WO1994018993A1

WO1994018993A1 - Therapeutic herbal composition

Info

Publication number: WO1994018993A1
Application number: PCT/US1994/002183
Authority: WO
Inventors: Johel M. Neiron
Original assignee: Pharmakon Usa, Inc.
Priority date: 1993-02-23
Filing date: 1994-02-23
Publication date: 1994-09-01
Also published as: AU6252394A

Abstract

A therapeutic herbal composition is beneficial for enhancing the immune system and treating such a diverse range of diseases as cancer, AIDS, Epstein Barr syndrom and depression. It is also useful as a general blood tonic. This composition includes the synergistic combination of Boswelia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allilum sativum bulb and Cyperus Rotundus root.

Description

- ^a- Therapeutic Herbal composition

Background of the Invention

The subject invention relates to a therapeutic herbal composition which is potentially beneficial for immune enhancement, prophylaxis and treatment of cancer, AIDS, Epstein Barr syndrome, depression and the like, and as a blood tonic. The Australian Therapeutic Goods Administration has approved this therapeutic composition for use as a blood tonic.

Acquired immune deficiency syndrome, commonly known as AIDS, is a disease caused by a retrovirus called human immunodeficiency virus (HIV) . First recognized in 1981, this devastating disease has spread on an international scale with millions of people world-wide considered to be

HIV-infected. The virus preferentially targets the helper T cells, which play a central role in the functioning of the immune system. In most cases the virus, once incorporated into the helper T cell, remains dormant for an unspecified period of time. Once activated, however, the virus rapidly destroys the helper T cells, thereby crippling the immune system. It is at this stage that the symptoms of AIDS become evident. These include: o enlarged lymphoid glands o unexplained rapid weight loss and diarrhoea o fever and night sweats o dermatitis and skin eruptions and lesions o diminished sensitivity to skin tests o memory disorder and behavioral changes o increased incidence of certain cancers. A common tumor of AIDS patients is Kaposi's sarcoma, resulting in purplish marks on the skin, o increased susceptibility to opportunistic infections that rarely infect normal individuals.

It is these infections that generally cause the patient's death within a few years of the onset of symptoms.

Currently, there is no cure for AIDS and attempts to produce a vaccine have been hindered by the fact that the virus is capable of changing its outer membrane configuration.

Although the use of various herbs has been described in related areas, the synergistic combination of the subject invention has never previously been described.

Turmeric extract prepared from Curcuma longa was shown in Japanese Patent Publication No. 4,095,032 to stimulate transdermal absorption and to increase the effect of pharmacologically active components. Likewise, Japanese Publication No. 4,091,029 describes the combination of Curcoma longa and Cinnamomum cassia to obtain a similar effect. Japanese Patent Publication No. 4,005,237 teaches the combination of Cinnamomum sieboldii and Allium sativum for superoxide scavenging in the treatment of inflammatory disorders. German Patent Publication No. 3,724,341 teaches the use of Cinnamomum zeylanicum as an anti-inflammatory agent which exerts a synergistic anti-inflammatory effect in combination with Pumica granitum cortex, Cardamon zingiberaceie fruit and Piper longum fruit.

Japanese Patent Publication No. 2,069,431 discloses the use of Curcuma longa for use as an antioxidant in foods and pharmaceutical products.

German Patent Publication No. 1,767,469 teaches the use of Allium sativum for use in preparations having an anti- cancer, anti-bacterial and chemotherapeutic effect.

In view of the above, there exists a great need for therapeutic compositions useful in enhancing the immune system. Although not wishing to be bound by theory, it is believed that the composition of herbs described herein functions to augment the immune system through the synergistic interaction of the herbal components, and thus represents a potential tool in the treatment of cancer, AIDS, Epstein Barr virus and depression, as well as a general blood tonic. Summary of the Invention

The subject invention provides a therapeutic composition comprising Boswelia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcuma zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark, Impatiens balsamina bark, Costus spicatus root, Allilum sativum bulb and Cyperuε rotundus root in amounts effective to produce a physiological benefit.

