Scientific Basis for Ayurvedic Therapies -6

  

Scientific Basis for

Ayurvedic Therapies 

edited by

Brahmasree Lakshmi Chandra Mishra

Immunomodulation: Therapeutic Strategy through

Ayurveda

Ashish A. Mungantiwar and Aashish S. Phadke

5.1 Introduction

Why is it that there is always some lucky soul who does not get sick when the flu is going

around the office? Or why is it when the chicken pox is sending all the kids home from

school, there are a few who remain untouched? Why do only some in a family develop

allergies or bacterial infection? Some attribute this phenomenon to simple luck, whereas

others attribute it to strong genes. The answer is a bit more complex.

A large number of diverse disease states threatening mankind, such as chronic and

recurrent viral and fungal infections, human immunodeficiency virus (HIV) infection,

allergies, and cancer, are believed to have resulted from altered functioning of the immune

system. The immune system helps an individual toward establishing an infection-free

state. Disturbances in the internal state of order of the host immune system results either

in the terms of hyperactivity, hypoactivity, or the inability to distinguish self from nonself

that would lead to disease. Such multidimensional response would require proper control

through immunomodulation.

It is true that our genes affect our immune system; we call that

influence of natural

constitution

. We cannot change our genetic makeup, but we can definitely strengthen our

immune system to fight against diseases.

The immune system can be stimulated and suppressed by various physical, chemical,

and biological agents. These include steroids, cytotoxic drugs, and various natural products

of microbial, animal, and plant origin.

1

Although an antigen-specific immunomodulator

is desirable, reliable agents for sustained therapeutic effects are being investigated.

The suppression of the immune system associated with tuberculosis (TB), cancer,

2

surgery,

3

or HIV infection is characterized by a reduction in the number and phagocytic

function of neutrophils and macrophages

4

as well as a reduction in the intracellular

bactericidal capacity of these cells. This profound suppression of the individual elements

of the system allows opportunistic pathogens to overwhelm the host so that secondary

infection becomes the most common cause of the mortality in such individuals.

5

An attempt to overcome this problem has been made by introducing the concept of prohost

therapy.

6

This approach aims at administering drugs to bolster immune defense

against infections.

7

Several naturally occurring and synthetic substances like bacillus calmette

and guerin (BCG),

8

muramyl dipeptide,

9

interleukin–1 (IL-1),

10

and colony-stimulating

factors

11

have been used to enhance resistance against infections. However, these

substances share several limitations. One of their major drawbacks is the necessity to

administer them parenterally, which often leads to local reactions such as granuloma

formation. Another factor is the cost of therapy, which can be prohibitive. Against this

background, the potential of Ayurvedic therapy appears to be encouraging.

12

Ayurveda emphasizes the promotion of health with a concept of strengthening host

defense against diseases. The concept of immunostimulation through Ayurveda has been

used successfully in the treatment of immunocompromised conditions like acquired

immune deficiency syndrome (AIDS), TB, cancer, and hepatic disease.

5.2 Etiology

The cellular components of the immune system, which are essential in controlling

infections, include macrophage, T-cell and B-cell subset, natural killer cell, lymphokine

activated killer cell, and cytotoxic lymphocyte. Generation of an effective immune

response involves two major groups of cells: lymphocytes and antigen-presenting cells.

Lymphocytes are one of many types of white blood cells produced in bone marrow that

circulate in the blood and lymph system and reside in various lymph organs. The major

population of lymphocytes is B-lymphocytes (B-cell) and T-lymphocytes (T-cell). There

are two well-defined subpopulations of T-cells: T helper cells (T

H

) and T cytotoxic cells

(T

C

). T

H

- and T

C

-cells can be distinguished from one another by the presence of either

membrane glycoprotein CD4 or CD8 on their surfaces. T-cells displaying CD4 generally

function as T

H

-cells, whereas those displaying CD8 generally function as T

C

-cells. The

T

H

-cell recognizes and interacts with the specific antigen (microbe). Interaction takes

place with the help of major histocompatability complex (MHC) II molecule. Once the

interaction takes place, T

H

-cell activates and secretes various growth factors known as

cytokines. The secreted cytokines play an important role in activating various cells of

the immune system, like the B-cell, T

C

-cell, and macrophage.

13

Recently, it has become clear that two distinct subsets of CD4 helper T-cells (T

H

1

-

and

T

H

2

-cells) secrete different pattern of cytokines as shown in the Table 5.1. T-cells respond

to antigenic stimulation with a transient burst of cytokine production.

14

The key differences

are expressions of interferon-gamma (IFNg

), tissue necrosis factor-alpha (TNFa

), interleukin-

2 (IL-2), and granulocyte macrophage colony-stimulating factor (GM-CSF) by T

H

1

clones and interleukin-4 (IL-4) and interleukin-5 (IL-5) by T

H

2

clones. T

H

2

-cells stimulate

the production of three of the hallmark features of the allergic disease: mast cells, eosinophils,

and immunoglobin E (IgE) antibodies. The cytokines responsible for these activities

are IL-4 for IgE production

15

and IL-5 for eosionphilia.

16

Cytokines released by T

H

1

lead

to a substantial increase in the ability of macrophages to kill a wide variety of intracellular

pathogens and to enhance the development of long-term immunity to those organisms.

