06nov Dec Sf2

TECH MONITOR Nov-Dec 2006 23

Special Feature : Traditional Medicine: S&T Advancement

Traditional herbs for modern medicine

Pioneering efforts by India's Central Drug Research Institute

Rakesh Maurya and C. M. Gupta

This article compares traditional therapeutic claims of important plant drugs withthe investigative findings of modern science. It examines the therapeutic attributesof plants and their potential for use as modern herbal drugs. It demonstrates theprocess of technology transfer and commercialization by India's Central Drug Re-search Institute in the pharmaceutical area. Two case studies reveal that severalfactors have to work together to ensure success in technology transfer and commer-cialization in the biomedical area of a developing country.

Dr. Rakesh MauryaDr. C. M. Gupta

Central Drug Research InstituteChattar Manzil Palace

Lucknow 226 001, IndiaTel: (+91-522) 2612411 18

Fax: (+91-522) 2623405/2623938/2629504

E-mail: [email protected]

Although modern medicine iswidely spread, TM still exists in allcountries. It is interesting to note that25 per cent of modern medicines arederived from plants that were usedtraditionally. For example, the Chi-nese herbal remedy Artemisia annua,used in China for almost 2000 years,has been found to be effective againstresistant malaria, and has created abreakthrough in preventing almost amillion deaths annually, most of themof children, from severe malaria.

TM systemsThe major systems of TM in South-East Asia are Ayurveda and ChineseTM. Ayurveda originated in India longback in the pre-Vedic period. TheRigveda and Atharva-veda (5000 BC),the earliest Indian documents havereferences on health and diseases.

Introductionraditional medicine refers to theancient medical practice that ex-isted in human societies before

the application of modern science tohealth. The importance of traditionalmedicine (TM) as a source of primaryhealth care was first officially recog-nized by the World Health Organiza-tion (WHO) in 1976 by globally address-ing its Traditional Medicine Programme.

Traditional medicine refers tohealth practices, approaches, knowl-edge and beliefs incorporating plant-,animal- and mineral-based medicines,spiritual therapies, manual techniquesand exercises, applied singularly orin combination, in maintenance ofhealth and the treatment of diseases.The WHO estimates that about 80 percent of world population relies on TMfor primary health care.


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24 TECH MONITOR Nov-Dec 2006


Ayurvedic texts like Charaka Samhitaand Sushruta Samhita were docu-mented about 1000 BC. Ayurveda,developed from the Vedic concept oflife, became the important source ofall systems of medical sciences. Incourse of time, it became a part of theculture and heritage of the people ofthe Indian subcontinent.

Ayurvedic medicinal prepara-tions consist mainly of plant materialsin the form of powders, semi-solidpreparations, decoctions, elixirs anddistillates. Many of them also containinorganic chemical substances, min-erals and animal products. Alcoholicextracts and alcoholic solutions of theingredients, tinctures and elixirs arealso frequently used in Ayurvedic med-icine.

Over thousands of years, tradition-al Chinese medicine has developed atheoretical and practical approach tothe treatment and prevention of dis-eases. The first documented source ofChinese medical theory, the HuangdiNei Jing (“Inner Classic of the YellowEmperor”) was written between 300and 100 BC. It describes the diagno-sis and treatment of a huge range ofdisorders and gives advice abouthealthy lifestyles, exercise, and diet,which conforms remarkably well tocurrent recommendations for the pre-vention of chronic diseases.

Some of the plants used in TMsystems are presented in this review,particularly in the areas of fertility reg-ulation, osteoporosis, diabetes, can-cer, malaria and analgesics.

