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 DOI: 10.1177/1534735413490233 2013 12: 455 originally published online 4 June 2013Integr Cancer Ther

Manjeshwar Shrinath Baliga, Sharake Meera, Lalit Kumar Vaishnav, Suresh Rao and Princy Louis PalattyTreatment

Rasayana Drugs From the Ayurvedic System of Medicine as Possible Radioprotective Agents in Cancer  

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Article

Introduction

The effective use of ionizing radiation is compromised by the side effects resulting from the sensitivity of the border-ing normal tissues. Accordingly, the use of compounds that can protect normal tissues against radiation injury has been a long-sought goal as in addition to protecting the normal tissue it will also permit use of higher doses of radiation to obtain better cancer control and possible cure.1 Since the discovery by Patt et al2 that pretreatment with cysteine pro-tected rats against X-ray-induced mortality, several com-pounds have been synthesized and tested for their radioprotective properties. The sulfydryl compounds were found to be good radioprotectors but unfortunately their inherent toxic effects at their optimal protective doses were a major deterrent to their clinical use.3,4

Herbal drugs offer an alternative to synthetic compounds and are considered either nontoxic or less toxic3 and experi-mental studies have shown that the Ayurvedic drugs Amritaprasham,5-7 Ashwaganda Rasayana,5-7 Brahma Rasayana,6-14 Chyavanaprasha,14 Narasimha Rasayana,5-7 and Triphala15-18 possess radioprotective effects. In the cur-rent review, for the first time an attempt is made to summa-rize these observations with emphasis on the plausible reasons responsible for the radioprotective effects.

Traditional Ayurvedic Drugs With Radioprotective Effects

Ayurveda (in Sanskrit Ayur means life, and Veda means knowledge) the traditional Indian system of medicine, is one of the world’s oldest medical systems.3 The concept and treatment principles of Ayurveda are different from that of the modern medicine. Whereas modern medicine is evidence based and makes use of a distinct well-defined chemical entity for treatment, emphasis in Ayurveda is mainly on disease prevention and promotion of good health by following proper lifestyle and by adopting measures of rejuvenation.19,20

According to the Ayurvedic system of medicine, the body is composed of tridosha, known as Vata, Pitta, and Kapha, the psychophysiological principles that regulate various functions in the body. Vata governs functions

490233 ICTXXX10.1177/1534735413490233Integrative Cancer TherapiesBaliga et alresearch-article2013

1Father Muller Medical College, Mangalore, Karnataka, India2Sanjeevini Ayurveda, Mangalore, Karnataka, India3Mangalore Institute of Oncology, Mangalore, Karnataka, India

Corresponding Author:Manjeshwar Shrinath Baliga, Research and Development, Father Muller Medical College, Kankanady, Mangalore 575002, Karnataka, India. Email: shrinath.research@gmail.com

Rasayana Drugs From the Ayurvedic System of Medicine as Possible Radioprotective Agents in Cancer Treatment

Manjeshwar Shrinath Baliga, PhD, MBA1, Sharake Meera, BAMS2, Lalit Kumar Vaishnav, BAMS3, Suresh Rao, MD3 and Princy Louis Palatty, MD1

AbstractThe use of ionizing radiation, which is the cornerstone of cancer treatment, is compromised by the radiosensitivity of normal tissues. A chemical that can give selective benefit to the normal cells against the deleterious effects of ionizing radiation has been a long-sought goal. However, most of the compounds studied have shown inadequate clinical application owing to their inherent toxicity, undesirable side effects, and high cost. Studies carried out in the past 2 decades have shown that some of the classical Indian Ayurvedic drugs (Amritaprasham, Ashwagandha Rasayana, Brahma Rasayana, Chyavanprasha, Narasimha Rasayana, and Triphala Churna) possess radioprotective effects. In the current review, an attempt is made to summarize the radioprotective observations of these Ayurvedic drugs and the mechanisms responsible for the radioprotective effects.

Keywordsradiation protection, cancer, Ayurveda, Rasayana drugs, polyherbal preparations

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associated with the movement and communication. Pitta governs functions associated with metabolism, digestion, and transformation. Kapha governs the structure and cohe-sion of the body. For optimal functioning of the body, the 3 doshas need to be in a state of equilibrium with each other and its alterations affect the normal functions and health of the individual. The balance in tridosha is highly sensitive and is susceptible to variation because of age, environmental changes (diurnal, nocturnal, and seasonal modifications) and altered lifestyle (changes in food hab-its, physical activity).19-21

Exposure to ionizing radiation alters the balance and leads to the irreversible changes in the tridoshas that are visible as radiation sickness and when severe causes mortality.15 The classical Ayurvedic drugs Amritaprasham,5-7 Ashwaganda rasayana,5-7 Brahma Rasayana,6-14 Chyavanaprasha,14 Narasimha Rasayana,5-7 and Triphala,15-18 which belong to Rasayana group of drugs in Ayurveda (drug that imparts reju-venating effects to the cell and tissues) are reported to possess radioprotective effects and are addressed in this review.