17

The understanding of T-cell-mediated immunoregulation suggests a number of potential

therapeutic applications in TB, hepatic disorders, HIV infections, etc.

5.2.1 Apoptosis

Apoptosis is a mode of cell death in which single cells are deleted in the living tissue.

18

The term is derived from ancient Greece, meaning the falling of leaves from trees or petals

from flowers. It is characterized by structural changes that appear with great fidelity in

cells of widely different lineage.

TABLE 5.1

Cytokines Released by CD4 T-cells

Cytokines Functions T

H

1

-Cells T

H

2

-Cells

IL-2 T-cell proliferation + _

IL-3 T- and B-cell proliferation ++ ++

IL-4 Activation of T-cell, B-cell, and

macrophage

_ ++

IL-5 Eosinophil production _ ++

IL-10 Inhibition of T-cell _ ++

IFNg

Activation of macrophage ++ _

TNFa

Stimulation of inflammation ++ _

GM-CSF Stimulation of macrophage ++ +

5.2.2 Signal Pathway to Trigger Apoptosis and Its Intervention through Ayurveda

Several pieces of evidence implicate a rise in cellular-free calcium as a critical event for

apoptosis. A moderate but sustained increase in intracellular calcium has been demonstrated

to produce cell death. However, because calcium is implicated in signaling for a

multitude of cellular activities, including proliferation and differentiation, it seems

unlikely that a simple influx of calcium from outside the cell activates a specific pathway

for apoptotic death. Apart from increased calcium levels, there are signals that contribute

toward apoptosis. These are protein kinase A and protein kinase C. Protein kinase C has

a negative effect on apoptosis. Therefore, factors that stimulate protein kinase C will inhibit

apoptosis. For example, activated macrophage, IL-1, and GM-CSF both activate protein

kinase C and inhibit apoptosis.

Inhibition of apoptosis is useful in the treatment in AIDS, making Ayurveda a potential

treatment as well. Many ayurvedic medicinal plants have been found to modulate the

process of apoptosis. For example, the plants

Boerhaavia diffusa

19

and

Tinospora cordifolia

20

have been shown to stimulate macrophage and GM-CSF and inhibit apoptosis.

Other diseases in which apoptosis is implicated are cancer, autoimmune disease, and

neurodegenerative disease. The rate at which cancer grows depends on the comparative

rates of cell division and cell death. Apoptosis is an efficient way of preventing malignant

transformation because it removes genetically malformed cells. Abnormal apoptosis can

promote the development of cancer by either allowing the accumulation of normal cells

or preventing their removal. AIDS is another condition where the balance between the

rate of CD4 death and cell replacement becomes abnormal. It is believed that apoptosis

plays an important role in lymphocyte depletion in AIDS.

Neurodegenerative diseases are also becoming the focus of much research as the census

of the aging population increases. For example, it is hypothesized that apoptosis may play

a role in Alzheimer’s disease or motor neurone disease. In addition, anticancer effects

produced by several anticancer drugs have been shown to induce apoptosis, thus aiding

in removal of cancerous cells. The modulation of apoptosis may assist the manipulation

of the aging process. Indian medicinal plants offer prospects for the modulation of the

balance between proliferation and apoptosis. The potential of several medicinal plants

described in Ayurveda needs to be tapped.

5.3 Immunomodulation and Concept

Rasayana

in Ayurveda

Out of the eight branches of Ayurveda, the

rasayana

and

vajeekarana tantra

branch is the

one that is concerned with the immunomodulation. According to Ayurveda, the common

cause of all diseases may be due to contact with environmental factors and aging. The

latter is inevitable and the other cause can be avoided only by scrupulously puritan

patterns of living. Ayurveda claims to be able to slow down the process of aging successfully.

Rasayana

is a treatment in which the body constituents are prepared to adapt to a

selective tissue endowment program. This concept in modern scientific understanding

would mean the enhancement of immune responsiveness of an organism against pathogens

by nonspecifically activating the immune system with immunomodulatory agents

of plant origin. It is now recognized that immunomodulation could provide an alternative

or complement to conventional chemotherapy for a variety of diseased conditions; this is

especially the case when host defense mechanisms have to be activated under the conditions

of impaired immune responsiveness.

© 2004 by CRC Press LLC

Immunomodulation: Therapeutic Strategy through Ayurveda

67

Rasayan

drugs are believed to slow down the aging process (

jara

) and provide a defense

against diseases (

vyadhi

).

Rasayanas

improve the host resistance of an individual, helping

to prevent aging and diseases. Specific diets and lifestyle changes are also advised in

rasayana

therapy.

Rasayana

is made up of

rasa

and

ayana

.

Rasa

primarily means essential seven vital tissues:

rasa (lymphatics),

rakta

(blood),

mamsa

(muscle),

meda

(adipose tissues),

asthi

(bones),

majja

(bone marrow and nervous tissue), and

shukra

(reproductive element).

Ayana

means the

path or channel for the same. So,

rasayanas

are those that bring about proper uptake,

growth, and improvement of essential seven vital tissues.

Rasayanas

provide long life,

good intellect, the ability to remain young, and general well-being.