Detailed Description of the Invention

The subject invention will now be described in terms of its preferred embodiments. These embodiments are set forth to aid in the understanding of the subject composition and method of use. However, these preferred embodiments are not to be construed as limiting.

The subject composition comprises the eleven plants of the following list for typical administration: wt. % bv wt. Ranσe fwt. %. Boswelia carterii stem resin 90 mg 15.5 1.5 - 75 Styrax benzoin stem resin 90 mg 15.5 1.5 - 75 Cinnamomum zeylanicum bark 40 mg 6.9 0.7 - 35 Curcuma zedoaria root 35 mg 6.0 0.6 - 30 Syzygium aromaticum fruit 35 mg 6.0 0.6 - 30 Nardostachys chinensis root 35 mg 6.0 0.6 - 30 Betula alJba bark 90 mg 5.5 1.5 - 75 Impatiens balsamina bark 90 mg 5.5 1.5 - 35 Costus spicatus root 25 mg 4.3 0.4 - 25 Allilum sativum bulb 25 mg 4.3 0.4 - 25 Cyperus rotundus root 25 mq 4.3 0.4 - 25

580 mg

The above herbs are typically dried and ground to a fine powder. All weights are expressed in milligrams and all percentages are by weight of the essential elements in the composition. The composition is typically an intimate mixture of powders. However, extracted herbs may also be used.

The known biological active components include choline and thiamine. Under normal conditions a 580 mg dose would be administered several times daily. The dosage of course may vary depending on body weight and other conditions readily determinable by those skilled in the art who have read the subject application. Administration is typically oral, with administration being via a capsule. In addition to the above herbs, various fillers, such as ash, may be present.

A unique natural composition derived from plant extracts has been demonstrated to overcome many of the debilitating symptoms of AIDS. This composition, which is typically orally ingested, represents a breakthrough in the pharmaceutical management of AIDS patients. Pilot studies have demonstrated that the subject composition causes: o reversal of gland swelling o restoration of feeling of well being and associated weight gain o improvement in response to skin hypersensitivity tests o increase in the circulating concentration of helper T cells (CD4-positive cells) . Associated with this is an improvement in the CD4/CD8 ratio, with many patients returning to a normal ratio.

It is expected that the optimal time for therapy with the subject composition should commence in relation to the first appearance of symptoms, or may be used as a prophylactic prior to any indications.

Pilot studies on the effectiveness of the subject composition in protecting AIDS patients against depletion of the helper T cells have been conducted in several countries, In Australia, fifteen patients have been evaluated to determine the clinical responses in AIDS-affected patients to the administration of the subject composition.

Four capsules of the subject composition were taken orally twice daily (morning and evening) , one hour before meals. The composition was shown to be a low toxicity product capable of dramatically elevating the population of helper T cells. Detailed hematological and biochemical tests were conducted on each patient, the most significant data are presented in Table 1.

Table 1. Clinical data obtained from pilot studies on the effectiveness of the subject composition in protecting AIDS-infected patients from the debilitating effects of the disease.

Patient Duration CD4/CD8 ratio Fold Body weight (kg) of increase treatment Before After Before After Gain (months)

