. D. Fernandez & al. 1
st
World Congress on Medicinal and Aromatic Plant for Human Welfare, Maastricht, 1992; J. Rayward et al., 2
nd
International Congress on Biological Response Modifiers, San Diego, USA, S. Gonzalez & al., Photodermatol, Photoimmunol, Photomed, 1996, 12,45]
The use of extracts from the genus Polypodium, and more specifically from
Polypodium leucotomos,
as antioxidants and photoprotectants has been claimed in the patent PCT/US 96/01808 by Pathak et al. (1996).
The present invention provides a water soluble fraction obtained from the leaves of a cultivated variety of
Phlebodium decumanum,
purified and standardized, identified as EXPLY-37, its production and its use in the manufacturing of formulations useful as nutritional supplements. The plant material from which the water soluble extract employed herein, identified as “EXPLY 37”, is obtained from the leaves of a cultivated variety of
Phlebodium decumanum
found in the Yojoa Lake region of northern Honduras. In accordance with the provisions of 37 C.F.R. 1.802 this plant material has been deposited in an International Depositary Authority (IDA) established under the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure. This deposit was made by transmission of a number of spores of the variety of
Phlebodium decumanum
from which EXPLY 37 is extracted on Oct. 19, 2000 to the National Collection of Industrial and Marine Bacterial Ltd. (NCIMB), Aberdeen, Scotland (United Kingdom). The deposit was received on Oct. 16, 2000.
DESCRIPTION OF THE INVENTION
This invention is addressed, but not limited, to the manufacturing of a water-soluble fraction from the leaves of a cultivated variety of
Phlebodium decumanum,
purified and standardized, identified as EXPLY-37, to the preparation of EXPLY-37 formulations and to the use of these formulations as nutritional supplements in AIDS and cancer patients. The formulations can be used together with anti-retroviral drugs in AIDS patients and associated to conventional oncology treatments (surgery and/or radio-and chemotherapy), in order to improve the efficacy and reduce the side effects in the recovery of patients under those treatments.
1.
Phlebodium decumanum
This Polypodiacee, belonging to the Subgenus Phlebodium, within the Genus Polypodium, is organically cultivated and processed in the faci
Caceres Giovanna Marisol Ruiz
Ferrer Miguel Yesares
Garcia Antonio Alcaide
Medina Jorge A. Mendoza
Morillas Miguel Enrique Yesares
Fink Edward M.
Helsint, S.A.L.
Michaelson Peter L.
Michaelson & Wallace
Tate Christopher R.
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