Amritaprasham

According to Ayurveda, regular intake of Amritaprasham early morning is supposed to improve strength, stamina, and to retard aging.20,21 It is also advocated for the treatment of fever, cough, bronchial asthma, burning sensation, and seminal abnormalities such as azoospermia, oligospermia, erectly dysfunction, and menstrual disorder. It is indicated in urinary disorders, hemorrhoids, gastrointestinal disor-ders, epistaxis, anorexia, thirst, vomiting, and loss of con-sciousness. It is supposed to improve strength and provide hemopoetic stimulatory action.20,21

Preclinical studies have shown that the administration of Amritaprasham reduced the radiation-induced loss of body weight and arrested the decrease in the weight of liver, kid-ney, and spleen of mice. Treatment with Amritaprasham caused a 35.5%, 56.73%, and 40% decrease in serum gluta-mate pyruvate transaminase (GPT), serum lipid peroxide, and hepatic lipid peroxide levels, respectively, on day 2 and 54.67%, 40%, and 60% decrease in serum GPT, serum lipid peroxide, and hepatic lipid peroxide levels, respectively, on day 7 postirradiation.6

Ashwagandha Rasayana

Ashwagandha Rasayana is accredited to be a bhalya (drug that improves strength) and vajikara (aphrodi-siac).21 Regular consumption is believed to retard senes-cence, rejuvenate the reproductive organs, and increase fertility in both men and women.20-23 With respect to radiation protection, Vayalil et al6 have shown that the oral feeding of Ashwagandha Rasayana to mice at 50 mg/kg body weight for 28 consecutive days prevented the

radiation-induced emaciation and decrease in the organ weight when compared with the irradiated controls. It also inhibited radiation-induced increase in serum GPT levels and lipid peroxidation levels.6

Brahma Rasayana

Brahma Rasayana is a brain-specific geriatric drug and its regular consumption is supposed to promote mental clarity, improve resilience to mentally demanding chores, and improve memory and cognition. It is also supposed to reduce the symptoms of ageing such as wrinkling and gray-ing of hair.13 Animal studies have shown that feeding Brahma Rasayana protected mice from radiotoxic effects, reduced the loss of organ (spleen liver and kidney) and body weight, decreased the levels of serum and liver lipid perox-ides, alkaline phosphatase, and GPT.6 Clinical studies have also shown that oral administration of Brahma Rasayana increased the levels of lymphocytes and neutrophils in can-cer patients undergoing radiotherapy.13 Leukopenia, neutro-penia, lymphopenia, and the level of serum lipid peroxidation were decreased, suggesting its benefit.13

Chyavanaprasha

Chyavanaprasha is a polyherbal preparation made of more than 65 plants is one of the oldest and most popular Ayurvedic preparations. It is named after its inventor sage Chyavana and the first documented evidence of this formu-lation is observed in the principal Ayurvedic text Charak Samhita where it is advocated to treat kasa (cough), svasa (dyspnea), kshaya (consumption), svarabheda (voice prob-lems), and hrdroga (cardiac problems).20 Because of this it is also termed as the elixir of life. Chyavanaprasha is sup-posed to be an anabolic agent and its regular consumption is believed to give health benefit to people of all ages and health.20,24

Chyavanaprasha also possess radioprotective effects and administering graded doses of hydroalcoholic extract (5-80 mg/kg body weight) for 5 consecutive days by intraperito-neal route before exposure to supralethal dose of γ-radiation (10 Gy) protected animals against the radiation-induced sickness and mortality.14 The best effect was observed at 15 mg/kg, where the highest survival of 58.33% was observed on day 30 postirradiation. The chyavanaprasha extract was nontoxic up to a dose of 6 g/kg body weight suggesting it to be safe and devoid of systemic toxicity.14 Studies have shown that Chyavanaprasha decreases the carbon tetrachloride–induced liver damage in rats25 and that it reduces the ascites and solid tumor volume of tumor-bearing animals, which then concomitantly increases their life span.26 Intake of Chyavanaprasha (20 grams) twice a day for 2 months by bidi smokers, decreased their coughing, increased their appetite, and helped them gain body weight.27

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Narasimha Rasayana

Ashtangahridayam, one among the major ancient Ayurvedic treatise by Acharya Vagbhata describes the Narasimha Rasayana in detail and it is said to be of use in reversing aging, improving immune function, and increasing sexual vigor and potency.20,21 Feeding mice with 50 mg/kg body weight of Narasimha Rasayana consecutively for 5 days prior to, and for a month after, radiation arrested the radiation-induced deleterious effects. Treatment with Narasimha Rasayana increased the body weight and the organ weights of the recipient mice.6 It also decreased the levels of radio-toxic biochemical endpoints and the levels of serum and tis-sue lipid peroxides, serum alkaline phosphatase, and GPT.6

Triphala

Triphala churna, which in Sanskrit means 3 fruits, is made of Terminalia chebula Retz, Terminalia bellerica Roxb, and Phyllanthus emblica Linn or Emblica officinalis gaertn and is an important Ayurvedic formulation. The ancient Indian physicians used Triphala for many ailments but most impor-tantly for gastrointestinal disorders such as dyspepsia, poor food assimilation, cleansing of colon, constipation, gastro-intestinal tract, and colon tonifier.20 Triphala has been reported to cause weight loss and to be useful in anemia, jaundice, constipation, cough, asthma, fever, chronic ulcers, leucorrhea, and pyorrhea.20,28 Preclinical studies have shown that Triphala is a potent free radical scavenger and possesses antioxidant, anti-inflammatory, antipyretic, anal-gesic, antibacterial, antimutagenic, adaptogenic, anticancer, and hypoglycemic effects.15