A.L. 23.3 0.71 0.86 1 .2 74.0 78.4 4.4

L.W. 19.8 0.66 1 .68 2.5 69.0 81.0 12.0

P.Y. 18.0 0.60 1 .39 2.3 49.0 54.0 5.0

H.C. 17.2 0.55 1 .40 2.5 57.4 72.6 15.2

D.F. 1 1 .8 0.15 0.16 1.1 51.0 64.0 13.0

P.P. 7.6 0.12 0.35 2.9 78.2 74.3 -3.9

D.A. 5.2 0.50 0.95 1.9 58.9 69.4 10.5

M.J. 5.0 0.24 1.10 4.6 N/A N/A N/A

B.S. 4.9 0.18 0.41 2.3 71.4 74.0 2.6

D.C. 4.9 0.15 0.21 1 .4 63.0 68.0 5.0

J.M. 4.7 0.25 1.30 5.2 67.0 80.0 13.0

J.A. 4.3 0.70 0.88 1.3 51.9 54.6 2.7

N.O. 4.2 1.19 1 .25 1 .1 63.5 70.9 7.4

G.S. 2.5 0.10 0.25 2.5 N/A N/A N/A

P.C. 2.0 0.27 0.37 1 .4 N/A N/A N/A

MEAN 0.42 0.84 2.0 62.9 70.1 7.2

Of the fifteen patients, the mean CD4/CD8 ratio (ratio of helper T cells to cytotoxic T cell and suppressor T cells) at the commencement of treatment was 0.42±0.08. (Note: The ratio in a healthy population is 1.0 - 3.5.) After a treatment period ranging from 2-23 months the CD4/CD8 ratio had significantly increased by two-fold to 0.84 ± 0.14 (p < 0.001). Concurrently with this change was an improvement in the response to skin hypersensitivity tests and a general increase in well-being. This latter effect is demonstrated by the overall restoration of body weight, increasing from 62.9 to 70.1 kg, a weight gain of 7.2 kg (p < 0.001) .

Of those ten patients commencing treatment with a CD4/CD8 ratio greater than 0.20, 60% had ratios in the range of normal, healthy people by the last date of assessment. For the five patients commencing with a CD4/CD8 ratio less than 0.20, none had ratios in the normal range, although the ratio had increased two-fold in value (Before: 0.14 ± 0.02; After: 0.28 ± 0.05) .

The chief function of the immune system is to protect against infection, by destroying and eliminating invading organisms and any toxic molecules they produce. The immune response is a highly sophisticated defense system, without an organism would die as a result of bacterial, viral, fungal, or parasitic infection. This protection against entry of foreign organisms into the tissues is, to a large extent, dependent on a particular type of white blood cell called the lymphocyte. Lymphocytes are found in large numbers in the blood and the lymph (the colorless fluid inthe lymphatic vessels that connect the lymph nodes of the body) and in specialized lymphoid organs, such as the thymus, lymph nodes, spleen, tonsils and appendix. Lymphocytes can be separated into two major classes based on the type of immune response. Both classes, called B cells and T cells, arise from common stem cells in the bone marrow. When produced in the bone marrow, lymphocytes are immature and require further processing in order to become mature, functional cells. In mammals, some cells differentiate within the bone marrow to become B cells, whereas others are processed in the thymus to generate T cells. These two cell types also differ in terms of their response to foreign substances, called antigens. Binding of an antigen transforms a B cell into a plasma cell, which is responsible for humoral or antibody-mediated immunity. The plasma cell produces and secretes antibodies which bind to an invading cell, either causing it to be inactivated or targeting it for removal from the body.

A second type of response, involving T cells, is called cell-mediated immunity. This involves the production of specialized cells that react with foreign antigens on the surface of other host cells. The effector cell can kill a virus-infected host cell that has viral proteins on its surface, thereby eliminating the infected cell before the virus has replicated. In other situations the reacting cell activates macrophages to destroy the foreign microorganism. The cell-mediated immune response is also responsible for the rejection of skin grafts and organ transplants. Although the main function of the immune system is to save us from disease-causing microorganisms, the system cannot actually distinguish between pathogenic and non- pathogenic organisms. Rather, it is because they are recognized as foreign (or non-self) that our immune system is induced to react against them. Before B cells differentiate to mature antibody-secreting cells, called plasma cells, they carry their antibodies as membrane-bound surface molecules. These antibodies act as cell-surface receptors for antigens, thereby providing a means of distinguishing foreign invading cells from the body's own cells. When an antigen (associated with a bacteria, virus, etc.) interacts with a corresponding cell-surface receptor on an immature B cell, the specific binding, together with other cellular interactions, triggers the proliferation and maturation of that particular B cell. The resultant plasma cells secrete antibodies of the same specificity as the original antibody on the surface of the immature B cell.