5.3.1 Mode of Action of

Rasayanas

Rasayana

drugs act on the immune system. On ingesting the appropriate formulation of

the

rasayana

in the appropriate season by a qualified Ayuravedic physician, the beneficial

effects of

rasayana

are seen. What, then, are these

rasayana

drugs that have so many vital

life-enhancing properties? The ancient writers of Ayurveda have endowed the drugs with

multiple properties of delaying aging, improving mental functions, and giving freedom

from several diseases including those caused by infections. How can these

rasayanas

, which

otherwise seem to be simple herbs having a different number of phytochemicals, influence

such a wide variety of body functions? To the scientific mind, it appears impossible to

credit one plant with such an apparently disparate variety of effects — almost as though

it were a magic potion! It seemed possible only if the drugs were modulating an endogenous

system of the body, setting into motion a whole cascade of events that will act on

the different organs and produce its myriad actions.

The immune system has connections with a number of other organs and can directly

or indirectly influence the actions of many other organs, including the brain. By acting

primarily on the immune system like macrophages, the simple chemical of the herbs

through the activating cytokine network could produce all the actions that have been

attributed to them. This hypothesis was proved scientifically by Dhanukar et al.

24

In one

set of experiments,

rasayanas

were given to rats whose macrophages had been overloaded

with a fat lipofundin. In this setup, the rasayanas were unable to stimulate macrophages

further and were thus unable to prevent stress-induced organ damage. Rasayana shows

myriad actions on other organs by acting on the immune system. The classification of

25

5.4 Scientific Basis of Ayurvedic Immunomodulation Therapies

Commercially available rasayana herbal formulas and supporting clinical and biological

5.4.1 Terminalia Chebula (Haritaki)

Terminalia chebula is an antibacterial, antioxidizing, anti-inflammatory, and immunomodulatory

agent. The topical administration of an alcoholic extract of the leaves of T. chebula

was found to heal much faster as indicated by decreased period of epitheliazation. The

tensile strength of the tissue, which was treated with T. chebula, was increased by 40%.26

rasayanas is presented in Table 5.2.

studies are listed in Table 5.3. Studies on single rasayana herbs are presented here.

© 2004 by CRC Press LLC

68 Scientific Basis for Ayurvedic Therapies

Biochemical studies revealed a significant increase in total protein, DNA, and collagen

contents in the granulation tissue of the treated wound. Reduced lipid peroxide levels

in the treated wounds suggest that T. chebula possesses antioxidant activity. The extracts

of T. chebula were found to significantly suppress yields of cytomegalo virus (CMV) in

lungs of mice. Thus, T. chebula may be beneficial for the prophylaxis of CMV disease in

immunocompromised patients.27 The extract of T. chebula was also found to inhibit

human immunodeficiency virus-1 reverse transcriptase with (IC50) £ 50 mg/ml.28

5.4.2 Emblica officinalis (Amlaki)

Emblica officinalis is a rich source of vitamin C. The fruits of E. officinalis have been used

by Ayurveda as potent rasayana and also for the treatment of diverse etiology disease.

Perhaps there is no other drug in any other system of natural medicine with such a vast

range of attributed effects. In an experimental study, it was reported that E. officinalis could

bring about a significant weight gain in the subjects together with an increase in serum

total protein content.29 It is used as an antioxidizing, antibacterial, and anti-inflammatory

agent.30 The antioxidant activity of E. officinalis resides in tannoids. Tannoids have been

found to increase superoxide, catalase, and glutathione peroxidase.31

TABLE 5.2

Classification of Rasayanas

No. Classification Remarks

1 Kutipraveshika Patient has to stay in a very specialized manner in the kuti (hut or

home) specifically made as per the needs of rasayana

2 Vatatapika rasayana Can be given on an out-patient department basis; person can

consume it while doing his or her normal duties and staying at

his or her own home

3 Kamya rasayana Rasayana that are specifically used for benefit of specific system

(e.g., for bone marrow Withania somnifera and Asparagus

racemosus)

4 Naimittika rasayana Rasayana given only for partial period for certain number of days

5 Agasrik rasayana Rasayana commonly used to keep the process of formation of vital

tissue (e.g., milk)

6 Sharira rasayana Rasayana working on physical levels (e.g., Emblica officinalis)

7 Medhya rasayana Rasayana working on mind for the improvement of intellect (e.g.,

Bacoppa manorial, Centella asiatica)

8 Vardhanana rasayana Dosage of drug has to be increased slowly and kept at highest level

and then once again tapered down (e.g., Piper longum, Semecarpus

anacardium)

9 Achara rasayana Based on a code of conduct, which keeps oneself to attain good

mental and spiritual health; if one follows Achara rasayana, one

can be keep away from anxiety, stress, and thereby from all

diseases that are generated due to stress

10 Ahar rasayana Food is considered as rasayana (e.g., milk)

11 Dravya rasayana Drug therapy is considered under this; drug therapy includes

single herbal, polyherbal, and herbo-mineral formulation;

modern scientific medicine also states that good diet, nutrition,

proper lifestyle management, supportive family, good counseling,

and stress control help reverse the damage already done to the

immune system

TABLE 5.3

Clinical Evidence of Some Compound Formulas

Compound Formula Clinical and Biological Studies Ref.