Fertility regulationFertility regulation with plants or plantpreparations and medicaments hasbeen mentioned in the ancient textsof indigenous systems of medicine ofmany countries. The use of plants asemmenagogues, abortifacients and aslocal contraceptives was well knownto the ancient physicians of India.1-4

Abortion was usually induced by theinsertion of irritant twigs of plants orsticks coated with astringent plant juic-es into the cervix or by oral adminis-tration of plant decoctions to initiateuterine contractions for expulsion ofthe foetus.5 Emmenagogues, which

often increase menstrual flow in thenon-gravid uterus, were extensivelyused to induce abortion. These agentsinclude drastic purgatives and irritantvolatile oils, which are believed to in-duce uterine contractions secondaryto intestinal irritation and violent gas-tro-enteritis.

Even today, rural folks and aborig-inal tribes all over the world, includingIndia, are believed to use plant con-traceptives to limit their family size.5

Traditional use of plants for fertility reg-ulation in other countries, viz. China,6

Africa,7 Brazil,8 Haiti,9 Korea10 andRussia11 is also evident from the avail-able reviews. Farnsworth12, 13 has pub-lished a comprehensive review onplants, including those used in tradi-tional or folklore medicine, as sourc-es of new fertility agents.

The powdered seeds of Abrusprecatorius L. (Jequerity) are used asoral contraceptives by Central Africantribes. A single dose of about 200 mg issaid to be effective for 13 menstrualcycles. Discorea composita (Hemsl.)and other species of wild yam (Dis-corea belophylla Voigt.) were used bynative American people for hundredsof years to block fertilization. Dieffen-bachia sequine (Jacq.) or dumbcanewas used to induce temporary sterilityin females in Central America, SouthAmerica and Cuba. In Mexico, the Car-ibbean and Central America, the rootdecoction of Gossypium barbadense(L.), is reportedly used to induce abor-tion. Tea made of the leaves of Solomon’sSeal (Polygonatum multiflora), drunk ev-ery day for a week, will produce perma-nent sterility. Hebrew women in Old Tes-tament times who no longer wanted tobear children would drink a “Cup ofRoots” to prevent childbearing.

Daucus carota L. seeds havebeen used as a contraceptive for over2,000 years. They act both as a con-traceptive and as an early-stage abor-tifacient. Women in the AppalachianMountains, from Pennsylvania to NorthCarolina, stir a teaspoonful of theseeds into a glass of water and drink itevery time after coitus. In several partsof India, women chew dry seeds ev-ery day to control their fertility.14 Rutagraveolens L. is one of the most an-

cient and effective contraceptiveplants. Pregnant women were con-stantly warned against eating itsleaves even in small amounts. Theactive ingredient is a volatile oil,whose very smell is said to induceabortion. It was usually used in an in-fusion to bring about a delayed men-struation, but it was also eaten daily insalads as a contraceptive. Hedeomapulegoides L. has been known as acontraceptive and abortifacient to theancient Greeks. It is taken in tepidwater. According to Macer’s Herbal,written in the 12th century, it shouldbe taken in tepid wine.

Tanacetum vulgare L. was firstmentioned as an emmenagogue in themedical writings of Saint Hildegard ofBingen, a twelfth century GermanBenedictine nun. Two or three tea-spoons of the crushed dried leavesand flowers would be steeped in 8-12ounces of hot water for about half anhour, then strained and drunk over aperiod of several hours. Senecio au-reus L. has been used in folk and na-tive American medicine for ages, asan emmenagogue. The dried andcrushed flowers, stems and leaveswere steeped in very hot water for anhour or so, and then drunk in smallcupfuls for a day or two until menstru-ation began. Artemisia absinthium L.has been used as an antifertility agentsince ancient times in Greece. It induc-es abortion. Other species, such as A.vulgaris (Mugwort) is also emmenag-ogic. A strong tea made from any spe-cies of Artemisia is used to promotemenstruation. Caulophyllum thalictroi-des L., Blue Cohosh, has been usedfor centuries by native American wom-en to induce menstrual flow.14

In India, Egypt,15 Korea,10 Jordanand Saudi Arabia16 women have tak-en the Ricinus communis L. beans toprevent pregnancy. In Algiers, wom-en used to dip castor beans in thewarm blood of a rabbit before ingest-ing the beans to prevent pregnancy.17