The process whereby antigens stimulate division and maturation of B cells to which they bind is referred to as clonal selection. This term is derived from the proposal that the immune system contains many millions of different families, or clones, of B cells each committed to make one particular antibody. The presence of a foreign antigen is immediately recognized by one (or more) of these millions of clones, and those that react with the antigen are induced to proliferate and mature. Each cell produced from a clone therefore produces the same antibody and this leads to a build-up of the specific antibody. These antibody molecules are then directed against the foreign antigen. If the foreign antigen is toxic, binding of antibody generally inactivates the toxin. If it is an invading microorganism, antibody binding leads to destruction of the microorganism.

It is now recognized that although the B cells are responsible for the production of antibodies, a complex cellular interaction is required in order to activate this process. Central in this process are a specific type of T lymphocytes, the helper T cells (T_H cells) , which enhance the activation of the B cells. Although the details of this activation event are still being determined, it is known that the presence of a foreign organism (antigen) within our body causes macrophages to bind the antigen and process it. The processed antigen is then presented to the B cells and helper T cells. The helper T cells respond by releasing growth factors, called interleukins (or lymphokines) , which stimulate cell division and maturation of the B cells, ultimately inducing the production of memory cells and plasma cells, which are specialized for producing large quantities of antibodies.

T lymphocytes are involved in two very different types of cellular immune responses. One is to destroy cells that contain foreign antigens on their surface, as occurs when a host cell becomes infected with a virus. Thus, often the target cells are an individual's own cells shortly after they have become infected by a virus. The cells responsible for this response are referred to as cytotoxic T cells. Because viruses proliferate within cells, where they are protected from attack by antibodies, the cytotoxic T cells provide an important defense against the spreading of the viral infection to other cells, by destroying the infected cell before virus proliferation and assembly has occurred. Cytotoxic T cells are also responsible for the rejection of skin grafts and organ transplants.

When an antigen binds to the immature T cell via specific cell-surface receptors, the cell is transformed into a lymphoblast which divides to produce a population of activated T cells. These T cells subsequently differentiate to produce cytotoxic T cells, memory cells, helper T cells

(T_H cells) and suppressor T cells (T_s cells) . The latter two cell types represent the majority of the T lymphocyte cell population and are responsible for the second major function of the T lymphocytes, that is the regulation of the immune system.

The T_H cells are critical in facilitating the response of both B cells (as discussed earlier) and the cytotoxic T cells. As a consequence, any reduction in the circulating level of T_H cells leads to a dramatically impaired immune response. The T_s cells have the opposite effect by blocking B and T cell responses. Thus, although cytotoxic T cells and B cells are the cells directly responsible for the immune responses against infection, their effectiveness in the elimination of the infection is dramatically modulated by the relative level of helper T cells and suppressor T cells in the blood.

The various classes of T lymphocytes are small, round cells which are not readily distinguishable under the microscope. They can be identified, however, by the presence of specific glycoproteins that are present on their surface (see Table 2) . Whereas all T cells have the CD3 glycoprotein, only helper T cells have the CD4 glycoprotein and both cytotoxic T cells and suppressor T cells have the CD8 glycoprotein. The importance of these differences is that they can be used to determine the relative concentration of the various types of T cells. For instance, the CD4/CD8 ratio can be used to determine the concentration of helper T cells relative to the concentration of both the cytotoxic and suppressor T cells.

Table 2. Cell surface glycoproteins on the various types of T lymphocytes.

+ = glycoprotein present; - = glycoprotein absent

Cell type Cell surface Glycoprotein

CD3 CD4 CD8

Helper T cells (T_H) + + -

Cytotoxic T cells + - +

Suppressor T cells (T_s) + - + The host cell for the human immunodeficiency virus (HIV) is the helper T cell (T_H cell) . Indeed, the disease is transmitted when a T_H cell, infected by the virus, is transferred through the blood or via semen or vaginal secretions, to an uninfected individual. The T_H cells of that individual immediately recognize the virus-infected cell as foreign. However, before any immune response can be invoked, the foreign HIV particles have bound to the T_H cells, been incorporated into the cells and rendered them inactive. The virus is surrounded by a lipid bilayer membrane containing two glycoproteins, one of which binds tightly to the CD4 protein on the membrane of the T_H cells. Thus, one of the features which distinguish them from other T cells, namely the presence of the CD4 protein on their surface, renders them susceptible to attack. Once bound, the membranes of the cell and virus fuse and the genetic elements of the virus are readily incorporated into the genetic material of the host cell.