Septilin tableta

Each tablet contains Balsamodendron mukul,

Exts. Maharsnadi, Phyllanthu emblica,

Tinospora cordifolia, Rubia cordifolia,

Moringa pterygosperma, Glycyrrhizasperma

Σ Septilin possesses immunomodulatory and antiinflammatory

plant principles, which strengthen

the nonspecific immune responses of the body;

Septilin stimulates the phagocytosis by

macrophage activation, increases the

polymorphonuclear cells, and helps overcome the

infections; Septilin builds up resistance to disease

and helps prevent reinfection

Σ Septilin significantly enhanced gain in tensile

strength in incision wounds and wound contraction

and epithelialization in excision wounds

79

Σ One tablet was given to younger patients twice a

day, and one tablet was given to elder patients three

times a day; doses have been found to be useful for

upper respiratory tract infections; 50% of the

patients showed excellent results; 30% reported

good results with no recurrent attacks upon 6-

month follow-upc

80

Σ Septilin enhances both primary and secondary

immune response in mice immunized with sheep

red blood cells and counteracts IgG and IgM

suppression induced by prednisolone when

administered orally with immunosuppressive drug

(prednisolone); the mechanism of immune

protection by Septilin treatment could probably be

due to increased number of activated macrophages

by Septilin treatmentd

81

Mentat Tableta

Each tablet contains Hydrocotyl asiatica,

Withania somnifera, Acorus calamus,

Aspargus racemosus, Emblica officinalis,

Evolvulus alsinoides, triphala

Σ Mentat tablets have been used as a general tonic

and vitalizer and as a memory enhancer

Σ Clinical studies have shown that it improves

memory quotient in normal subjects of different age

groups, increases memory span and attenuates

fluctuations of attention in normal subjects, and

improves learning ability in childrene

82

Liv 52a

Each tablet contains Capparis spinosa,

Cinchorium intybus, Solanum nigrum,

Cassia occidentalis, Tamarix gallica,

Terminalia arjuna, Achillca millefolium,

Mandhura bhasma

Σ In a clinical trial of Liv 52 vs. placebo in 60

malnourished children, a dose of one tablet twice

a day for 6 months showed significant

improvement in body weight, height, total protein,

albumin, and globulin levels; appetite also

improved remarkablyf

83

Σ Liv 52 significantly improves chronic hepatitis and

cirrhosisg as observed from clinical trials on 300

patients with hepatitis.

84

TABLE 5.3 (continued)

Clinical Evidence of Some Compound Formulas

Compound Formula Clinical and Biological Studies Ref.

Geriforte Tabletsa

Each tablet contains Chyavanprash

concentrate, Exts. Capparis spinosa,

Solanum nigrum, Cassia occidentalis,

Terminalia arjuna, Achillea millefolium,

Tamarix gallica, Mandhur bhasma, saffron,

amber, makardhwaj, Asparagus

adscendens, Caesalpinia digyna, Asparagus

racemosus, Withania somnifera, Glycyrrhiza

glabra, Centella asiatica, shilajeet, Terminalia

chebula, Mucuna pruruiens, Myristica

fragrans, Piper longum, Maceeugenia

caryophyllata, Elettaria cardomomum,

Carum coptieum, Curcuma longa, Exts.

Berberis aristata, Adhatoda vasica, Eclipta

alba, Celastrus paniculaus, Argyreia apecosia,

Abhrak bhasma, loh bhasma, jasa bhasma

Σ Geriforte, an indigenous herbo-mineral

preparation, claimed to be a useful comprehensive

general tonic and restorative

Σ Geriforte prevented stress-induced changes in

adrenal, restraint ulcers, liver toxicity, and milkinduced

leucocytosis; these properties indicate the

presence of antistress (adpatogenic properties) of

Geriforteh

85

Σ A placebo-controlled clinical trial with Geriforte

was conducted in 280 postsurgical patients; it was

observed that Geriforte therapy promotes cellular

regeneration and helps in wound healing by

increasing the availability of essential amino acids

and elements for primary healing of the operative

wounds; a substantial improvement in well-being

was observed in 78.57% of patients, and 75% of

patients gained weighti

86

day for 15 days up to 6 months showed a significant

improvement in physical and mental activity and

improvement in appetite; weight gain was

observed in 80 to 85% of the patientsj

87

Chyawanprashb

Each supplement contains vitamin C

derived from Emblica officinalis (amla) and

several other herbal products

Σ Ten normal healthy volunteers were given

chyawanprash for 16 weeks; they received 15 g/day;

it was observed that chyawanprash reduces

postprandial glycemia in the oral glucose tolerance

test and reduces blood cholesterol level to a

significantly greater extentl

88

Σ In a controlled clinical study using chyawanprash

awaleha as an adjuvant in the treatment of

pulmonary TB, it was observed that the preparation

could augment the recovery process as well as an

improved nutritional status of the subjectsm

58

aHimalaya Drug House.

bZandu Pharmaceuticals, Dabur Pharmaceuticals, Baidynath Pharmaceuticals.

Σ In an open trial in 50 patients, two tablets twice a

5.4.3 Piper longum (Pippali)

Piper longum is indicated in treatment of chronic dysentery and worm infestations. Pippali

rasayana, an Ayurvedic herbal medicine prepared from P. longum and Butea monosperma,

is prescribed for the treatment of chronic dysentery and worm infestations. P. longum

significantly increases macrophage migration inhibition and phagocytic activity.32

Enhancement of host resistance is the possible mechanism of recovery from giardial

infection.