Triphala is observed to exert radioprotective effects when administered through both intraperitoneal15,16 and oral routes.17 Jagetia et al15 have observed that administra-tion of aqueous extract of Triphala (5-20 mg/kg) by the intraperitoneal route for 5 consecutive days prior to suprale-thal dose of 10 Gy γ-radiation protected mice against radia-tion sickness and mortality.15 The best protection was observed for 10 mg/kg Triphala as nearly 60% survival was observed at the end of the study period of 30 days postirra-diation.15 The optimum radioprotective dose of 10 mg/kg Triphala was found to be 1/28 of the LD

50 dose 280 mg/kg

body weight and caused a dose reduction factor of 1.15.16 Animal studies have also shown that oral feeding of Triphala powder for 14 consecutive days, 7 days prior to and 7 days after exposure to lethal dose of 7.5 Gy of whole-body γ-radiation. Triphala was ineffective when administered only after irradiation thereby indicating its benefit to be only when exposure to radiation is planned.17 Recently, Yoon et al18 also observed that administering Triphala (1 and 1.5 g/kg/d orally for 10 consecutive days) protected rats against the single fraction of 12.5Gy γ-irradiation-induced acute intestinal mucosal damage.

Mechanisms Responsible for the Radioprotective Effects

The exact mechanism of action responsible for the radio-protective effects of these Rasayana drugs is unknown. As these formulations contain many plants with diverse phar-macological properties with some of them possessing radio-protective effects (Table 1), it is logical to expect that myriad protective mechanisms are concomitantly operating (Figure 1). Some of the studied and reported mechanisms are explained in the following sections.

Free Radical Scavenging

Agents that can scavenge free radicals or reactive metab-olites without affecting the outcome of the treatment would be beneficial to the host and can enhance the effi-ciency of the treatment. Studies have shown that the Triphala, Chyavanaprasha, and Brahma Rasayana possess free radical scavenging and antioxidant effects. In vitro studies suggest that Brahma Rasayana scavenged Fe2+-ascorbate and Fe3+-ADP-ascorbate–induced lipid peroxi-dation and scavenged the hydroxyl, superoxide, and nitric oxide generated in vitro. It also inhibited the phorbol myristate acetate–induced superoxide generation in mice peritoneal macrophages and nitrite production in perito-neal macrophages.16 Triphala and Chyavanaprash have also been observed to scavenge nitric oxide in vitro.29 Rasayana drugs are composite herbal formulations and many plants that are an integral part of Rasayana prepara-tions possess free radical scavenging and antioxidant prp-perties (Table 2).3,6,7,30-32

Increase in Antioxidant Enzymes

Studies have shown that Triphala and Brahma Rasayana increase the levels of glutathione and antioxidant enzymes and protect against the oxidative stress.11,17,35 The admin-istration of aqueous extract of the medicinal plants such as Aegle marmelos, Terminalia chebula, Emblica offici-nalis, which are an integral part of many Rasayana formu-lations, have been reported to effectively modulate the oxidative stress and enhance the antioxidant status in rodents.36-39

Antimutagenic Activities

There is increasing evidence that many phytochemicals, plants, and their compound formulations present in rasay-ana can act as inhibitors of mutagenesis and carcinogene-sis.3,40,41 Studies by Yadav et al27 have shown that consumption of Chyavanaprasha by bidi smokers decreased the genotoxic risk caused by mutagenic agents present in tobacco smoke. When compared with bidi smokers alone,

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consumption of Chyavanaprasha decreased the mitotic index, chromosomal aberrations, sister chromatid exchanges, and satellite associations.27

Kaur et al40 have reported that aqueous, chloroform, and acetone extracts of Triphala was observed to possess anti-mutagenic effects against both direct and indirect mutagens in the Ames histidine reversion assay. The results demon-strate that the extracts inhibited the mutagenicity induced by both direct- and indirect-acting mutagens, but the inhibi-tion was greater for S9-dependent mutagens.40 The acetone and chloroform extracts were observed to be better than the aqueous extracts in the TA98 and TA100 tester strains of Salmonella typhimurium. Maximum inhibition was observed for the acetone extract.40

Triphala and its individual constituents are reported to prevent γ-radiation-induced DNA strand break formation in the plasmid DNA (pBR322) in vitro.42 Feeding of triphala was also observed to inhibit the radiation-induced DNA strand breaks in leukocytes and splenocytes of mice exposed to whole-body irradiation of 7.5 Gy.17 Furthermore, plants such as Ocimum sanctum, Podophyllum hexandrum, Phyllanthus amarus, Phyllanthus amarus, Moringa oliefera, Tinospora cordifoila, Mentha piperita, Syzygium

cumini, Aegle marmelos, and Aphanamixis polystachya have been reported to inhibit radiation-induced DNA dam-age as evaluated by chromosomal aberration or micronu-cleus assay.41

Inhibition of Lipid Peroxidation

In vitro studies have shown that the both alcoholic and aque-ous extracts of Rasayana inhibit enzymatic- and nonenzymatic-induced microsomal lipid peroxidation in a concentration-dependent manner.33,43 Triphala is also observed to decrease the radiation-induced lipid peroxida-tion in vitro.32 Brahma Rasayana treatment decreased the radiation-induced increase in the serum lipid peroxidation in cancer treatment13 and serum and liver lipid peroxidation in the chickens subjected to heat stress.44 Studies also indicate that several botanicals such as Centella asiatica, Ocimum sanctum, Podophyllum hexandrum, Amaranthus panicula-tus, Emblica officinalis, Phyllanthus amarus, Piper longum, Tinospora cordifoila, Mentha arvensis, Mentha piperita, Syzygium cumini, Zingiber officinale, Ageratum conyzoides, Aegle marmelos, and Aphanamixis polystachya protect against radiation-induced lipid peroxidation (Table 2).41

Table 1. Composition of Various Traditional and Proprietary Herbal Drugs Reported to Possess Radioprotective Effects.