As the virus is transferred from one T_H cell to another in the infected individual, an increasing proportion of the immune system is disabled, since the cells that are essential for mounting an immune response are rapidly being destroyed. The HIV virus may lie dormant inside the infected T_H cells for some time. However, once stimulated, the proliferation of the virus-infected cells overwhelms the remaining uninfected T_H cells and the immune system is rapidly rendered ineffective. The depletion of the T_H cell population can be clinically evaluated by measuring the CD4/CD8 ratio, which is a measure of the T_H cell population relative to that of the cytotoxic T cells and the T_s cells.

In summary, infection by the AIDS virus leads ultimately to the destruction of the T_H cell population.

Because of the key regulatory role of this particular cell population, which is essential for both the adequate functioning of the B cells (antibody response) and the cytotoxic T cells (cell-mediated response) , the entire immune system is rendered quite inactive. The infected individual is then prone to a greater incidence of certain cancers and to infection by other opportunistic microorganisms. It is this latter effect that frequently leads to the death of the infected person. The subject composition, by being able to elevate the T_H cell population, has the potential to prolong the life of AIDS sufferers by restoring the T cell profile to normal levels.

Testing results of capsules containing the subject composition show that the product complies with the British Pharmacopoeia specifications during its two year shelf life. The herbal powder is packed into moisture permeable gelatine capsules of zero size and next in 350 ml polyvinyl chloride bottles stored at range temperature 20-30°C. Susceptibility to moisture absorption change during storage and distribution was from 5.6% to 12% (an acceptable level). The batch studies of pH aqueous solutions indicate an inherent characteristic value between 4.4 and 4.8.

In degradation pathways of the digestibility test within pepsin solution according to Association of Official Analytical Chemists, 28% of the subject powder is digested during 16 hours at a temperature of 42-45°C. A method is applicable within 0.2% pepsin concentration demonstrating good market quality. Further comparative studies of digestibility for extracted powder of diethyl ether, chloroform and ethyl alcohol conform a stable minimum for protein decomposition for standard batches otherwise increasing a degradation in bioactive reactions. Moreover, data accumulated from clinical trials on the effectiveness of the subject composition in protecting AIDS-infected patients from the debilitating effects of the disease illustrate 2.5 fold increase with CD4/CD8 ratio during time ranging from 2.5-24 months. (Ratio of helper T cells to cytotoxic T cell and suppressor T cells) . Secondly, the mean hemoglobin concentration was 11.19 g/dL at the commencement of treatment, but was significantly elevated (p<0.001) to 14.3 g/dL after a treatment period (a 20.4% increase) .

The subject powder maintains a brown color and does not lose its character under the cycling effect of night and day. Smell and taste are unimpaired during storage. Alternative solubility of the subject composition in organic solvents, e.g. dichloromethane, chloroform and ethyl alcohol at room temperature and at 40°, 60° and 70°C, identify the product with a dissolution rate of 26-56%. However, the batches are sterilized within radiation or by ethylene oxide, the stability records show a lack of detectable amounts of degradation products and systematic bacteriological tests under conditions of high humidity proved satisfactory.

Upon reading the subject application, various alternative embodiments will become obvious to those skilled in the art. These embodiments are to be considered within the scope and spirit of the subject invention, which is only to be limited by the claims which follow and their equivalents.

Claims

What is claimed is:

1. A therapeutic composition which comprises Boswelia carterii stem resin, Styrax benzoin stem resin, Cinnamomum zeylanicum bark, Curcutπa zedoaria root, Syzygium aromaticum fruit, Nardostachys chinensis root, Betula alba bark,

Impatiens balsamina bark, Costus spicatus root, Allilum sativum bulb and Cyperus rotundus root in amounts effective to produce a physiological benefit.