5.4.4 Glycyrrihza glabra (Yashtimadhu [Parts Used: Roots])

Glycyrrihza glabra is an immunomodulator and antioxidant. Glycyrrhizin, a triterpenoid

glycoside obtained from G. glabra, is found to inhibit ribonucleic acid (RNA) viruses such

as measles; polio vaccine viruses type 1, 2, and 3; and deoxyribonucleic acid (DNA) viruses

such as herpes type 1 and 2.33 Polysaccharide fractions obtained from the root of G. glabra

induce nitric oxide production from macrophages.34

5.4.5 Allium sativum (Lahsuna)

Allium sativum (garlic) is an antimicrobial, antitumor, hypolipemic, antiarthritic, and

hypoglycemic agent. These characteristics have been linked to their influences on immune

functions in various ways.35 The herb has been found to enhance human immune functions

by stimulating peripheral blood mononuclear cells. Diallyl sulfide in A. sativum is known

to exert anticarcinogenic activity.36 Allicin from garlic has been found to induce programmed

cell death and the arrest of proliferation in cancer cells.

5.4.6 Semecarpus anacardium (Bhallatak [Parts Used: Nuts])

Extract of nut preparation of Semecarpus anacardium is effective against a variety of diseases

like arthritis, tumors, and infections. An extract of S. anacardium at a dose of 150 mg/kg

significantly reduced the lysosomal enzyme activity in arthritic animals37 and displayed

significant inhibition of tumor cells with IC50 of 1.6 mg/ml.38

5.4.7 Commiphora mukul (Guggul)

Commiphora mukul is used as an anti-inflammatory, antihyperlipidemic, and immunomodulatory

agent. A placebo double-blind randomized controlled trial of C. mukul, at 50 mg

twice daily, was conducted on patients with hypercholesterolemia.39 C. mukul decreased

total cholesterol by 11.7%, low-density lipoprotein (LDL) by 12.5%, triglyceride by 12%,

and the ratio of total cholesterol/high density lipoprotein (HDL) by 11.1%.

5.4.8 Tinospora cordifolia (Guduchi [Parts Used: Roots])

Tinospora cordifolia (TC) is used for the treatment of jaundice, skin disease, diabetes, anemia,

emaciation, and infections. Plant extracts are known to stimulate macrophages and

enhance their phagocytic activity and intracellular killing activity. Immunosuppression

associated with deranged hepatic function and sepsis results in poor surgical outcome in

© 2004 by CRC Press LLC

72 Scientific Basis for Ayurvedic Therapies

obstructive jaundice. T. cordifolia was reported to improve surgical outcome by strengthening

host defenses.31 Active principles of T. cordifolia were found to possess anticomplementary

and immunomodulatory activities. Syringin (TC-4) and cordiol (TC-7) inhibited

classical complement pathway. The compound also gave rise to significant increase in

immunoglobin G (IgG) antibodies in serum. Both humoral and cell-mediated immunity

enhancement were dose-dependent enhanced. T. cordifolia has been found to activate the

mononuclear cells to release cytokines like GM-CSF and IL-1. Whole aqueous extract of

T. cordifolia has been evaluated as an adjuvant in clinical conditions like obstructive

jaundice, TB, and cancer chemotherapy and has been found to increase the efficiency of

conventional therapies. T. cordifolia is also shown to specifically stimulate macrophages

and enhance their phagocytic activity. In a recent double-blind randomized controlled

trial,40 it also was shown to increase the production of nitric oxide in TB patients, causing

increased macrophage stimulations. TB patients who took T. cordifolia extract along with

conventional anti-TB treatment showed increased radiological recovery and sputum conversion

as compared with conventional anti-TB treatment alone.

5.4.9 Azardicta indica (Neem [Parts Used: Leaves])

Azardicta indica is reported to have several therapeutic effects, including being anti-infective

and anxiolytic and having general immunopotentiating ability.41 It is widely studied

for various beneficial properties. The aqueous extracts of neem leaves enhance the phagocytic

activity of macrophages. Neem is found to enhance the production of IL-2, IFN-g,

and TNF-a. In human volunteers, it stimulated humoral immunity by increasing antibody

levels and cell-mediated immunity by increasing total lymphocyte and T-cell count in 21

days. The therapeutic potential of neem is mediated through its influence on the immune

system, which is in consonance of the Ayurvedic concept of rasayana.

5.4.10 Asparagus racemosus (Shatavari [Parts Used: Whole Plant])

Asparagus racemosus is used as an immunomodulator and antioxidant. The aqueous extract

of the whole plant of A. racemosus gives protection from biological, physical, and chemical

stresses.42 Treatment with A. racemosus significantly inhibited suppression of chemotactic

activity and production of IL-1 and TNF-a by murine macrophages induced by 17 weeks

of treatment with ochratoxin A.43 Studies on the mechanisms of action revealed that it

produced immunostimulation. Aqueous extracts of A. racemosus are also found to suppress

the myelosuppressive effects of single and double doses of cyclophosphamide.44

5.4.11 Withania somnifera (Ashwagandha [Parts Used: Roots])

Withania somnifera is one highly acclaimed rasayana. W. somnifera is an immunomodulatory,

anti-inflammatory, and antioxidizing agent. W. somnifera effectively inhibits the inflammatory

process. It can also bring about a specific reduction in a-2 macroglobulin synthesis,

unlike the conventionally used nonsteroidal anti-inflammatory drugs (NSAIDs), and has

anti-oxidant activity.45 The herb is described to act as rasayana and medhya. In a clinical

study on patients of anxiety neurosis, ashwagandha was observed to reduce the symptoms

of anxiety. One month of treatment with the drug has shown symptomatic relief in mental

fatigue, and immediate memory span. In another study, the herb has been shown to be

effective in cases of depression. In yet another double-blind placebo-controlled clinical

study46 on the extract of ashwagandha involving both normal and depressive volunteers,

it was observed that the test extract showed an excellent improvement in mental functions.