Name Composition

Classical Ayurvedic formulationsAmritaprasham Holstemma annulare, Vigna vexilata, Phaseolus adenanthus, Glycyrrhiza glabra, Zingiber officinale,

Asparagus recemosus, Boerhaavia diffusa, Sida retusa, Clerodendrum serratum, Macuna pruriens, Hedychium spicatium, Phylanthus niruri, Piper longum, Vitis viniferra, Embelica officinalis, Purerira tuberose, Saccharum officinalum, Piper nigrum, Cinnamomum zeylanica, Elettaria cardamomum, Garcinia Morella, and Mesua ferrea5,6

Ashwaganda Rasayana Withania sominifera, Purerira tuberosa, Hemidesmus indicus, Ciminum cuminum, Aloe barbidensis, Vitis vinifera, Elettaria cardamomum, Zingiber officinale, Piper nigrum, and Piper5,6

Brahma Rasayana Embelica officinalis, Terminalia chebula, Urarira pitca, Desmodium gangeticum, Gmelina arborea, Solanum nigrum, Tribulus terrestris, Aegle marmelos, Premna tomentosa, Stereospermum suaveolens, Oroxylon indicum, Sida rhombilfolia, Boerhaavia diffusa, Ricinus communis, Vigna vexilata, Phaseolus adenanthus, Asparagus recemosus, Holostemma annulare, Leptadenia reticulata, Desmostachya bipinnata, Saccharum officinalum, Oryza malampuzhensis, Cinnamomum iners, Elettaria cardamomum, Cyperus rotundus, Curcuma longa, Piper longum, Aquilaria agallocha, Santalum album, Centella asciatica, Mesua ferrea, Clitoria ternate, Acorus calamus, Scirpus crossus, Glycyrrhiza glabra, and Embelia ribe5,6

ChyavanaprashaChyawanprashchyavanaprashachyavanaprashchyawanaprash

Emblica officinalis, Bambusa arundinacea, Agele marmelos, Clerodendrum phlomidis, Oroxylum indicum, Gmelina arborea, Stereospermum suaveolens, Sida cordifolia, Desmodium gangeticum, Uraria picta, Teramnus labialis, Piper longum, Tribulus terrestris, Solanum indicum, Solanum xanthocarpum, Pistacia integerrima, Phaseolus trilobus, Phyllanthus niruri, Vitis vinifera, Leptadenia reticulata, Inula racemosa, Aquilaria agallocha, Tinospora cordifolia, Terminalia chebula, Ellettaria cardamomum, Cinnamom cassia, Cinnamom iners, Habenaria intermedia, Microstylis walichii, Microstylis museifera, Mesua ferra, Hedychium spicatum, Cyperus rotundus, Boerhaavia diffusa, Polygonatum verticillatum, Nymphaea alba, Santalum album, Pueraria tuberosa, Adhatoda vasica, Roscoea alpina, Martynia diandra, and Sesamum indicum14

Narasimha Rasayana Acacia catechu, Plumbago xylanica, Xylia dolabriformis, Pterocarpus marsupium, Embelia ribes, Semicarpus anacardium, Eclipta alba, Terminalia chebula, Embelica officinalis, and Terminalia belerica5,6

Triphala Emblica officinalis, Terminalia chebula, and Terminalia belerica15-17

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Figure 1. Biochemical targets responsible for radioprotective effects of the Ayurvedic Rasayana drugs (arrows up = increase; arrows down = decrease).

Table 2. Plants With Various Pharmacological Properties That Are an Integral Part of the Rasayana Drugs.

Pharmacological Properties Plants

Radioprotective Emblica officinalis, Terminalia chebula, Terminalia bellerica, Asparagus racemosus, Tinospora cordifolia, Ocimum sanctum, Curcuma longa, Zingiber officinale, Agele marmelos, Phyllanthus niruri, Boerhaavia diffusa, Adhatoda vasica, Sesamum indicum, Cinnamomum zeylanica, Centella asciatica, Acorus calamus, Glycyrrhiza glabra, Embelia ribes, Hemidesmus indicus, Ciminum cuminum, Aloe barbidensis, Syzygium cumini, Mentha piperita, Mentha arvensis, and Podophyllum hexandrum4