2. A composition of claim 1, wherein the Boswelia carterii stem resin is present in an amount of from about 1.5 to about 75 weight percent of the composition, Styrax benzoin stem resin is present in an amount of from about 1.5 to about 75 weight percent of the composition, Cinnamomum zeylanicum bark is present in an amount from about 0.7 to about 35 weight percent of the composition. Curcuma zedoaria root is present in an amount from about 0.6 to about 30 weight percent of the composition, Syzygium aromaticum fruit is present in an amount from about 0.6 to about 30 weight percent of the composition, Nardostachys chinensis root is present in an amount from about 0.6 to about 30 weight percent of the composition, Betula alba bark is present in an amount from about 1.5 to about 75 weight percent of the composition, Impatiens balsamina bark is present in an amount from about 1.5 to about 35 weight percent of the composition, Costus spicatus root is present in an amount of from about 0.4 to about 25 weight percent of the composition, Allilum sativum bulb is present in an amount of from about 0.4 to about 25 weight percent of the composition, and Cyperus rotundus root is present in an amount of from about 0.4 to about 25 weight percent of the composition.

3. A composition of claim 2, wherein the Boswelia carterii stem resin is present in an amount of about 15.5% by weight of the composition, Styrax benzoin stem resin is present in an amount of about 15.5% by weight of the composition, Cinnamomum zeylanicum bark is present in an amount of about 6.9% by weight of the composition, Curcuma zedoaria root is present in an amount of about 6.0% by weight of the composition, Syzygium aromaticum fruit is present in an amount of about 6.0% by weight of the composition, Nardostachys chinensis root is present in an amount of about 6.0% by weight of the composition, Betula alba bark is present in an amount of about 5.5% by weight of the composition, Impatiens balsamina bark is present in an amount of about 5.5% by weight of the composition, Costus spicatus root is present in an amount of about 4.3% by weight of the composition, Allilum sativum bulb is present in an amount of about 4.3% by weight of the composition, and Cyperus rotundus root is present in an amount of about 4.3% by weight of the composition.

4. A composition of claim 1 further comprising fillers.

5. A capsule comprising the composition of claim 1.

6. A capsule of claim 5, wherein the Boswelia carterii stem resin is present in an amount of about 15.5% by weight of the composition, Styrax benzoin stem resin is present in an amount of about 15.5% by weight of the composition,

Cinnamomum zeylanicum bark is present in an amount of about 6.9% by weight of the composition, Curcuma zedoaria root is present in an amount of about 6.0% by weight of the composition, Syzygium aromaticum fruit is present in an amount of about 6.0% by weight of the composition,

Nardostachys chinensis root is present in an amount of about 6.0% by weight of the composition, Betula alba bark is present in an amount of about 5.5% by weight of the composition, Impatiens balsamina bark is present in an amount of about 5.5% by weight of the composition, Costus spicatus root is present in an amount of about 4.3% by weight of the composition, Allilum sativum bulb is present in an amount of about 4.3% by weight of the composition, and Cyperus rotundus root is present in an amount of about 4.3% by weight of the composition.

7. A capsule of claim 6, wherein the Boswelia carterii stem resin is present in an amount of about 90 mg, Styrax benzoin stem resin is present in an amount of about 90 mg, Cinnamomum zeylanicum bark is present in an amount of about 40 mg, Curcuma zedoaria root is present in an amount of about 35 mg, Syzygium aromaticum fruit is present in an amount of about 35 mg, Nardostachys chinensis root is present in an amount of about 35 mg, Betula alba bark is present in an amount of about 90 mg, Impatiens balsamina bark is present in an amount of about 90 mg, Costus spicatus root is present in an amount of about 25 mg, Allilum sativum bulb is present in an amount of about 25 mg, and Cyperus rotundus root is present in an amount of about 25 mg.