Experiments with extracts of Ashwagandha protected animals against infections in normal

and immunosuppressed states induced by hemisplenectomy or surgery. This plant also

produced leucocytosis with predominant neutrophilia and prevented leucopenia induced

by cyclophosphamide.47

5.4.12 Aloe vera (Ghritkumari)

Aloe vera is a plant exclusively used in skin-care preparation and other health-care products.

It is also found to possess anticancer activity. Supplementation of aloe vera gel has

been found to suppress the incidence of hepatocarcinogenesis induced by diethylnitrosamine

and 2-acetylaminofluorene in male rats.48 The extract from leaf gel contains glutathione

peroxidase activity.49 The low molecular weight constituent of this extract inhibits

the release of reactive oxygen species by human polymorphonuclear leucocytes. The

inhibitory effect of these compounds has been shown to be an indirect result of the

diminished availability of intracellular free calcium.50

5.4.13 Solanum nigrum (Kakamachi)

Solanum nigrum is an anti-inflammatory and hepatoprotective agent. Steroidal glycosides

isolated from S. nigrum are found to possess antineoplastic activity against solid tumor

cell lines.51 The hepatoprotective activity of S. nigrum may be due to their ability to

suppress the oxidative degradation of DNA in the tissue debris.52

5.4.14 Bacopa monnieri (Brahmi)

Bacopa monnieri is used as an antiallergic, antistress, and memory-enhancing agent. In a

double-blind randomized controlled clinical trial in 76 subjects,53 B. monnieri showed

significant effect on the retention of new information. Follow-up tests showed that the

rate of learning was unaffected, suggesting that B. monnieri decreases the rate of forgetting

newly acquired information.

5.4.15 Boerhaavia diffusa (Punarnava [Parts Used: Roots])

The plant Boerhaavia diffusa (BD) is used as an antiarthritic, immunomodulatory, and

antistress agent. Alkaloidal fraction of roots of BD was found to attenuate myelosuppressive

effects of cyclophosphamide. BD is known to potentiate macrophage phagocytic

activity. It is also shown to increase GM-CSF levels upon oral administration, inhibiting

apoptosis.19

5.4.16 Ocimum sanctum (Tulasi)

Ocimum sanctum is used as an antistress, antioxidizing, and immunomodulatory agent. The

ethanolic extract of O. sanctum revered the changes in plasma levels of corticosterone

induced by exposure to acute and chronic stress.54 Banerjee et al.55 have studied the modulatory

influence of the alcoholic extract of leaves of O. sanctum on various enzyme levels

in the liver, lung, and stomach of mice. Oral treatment with extract significantly elevated

the activities of cytochrome P 450, cytochrome b5, and arylhydrocarbon hydroxylase, all

of which are important in the detoxification of carcinogens as well as mutagens. These

observations suggest that leaf extract or its active principle may have a potential role in

the chemoprevention of chemical carcinogenesis.

5.4.17 Shilajit (Asphalt)

Shilajit is an exudate of selected rocks occurring in the Himalaya region. It is a complex

mixture of both organic and inorganic matter and is considered to be an effective remedy

for many diseases. It was investigated for its effect on memory, learning, and anxiety. It

was reported that Shilajit enhanced the acquisition of learning and memory in aged rats

while exhibiting a marked reduction in anxiety levels. This neurochemical effect of Shilajit

is attributed to decrease in 5-hydroxytryptamine turnover with an increase in dopaminergic

activity.56 To add the multifaceted activity of Shilajit, a study was designed by Oureshi

et al.57 to investigate the cytological and biological effects of Shilajit and its response to

the changes induced by cyclophoshamide. The study showed that Shilajit exhibited cytotoxic

effects and inhibited the carcinogenic potential of cyclophosphamide. In experimental

studies, it has also been observed that Shilajit activates macrophage and enhances cytokine

release.31

5.4.18 Chyawanprash Awaleha: A Polyherbal Rasayan Formulation

Chyawanprash awaleha (CA) is a polyherbal Ayurvedic rasayan preparation described in

Charak Samhita and contains the pulp of E. officinalis as the prime ingredient. This preparation

is popularly used in India and many other countries as a health supplement.

In a controlled clinical study using CA as an adjuvant in the treatment of pulmonary

TB, it was observed that the preparation could augment the recovery process in addition

to an improved nutritional status of the subjects.58

Recently, the anticarcinogenic property of CA has also been studied. It has been shown

to reduce tumor weight in mice. A clinical study was undertaken to estimate the radioprotective

effect of CA. The study included patients with head and neck cancers undergoing

radiotherapy. It was observed that CA conferred an excellent protection to the tissues

from the burning effects of radiation, in comparison with controls.59 The tumor regression

rate was also noted to be higher in the CA-treated group. These results may be suggestive

of possible antioxidant effects of E. officinalis contained in the preparation.