Free radical scavenging Emblica officinalis, Withania somnifera, Terminalia chebula, Terminalia bellerica, Asparagus racemosus, Tinospora cordifolia, Ocimum sanctum, Curcuma longa, Zingiber officinale, Agele marmelos, Oroxylum indicum, Sida cordifolia, Tribulus terrestris, Phyllanthus niruri, Vitis vinifera, Ellettaria cardamomum, Cinnamom cassia, Cyperus rotundus, Boerhaavia diffusa, Santalum album, Adhatoda vasica, Sesamum indicum, Cinnamomum zeylanica, Glycyrrhiza glabra, Centella asciatica, Acorus calamus, Glycyrrhiza glabra, Embelia ribes, Hemidesmus indicus, Ciminum cuminum, and Aloe barbidensis3,4,6,7,16,30-32

Antioxidant Asparagus racemosus, Ocimum sanctum, Podophyllum hexandrum, Tinospora cordifolia, Hippophae rhamnoides, Zingiber officinalis, Centella asiatica, Syzygium cumini, Ligusticum wallichii, Vitis vinifera3,4,6,7,16,30-32

Anti-inflammatory Glycyrrhiza glabra, Allium sativum, Aloe vera, Tinospora cordifolia, Hippophae rhamnoides, Curcuma longa, Centella asiatica, Syzygium cumini, Ocimum sanctum, Moringa oleifera, Zingiber officinale, Eleutherococcus senticosus4

Antimutagenic and prevention of DNA damage

Triphala, Chyavanaprasha, Ocimum sanctum, Curcuma longa, Zingiber officinale, Agele marmelos, Phyllanthus niruri, Tinospora cordifolia, Emblica officinalis, Terminalia chebula, and Terminalia belerica4

Immune modulatory and adoptogenic activities

Emblica officinalis, Withania somnifera, Viscum album, Ocimum sanctum, Tinospora cordifolia3,4,30,33,34

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460 Integrative Cancer Therapies 12(6)

Anti-Inflammatory Effects

Studies have shown that Rasayana drugs and some of their constituent plants are potent inhibitors of inflammation as shown by reduction in paw edema induced by carrageenan and various experimentally induced inflammatory reac-tions.45,46 They are also shown to alleviate rheumatoid arthritis.47 Triphala is also reported was effective in pre-venting the Freund’s adjuvant–induced arthritis and inflam-mation in mice.48 The effect was observed to be better than that of indomethacin and the levels of lysosomal enzymes, tissue marker enzymes, glycoproteins, and paw thickness were significantly altered in the Triphala group to near nor-mal conditions.48

Hemopoietic Stimulation

Studies suggest that the Rasayana drugs possess hemopoietic stimulatory function against cytotoxic effects of anticancer agents. Triphala, Brahma Rasayana, Narasimha Rasayana, Ashwaganda Rasayana, Amritaprasham Chayavanprasha have been observed to attenuate the radiation-induced dam-age to the hemopoietic system.6,7,15 The plants Acanthopanax senticosus, Embelica officinalis, Withania somenifera, Tinospora cordifolia, and Boerhaavia diffusa provide total-body radiation protection by stimulating hematopoiesis.3,41

Immune Modulation

Rasayanas are observed to possess immunomodulating effects and unlike the conventional agents activate immune system without altering other basic parameters of the body.6,7,48 Administering Rasayana to animals improved the total number of leukocytes, absolute num-ber of polymorphonuclear cells and lymphocytes in the peripheral blood of mice without altering liver or kidney function.5-7,49 Clinical studies have shown that adminis-tration of Brahma Rasayana did not alter the total leuko-cyte, the white blood cell counts, and the ratios. An increase in the activity of lymphocytes and increase in serum granulocyte macrophage colony-stimulating factor were also observed.13

Triphala has been reported to possess immunomodulatory activities and to stimulate the neutrophil functions in immu-nized rats and stress-induced suppression in the neutrophil functions.50 Additionally, some of the medicinal plants that are an integral part of the Rasayana, such as Picrorhiza kur-roa, Tylophora indica, Aconitum heterophyllum, Holarrhena antidysenterica, Tinospora cordifolia, and Ocimum gratissi-mum, are reported to improve the phagocytic function with-out affecting the humoral or cell-mediated immune system.51 Plants possessing immunomodulating and immunostimula-tory activities, for example, Podophyllum hexandrum, Hippophae rhamnoides, Viscum album, Ocimum sanctum,

and Tinospora cordifolia, have also been reported to provide protection by increasing spleen colony-forming units.

Several triterpenoids such as glycyrrhizic acids, ursolic acid, and oleanolic acid possess immunopotentiating activ-ity.3 Studies have also shown that the phytochemicals glyc-yrrhizin and glycyrrhizic acid, present in Glycyrrhiza glabra increased cellular immunocompetence.51 Tinospora cordifolia is suggested to activate macrophages and release granulocyte macrophage colony-stimulating factor activ-ity,52 whereas its active constituents syringin and cordiol are reported to enhance the humoral and cell-mediated immu-nity.53 Reports also indicate that the plants such as Allium sativum and Ocimum sanctum, which also possess radio-protective effects, augment NK cells, whereas Aloe vera is shown to stimulate synthesis of interleukin-1 and tumor necrosis factor-α3,54,55 (Table 2).