5.5 Immunomodulation Therapies

5.5.1 Tuberculosis

There is considerable evidence that failure to control or resolve infectious disease often

results from an inappropriate rather than insufficient immune response. A good example

is TB. In this condition, T-cell immunity is decreased; the TH-cell is not able to

produce sufficient IFN-g to activate macrophage, which can kill mycobacterium TB.

Intervention in this situation could be aimed at expanding protective TH

1-cells or

alternatively enhancing the key protective response macrophage activation by IFN-g.

Current therapy consists of antibacterial drugs like Rifampicin, Isoniazid, Pyrazinamide,

and Ethambutol for a period of 4 to 6 months. Significant success rate is achieved

with this regimen. Treatment of TB with rasayana has shown significant improvement

in treatment period.

Treatment of TB with Ayurveda includes various rasayana like T. cordifolia and CA. The

latter is a wonderful remedy that provides strength and sustenance to the patient. It was

mentioned earlier that using CA as an adjuvant in the treatment of pulmonary TB58 could

augment recovery process. It also increases the appetite. The dosage in the beginning

should be two teaspoonfuls with milk on an empty stomach twice daily; as the patient

gains strength, the dosage should be increased.

A double-blind randomized clinical trial40 of T. cordifolia was conducted in TB patients

along with a conventional anti-TB regimen for an initial 2-month intensive period. It

was observed that when conventional anti-TB regimen was given along with 500 mg of

T. cordifolia three times daily, the sputum conversion time was 2 weeks as compared

with 4 weeks in the conventional group; there was also hastened radiological recovery

as compared with the conventional regimen. This effect was observed due to increased

nitric oxide production by T. cordifolia, which caused increased macrophage phagocytic

activity.

5.5.2 Hepatic Disorder

In recent years, rapid progress has been made in understanding the relationship between

various cells of the liver and pathobiology of cellular events responsible for an acute and

chronic hepatic damage. Kupffer cells, which are present in the liver, are the most versatile

cells. The activity of these cells is a major determinant of outcome of any liver injury.60 It

has been reported that excess activation of Kupffer cells damages the liver,61–63 whereas

hepatic fibrosis is linked with suppressed or subnormal activity of these cells. Thus,

modulation of Kupffer64 cells activity through the immune system would be a weapon

against liver disorders.

5.5.2.1 Obstructive Jaundice

In the management of obstructive jaundice, present preoperative therapy aims at decompressing

the biliary tract and controlling infection with antibiotics and vitamin K if there

is a disturbance in hemostasis. Despite improvement in preoperative care, the surgical

outcome of these patients has remained poor.65,66 Endotoxemia resulting from depressed

Kupffer cells is a well-known feature of obstructive jaundice. Based on Ayurvedic literature,

it has been observed that rasayana like T. cordifolia could be a useful therapeutic

armamentarium in the treatment of obstructive jaundice. In a clinical trial of T. cordifolia

as an add-on regimen to conventional therapy, two groups of patients were well matched

with respect to clinical features and hepatic and immune functions.67 The neutrophil

activity of these patients was significantly lower as compared with normal healthy donors.

After biliary drainage, bactobilia was observed.67 Therapy with T. cordifolia significantly

decreased the mortality from 92 to 40%. This was also associated with a decrease in

speticemia. T. cordifolia was found to potentiate the depressed neutrophil activity.

A randomized double-blind placebo-controlled clinical trial also showed a significant

reduction in mortality rates.20 Moreover, at the cellular level remarkable results were

shown; patients suffering from obstructive jaundice taking T. cordifolia showed an increase

in serum GM-CSF levels. The neutrophils of these patients also showed an increased

phagocytic activity, making T. cordifolia an effective treatment for patients with obstructive

jaundice.20

5.5.2.2 Asymptomatic Carriers of Hepatitis B Antigen

In asymptomatic carriers of hepatitis B antigen, elimination of viral antigen is necessary

to prevent future hepatic dysfunction and to reduce transmission. Although the role of

nonspecific cellular immunity is not clearly defined, defects in monocyte have been

reported68 and immunomodulators like levamisole and interferons have been shown to

eliminate antigen.69 Therapy with rasayana such as T. cordifolia (16 mg/kg/day) for 2

months led to seroconversion in 37.5% of patients. This rate was three times higher than

that observed in the intracellular killing capacity of monocytes.20

5.5.2.3 HIV Infection

HIV is a disease starting from the stage of latent infection, progressing into the severe

immunodeficiency state of AIDS, and finally ending in death. HIV is a smart bug. Unlike

the other lente viruses, which possess only three genes, HIV has six more functional genes.

These are responsible for producing numerous drug-resistant mutant variants.

Review of the scenario of the modern highly active antiretroviral therapy (HAART) is

depressing. The scenario consists of reverse transcriptase inhibitors and a protease inhibitor.

Failure to eliminate the virus from sanctuaries, an increase in the number of resistant

variants of the virus, severe toxicity manifestations, a significant increase in risk of TB,

very poor improvement in longevity, and prohibitive costs are some of the reasons why

HAART cannot be considered as a choice therapy. The practical utility of a vaccine in

preventing the disease also holds very little hope.

Under these circumstances, certain studies mentioned in Ayurvedic texts have been

examined to find possible solutions. Ayurveda mentions sexually transmitted communicable

progressive wasting disorder. Excessive indulgence in sex and abnormal sexual

practices are suggested to be the cause of loss of vitality and immunity (ojakashaya) leading

to a wasting disorder.