Adoptogenic and Antistress Properties

Oral administration of Triphala is reported to significantly prevent the noise-induced56 and cold stress–induced57 behavioral and biochemical abnormalities in albino rats. With regards to radiation-induced stress it is logical to expect that the adoptogenic properties of triphala may con-tribute, at least in part, to the observed radiation protection. Studies have shown that the Rasayana drugs such as Chyavanaprasha, Triphala, and Brahma Rasayana as well as the plants used in them such as Withania somnifera, Emblica officinalis, Asparagus racemosus, and Tinospora cordifolia also possess these effects (Table 2).3,30,33,34

Conclusions

Scientific studies carried in the recent past have shown that the Rasayana drugs Chyavanprasha, Triphala, Brahma Rasayana, Ashwagandha Rasayana, Narasimha Rasayana, and Amritaprasham are effective in preventing the toxic effects of ionizing radiation and physiologically attainable nontoxic doses. A combination of factors such as free radi-cal scavenging, prevention of lipid peroxidation, inhibition of DNA damage, protection and rapid regeneration of bone marrow progenitors after cytotoxic therapy, and increase in or restoration of glutathione and antioxidant status of enzymes would have contributed to the radioprotective effects. With regard to radiation protection, all published studies with these Rasayana drugs have been carried out with animals and human studies are required.

With regard to the use of these individual rasayans in clinics as radioprotective agent, it is hypothesized that the organ-specific Brahma Rasayana and Triphala would be useful in brain and gastrointestinal cancers, whereas Amritaprasham, Ashwagandha Rasayana, Chyavanprasha, and Narasimha Rasayana would be useful in improving the overall health of the patient. However, for these to be of

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use in cancer treatment their selective radioprotective effects needs to be investigated. Suitable studies with tumor-bearing animals of different histological and meta-static potentiality are warranted as only then it will be of use in clinics. Studies are also required to understand the pharmacokinetic, pharmacodynamic, and safety issues of Rasayana at various doses and also the effects when admin-istered for prolonged periods of time. Additionally, mecha-nistic studies with cultured mammalian cells (normal and neoplastic) are also required for understanding the effect of these drugs, the principal plants, and phytochemicals at molecular level. Furthermore, Rasayana formulations are polyherbal and their biological actions depend on the pres-ence of bioactive compounds. It is a well known fact that the concentration of the bioactive compounds varies from place to place and the way in which the plants have been processed postharvesting in the preparation of Rasayana and that this affects the pharmacological action. In view of these observations, it is imperative to validate the unifor-mity of the herbal mixing and also the proportion by using standards and internationally accepted assays such as high-performance thin layer chromatography, ultra-high- performance liquid chromatography/ultraviolet spectros-copy/mass spectrometry, and reversed phase high-perfor-mance liquid chromatography.58,59

Rasayana drugs have been consumed by the habitants in the Indian subcontinent since time immemorial and this gives it an advantage over the synthetic drugs. The nontoxic nature of Rasayana drugs gives immense advantage as they can be easily recommended for human trials and at lesser costs when compared with their synthetic counterparts. Apart from applications in the clinics as an adjuvant in radiotherapy, Rasayana drugs can also be used as a radia-tion countermeasure agent in the management of nuclear incidents, for example, for the protection of defense person-nel from nuclear weapon radiations, for protecting reactor workers and rescue crew, and protection of astronauts from cosmic rays against radiation-induced genomic instability and carcinogenesis. As there are no existing safe and effec-tive synthetic radioprotectors, these studies are useful. Pilot studies should be initiated with personnel continuously exposed to low doses of radiation such as flight attendants and radiotherapy/nuclear medicine staff and technicians. Such study will give valuable information on the radiopro-tective effects of Rasayana drugs in humans and on the maximal permissible dose for optimal radioprotective effects.

These Rasayana drugs are of use in the treatment, pre-vention, and improvement of the quality of life of both healthy and diseased individuals, and their regular con-sumption may benefit humans against other age-related dis-eases and ailments. Most of these Rasayanas can be used regularly as a food for maintaining balanced mental and physical health. They may be used either alone or along

with other modalities of treatment as an adjuvant. Their free radical scavenging, antioxidant, anti-inflammatory chemo-protective, chemopreventive, and immunomodulatory effects will also be of immense use in maintaining a healthy lifestyle and a disease-free life.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, author-ship, and/or publication of this article.

References

1. Hall EJ. Radiobiology for the Radiologist. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.

2. Patt HM, Tyree EB, Straube RL, Smith DE. Cysteine protec-tion against X-irradiation. Science. 1949;110:213-214.

3. Baliga MS. Triphala, Ayurvedic formulation for treating and preventing cancer: a review. J Altern Complement Med. 2010;16:1301-1308.

4. Arora R, Gupta D, Chawla R, et al. Radioprotection by plant products: present status and future prospects. Phytother Res. 2005;19:1-22.

5. Kumar VP, Kuttan R, Kuttan G. Effect of “rasayanas,” a herbal drug preparation on immune responses and its sig-nificance in cancer treatment. Indian J Exp Biol. 199;37: 27-31.

6. Vayalil PK, Kuttan G, Kuttan R. Protective effects of Rasayanas on cyclophosphamide and radiation-induced dam-age. J Altern Complement Med. 2002;8:787-796.

7. Vayalil PK, Kuttan G. Kuttan R. Rasayanas: evidence for the concept of prevention of diseases. Am J Chin Med. 2002;30:155-171.

8. Rekha PS, Kuttan G, Kuttan R. Immunopotentiating activity of Brahma Rasayana. Amala Res Bull. 1998;18:85-90.

9. Rekha PS, Kuttan G, Kuttan R. Effect of herbal preparation, Brahma Rasayana, in amelioration of radiation induced dam-age. Indian J Exp Biol. 2000;38:999-1002.

10. Rekha PS, Kuttan G, Kuttan R. Antioxidant activity of brahma rasayana. Indian J Exp Biol. 2001;39:447-452.

11. Rekha PS, Kuttan G, Kuttan R. Effect of Brahma Rasayana on antioxidant system after radiation. Indian J Exp Biol. 2001;39:1173-1175.

12. Rekha PS, Kuttan G, Kuttan R. Effect of Brahma Rasayana on antioxidant systems and cytokine levels in mice during cyclophosphamide administration. J Exp Clin Cancer Res. 2001;20:219-223.

13. Joseph CD, Praveenkumar V, Kuttan G, Kuttan R. Myeloprotective effect of a non-toxic indigenous preparation Rasayana in cancer patients receiving chemotherapy and radiation therapy. A pilot study. J Exp Clin Cancer Res. 1999;18:325-329.

14. Jagetia GC, Baliga MS. The evaluation of the radioprotec-tive effect of chyavanaprasha (an ayurvedic rasayana drug) in mice exposed to lethal dose of γ-radiation: a preliminary study. Phytother Res. 2004;18:14-18.

by Gheorghies Alina on October 30, 2014ict.sagepub.comDownloaded from

462 Integrative Cancer Therapies 12(6)

15. Jagetia GC, Baliga MS, Malagi KJ, Sethukumar Kamath M. The evaluation of the radioprotective effect of Triphala (an ayurvedic rejuvenating drug) in the mice exposed to gamma-radiation. Phytomedicine. 2002;9:99-108.

16. Jagetia GC, Malagi KJ, Baliga MS, Venkatesh P, Veruva RR. Triphala, an ayurvedic rasayana drug, protects mice against radiation-induced lethality by free-radical scavenging. J Altern Complement Med. 2004;10:971-978.

17. Sandhya T, Lathika KM, Pandey BN, et al. Protection against radiation oxidative damage in mice by Triphala. Mutat Res. 2006;609:17-25.

18. Yoon WS, Kim CY, Yang DS, et al. Protective effect of triphala on radiation induced acute intestinal mucosal damage in Sprague Dawley rats. Indian J Exp Biol. 2012;50:195-200.

19. Kulkarni RD. Principles of Pharmacology in Ayurveda. Mumbai, India: Ram Sangam Graphics; 1997.

20. Nadkarni AK. Indian Materia Medica. 3rd ed. Mumbai, India: Popular Press; 1976.

21. Kaviratna AC, Sharma P. Caraka Samhita Vols. 1-4. New Delhi, India: Sri Satguru Publications; 1996.

22. Mahdihassan S. The tradition of alchemy in India. Am J Chin Med. 1981;9:23-33.

23. Mahdihassan S. Indian Alchemy or Rasayana in the Light of Ascetism and Geriatrics. New Delhi, India: Motilal Banarsidass; 1991.

24. Singh K. Concept of Ojas and the effect of Rasayanas in the management of cancer. In: Proceedings of Ayurveda Seminar on Cancer, Thrissur, India. 1990:15-18.

25. Jose JK, Kuttan R. Hepatoprotective activity of Emblica offici-nalis and Chyavanaprash. J Ethnopharmacol. 2000;72:135-140.

26. Jose JK, Kuttan G, Kuttan R. Antitumour activity of Emblica officinalis. J Ethnopharmacol. 2001;75:65-69.

27. Yadav JS, Thakur S, Chadha P. Chyawanprash Awaleha: a genoprotective agent for bidi smokers. Int J Hum Genet. 2003;3:33-38.

28. Mukherjee PK, Rai S, Bhattacharya S, et al. Clinical studies of ‘Triphala’—a well known phytomedicine from India. Iran J Pharmacol Ther. 2006;5:51-54.

29. Jagetia GC, Rao SK, Baliga MS, Babu KS. The evaluation of nitric oxide scavenging activity of certain herbal formulations in vitro: a preliminary study. Phytother Res. 2004;18:561-565.

30. Rege NN, Thatte UM, Dahanukar SA. Adaptogenic properties of six rasayana herbs used in Ayurvedic medicine. Phytother Res. 1999;13:275-291.

31. Scartezzini P, Speroni E. Review on some plants of Indian tra-ditional medicine with antioxidant activity. J Ethnopharmacol. 2000;71:23-43.

32. Naik GH, Priyadarsini KI, Satav JG, et al. Comparative anti-oxidant activity of individual herbal components used in Ayurvedic medicine. Phytochemistry. 2003;63:97-104.

33. Hanna AN, Kauffman EM, Newman HA, Sharma HM. Prevention of oxidant stress by Student Rasayana (SR). Adv Exp Med Biol. 1994;366:444-445.

34. Suresh K, Vasudevan DM. Augmentation of murine natu-ral killer cell and antibody dependent cellular cytotoxicity activities by Phyllanthus emblica, a new immunomodulator. J Ethnopharmacol. 1994;44:55-60.

35. Deep G, Dhiman M, Rao AR, Kale RK. Chemopreventive potential of Triphala (a composite Indian drug) on benzo(a)pyrene induced forestomach tumorigenesis in murine tumor model system. J Exp Clin Cancer Res. 2005;24:555-563.