According to Ayurveda, the loss of ojas is responsible for a progressively wasting disorder.

Ojas is the creamy by-product of shukra dhatu. It is the ultimate strength of the body.

Debility, wastage, fear, depression, a feeling of wretchedness, and a loss of coordination

in sense and motor organs are all signs of damage to ojas. Ayurvedic texts also reveal that

shukra, the seventh tissue of the body, is of two types. One type is present all over the

body and responsible for strength, vitality, and glow (shukra is probably related to the

steroid hormones of the body). The other type, beej shukra, is responsible for gamete

production. Ayurveda authoritatively states that the formation of shukra begins only after

the complete development of bone marrow (majja dhatu). The complete formation of shukra

dhatu occurs in females and males at 16 and 23 years of age, respectively. According to

modern endocrinology, adolescent changes occur when red bone marrow in the long bones

of a child is transformed into fatty yellow marrow. This produces extra gonadal steroids,

which send a positive feedback to the hypothalamus and activate the hypathalmopituitary

gonadal axis. This is the beginning of functioning of the gonads. The Ayurvedic hypothesis

of the origin of shukra from majja dhatu appears meaningful.70

Cells need oxygen for survival, but the uncoupled single oxygen radical also causes

oxidation damage to the cell. It is indeed an oxygen paradox of the cell. In HIV, reactive

oxygen species activate nuclear transcription factor, an obligatory factor for HIV replication.

It also aids apoptosis of CD4 cells and thus helps disease progression.

With this background of HIV disease pathology, the mind–body holistic concept of

Ayurveda should be an interesting option for treating psychological factors and for treating

HIV. Rasayana that are classified as achar rasayana, ahar rasayana, and dravya rasayana are

helpful in reversing the damage already done to the immune system. Ahaar rasayana (food

as a drug) such as black gram, milk, ghee, and meat are advised. Black grams are well

known to be a good source of alpha lipoic acid. Ghee has a special place in increasing the

ojas.

Some of the plants that have shown anti-HIV activity include Cichorium intybus,70 Glycyrrhiza

glabra,71,72 Grifola frondosa,73 Punica granatum,70 curcumin,70 and aloe vera.74 In one

study, aloe vera juice (20 oz/day) was used in conjunction with essential fatty acids and

amino acid supplements to treat 29 patients. There were 15 AIDS, 12 AIDS-related complex

(ARC), and two HIV seropositive patients that continued with regular medication, including

Azidothymidine (AZT),74 an antiviral drug used to combat AIDS. After 6 months, all

patients showed clinical improvement; 25% of those positive for p24 core antigen converted

to nonreactive, anemia induced by AZT showed improvement in all patients, and

the patients gained an average of 7% in body weight.

Acemennan, a water-soluble polysaccharide obtained from aloe vera, is found to be

responsible for this anti-HIV activity. The anti-HIV activity of acemannan probably results

from inhibiting glycosylation of viral glycoproteins. However, the prominent effect is by

enhancing the effect of AZT. Researchers believe that use of acemannan may reduce the

amount of AZT by as much as 90%.75 This is quite significant. AZT is extremely expensive

and is also associated with side effects such as anemia and a decrease of white blood cell

production. Acemannan is commercially available as CARRISYN by Carrington Laboratories

in Irving, TX.

In a clinical study in patients in the early stages of AIDS, Acemannan showed some

promise. In this study, 14 HIV patients who were prescribed oral Acemannan (800 mg/

day) demonstrated significant increases in circulating monocytes and macrophages. In

particular, the number of large circulating monocytes increased significantly, indicating

improvement in phagocytizing, processing, and presenting cells in blood.75

Although Acemannan may be helpful in the beginning stages of AIDS, a recent study76

indicates that it may be of little value in patients with advanced HIV disease.

Glycyrrhizin, a major constituent of G. glabra, is also showing great promise in the

treatment of HIV-related disease, including AIDS. In one study, 10 HIV patients without

AIDS took 150 to 225 mg of glycyrrhizin daily.77 After 1 to 2 years, none developed

symptoms associated with AIDS or ARC; however, one of the 10 patients in a matched

control group developed ARC and two progressed to AIDS and subsequently died. In yet

another study, when glycyrrhizin was administered in daily doses of 200 to 800 mg

intravenously, after 8 weeks the groups presented increased helper T-cell count, improved

helper/suppressor T-cell ratio, and improved liver function.78

5.6 Conclusions and Future Prospective

The immune system is a complex system, involving an interwoven network of biochemical

mechanism. The concept of rasayana as mentioned is Ayurveda is a holistic approach and

constitutes an important approach to handle with subjects of immunity. The objective of

research on rasayana should focus not only on its immunomodulatory activity, but also on

other effects such as antistress, antiaging, antioxidant, adaptogenic, and anti-HIV. The list

of herbs in rasayana is exhaustive by itself. Rasayana formulas provide tremendous potential

to be tapped for immunomodulatory activity. It is equally important to arrive at a

consensus in regards to the utilization of herbs in a holistic manner in order to deliver

their multidimensional benefits to mankind.

Om Tat Sat

                                                        

(Continued...) 

(My humble salutations to H H Maharshi ji,  Brahmasri Sreeman Lakshmi Chandra Mishra ji and other eminent medical scholars and doctors   for the collection)