36. Singh RP, Banerjee S, Rao AR. Effect of Aegle marmelos on biotransformation enzyme systems and protection against free-radical-mediated damage in mice. J Pharm Pharmacol. 2000;8:991-1000.

37. Bhattacharya A, Ghosal S, Bhattacharya SK. Antioxidant activity of tannoid principles of Emblica officinalis (amla) in chronic stress induced changes in rat brain. Indian J Exp Biol. 2000;38:877-880.

38. Yokozawa T, Kim HY, Kim HJ, et al. Amla (Emblica offi-cinalis Gaertn.) attenuates age-related renal dysfunction by oxidative stress. J Agric Food Chem. 2007;55:7744-7752.

39. Mahesh R, Bhuvana S, Begum VM. Effect of Terminalia che-bula aqueous extract on oxidative stress and antioxidant status in the liver and kidney of young and aged rats. Cell Biochem Funct. 2009;27:358-363.

40. Kaur S, Arora S, Kaur K, Kumar S. The in vitro antimuta-genic activity of Triphala—an Indian herbal drug. Food Chem Toxicol. 2002;40:527-534.

41. Jagetia G. Radioprotective potential of plants and herbs against the effects of ionizing radiation. J Clin Biochem Nutr. 2007;40:74-81.

42. Naik GH, Priyadarsini KI, Bhagirathi RG, et al. In vitro antioxidant studies and free radical reactions of triphala, an ayurvedic formulation and its constituents. Phytother Res. 2005;19:582-586.

43. Sharma HM, Hanna AN, Kauffman EM, Newman HA. Effect of herbal mixture Student Rasayana on lipoxygenase activity and lipid peroxidation. Free Radic Biol Med. 1995;18:687-697.

44. Ramnath V, Rekha PS, Sujatha KS. Amelioration of heat stress induced disturbances of antioxidant defense system in chicken by Brahma Rasayana. Evid Based Complement Alternat Med. 2008;5:77-84.

45. Rekha PS, Kuttan G, Kuttan R. Antioxidant and anti-inflammatory activity of Brahma Rasayana. Amala Res Bull. 1997;17:68-72.

46. Jain P, Khanna NK, Trehan N, Pendse VK, Godhwani JL. Anti-inflammatory effects of an Ayurvedic prepa-ration, Brahmi Rasayan, in rodents. Indian J Exp Biol. 1994;32:633-636.

47. Chopra A. Ayurvedic medicine and arthritis. Rheum Dis Clin North Am. 2000;26:133-144.

48. Rasool M, Sabina EP. Anti-inflammatory effect of the Indian Ayurvedic herbal formulation Triphala on adjuvant-induced arthritis in mice. Phytother Res. 2007;21:889-894.

49. Praveen Kumar V, Kuttan R, Kuttan G. Effect of “Rasayanas” an herbal drug preparation on immune responses and its significance in cancer treatment. Indian J Exp Biol. 1999; 37:27-31.

50. Srikumar R, Jeya Parthasarathy N, Sheela Devi R. Immunomodulatory activity of triphala on neutrophil func-tions. Biol Pharm Bull. 2005;28:398-403.

51. Lin IH, Hau DM, Chen WC, Chen KT, Lin JG. Effects of glycyrrhizae and glycyrrhizic acid on cellular immunocompe-

by Gheorghies Alina on October 30, 2014ict.sagepub.comDownloaded from

Baliga et al 463

tence of gamma-ray-irradiated mice. Chin Med J. 1996;109: 138-142.

52. Thatte UM, Chabria S, Karandikar SM, Dhanukar S. Immunotherapeutic modification by Indian medicinal plants. Indian Drugs. 1988;25:95-97.

53. Kapil A, Sharma S. Immunopotentiating compounds from Tinospora cordifolia. J Ethnopharmacol. 1997;58:89-95.

54. Agarwal SS, Singh VK. Immunomodulation: a review of studies on Indian medicinal plants and synthetic peptides. Proc Indian Natl Acad Sci. 1999;65:179-204.

55. Atal CK, Sharma ML, Kaul A, Khajuria A. Immunomodulating agents of plant origin. I: preliminary screening. J Ethnopharmacol. 1986;18:133-141.

56. Srikumar R, Parthasarathy NJ, Manikandan S, Narayanan GS, Sheeladevi R. Effect of Triphala on oxidative stress and on

cell-mediated immune response against noise stress in rats. Mol Cell Biochem. 2006;283:67-74.

57. Dhanalakshmi S, Devi RS, Srikumar R, Manikandan S, Thangaraj R. Protective effect of Triphala on cold stress-induced behavioral and biochemical abnormalities in rats. Yakugaku Zasshi. 2007;127:1863-1867.

58. Pawar V, Lahorkar P, Anantha Narayana DB. Development of a RP-HPLC method for analysis of Triphala Curna and its applicability to test variations in Triphala Curna preparations. Indian J Pharm Sci. 2009;71:382-386.

59. Avula B, Wang YH, Wang M, Shen YH, Khan IA. Simultaneous determination and characterization of tannins and triterpene saponins from the fruits of various species of Terminalia and Phyllantus emblica using a UHPLC-UV-MS method: applica-tion to Triphala. Planta Med. 2013;79:181-188.

by Gheorghies Alina on October 30, 2014ict.sagepub.comDownloaded from