Ayurvedic physicians of India useRivea hypocrateriformis Choisy to pre-vent fertility in women.18 Traditionalphysicians in and around Kotagiri vil-lage near Ootacamund use a mixtureof powder roots of Cassia occidental-



is Linn., Derris brevipes and Justiciasimplex to control fertility.19 In Koraputdistrict of Orissa, tribal women makepea-sized pills of white seeds Abrusprecatorius Linn. with black pepperand take one every morning for 21days on completion of menstruation.5, 20

In Mayurbhanj district, a decoction ofAchyranthes aspera Linn.20 is takenwith honey for 5-7 days within a monthof conception for abortion and Hibis-cus rosasinensis Linn. Flower5, 20 ispowdered with henna (Lawsonia in-ermis Linn.) root and is taken once aday for 3-7 days from the third day ofperiods to avoid conception. In Phul-bani district, tribal women take a rootpowder of Plumbago rosea Linn.5, 20

with milk once a day for three daysafter cessation of menses to avoid con-ception, and also the root powder ofVinca rosea Linn. orally with blackpepper to terminate pregnancy.1 InKurab district they take Plumbago zey-lanica Linn. root powder thrice a dayto terminate a pregnancy as old asthree months.5, 20 Further, a three-month-old pregnancy is terminated bytribal women of Kalahandi district ofthe state of Orissa by taking a root de-coction of Stephania japonica Miers.21

In Ganjam district women take a near-ly centimetre long powdered root ofGloriosa superba Linn. with threeseeds of black pepper, and take a sin-gle dose with milk to terminate preg-nancy as late as 4 months.5, 20 In Kheridistrict of Uttar Pradesh, the root ofPoya (Basella alba Linn.) is used asan anti-fertility agent after menstrualperiods. In Mirzapur district, tribal wom-en use the pseudostem of banana(Musa sapientum Linn.)22 for contra-ception. The pseudostem is crushedand mixed with jaggery and made intopills. Each pill is taken early in themorning for nine days after menstrua-tion. In Netarhat plateau of Bihar, adecoction of the bark of Celastrus pan-iculata Willd. is prepared and given topregnant women as an abortifacient.5

In Jhumritalaiya, a bark paste of Ail-anthus excelsa Roxb. is given withwater once a day for 2-3 days on anempty stomach, to terminate pregnan-cies as old as 2-3 months.5 Tribal wom-en around Salem in Tamilnadu chew

leaves of Bambusa arundinacea Retz.Willd. in the morning and evening for1-3 days to induce abortion of an earlyconception.21

AntiosteoporoticOsteoporosis, which has been de-fined as a “state of low bone mass”, isone of the major problems in our ag-ing society. Osteoporosis results inbone fractures in older members of thepopulation, especially in postmeno-pausal women. Osteoporosis and re-lated fractures represent major publichealth concerns. It has been recog-nized as a global problem by the WorldHealth Organization.23 Pharmacolog-ical agents, that are used to manageosteoporosis, act by decreasing therate of bone resorption, thereby slow-ing the rate of bone loss, or by pro-moting bone formation. A large vari-ety of herbal drugs mentioned in TMsystems to promote bone health andcontrol of osteoporosis have been re-ported.24

Various plants formulations havebeen screened and studied for the an-tiosteoporotic activity. Glycine max,commonly known as soyabean, hasbeen exhaustively studied for its anti-osteoporotic activity. Its ethanol extractas well as its constituents, which areisoflavones and lignans, are very ac-tive antiosteoporotic agents, whichhas already been proved by the num-ber of studies.

The effect of soybean ethanol ex-tract on the activity of osteoblastsMC3T3-E1 cells has been studied. Theextract increased survival (P<0.05) andDNA synthesis (P<0.05) of MC3T3-E1cells at a concentration range of 0.01-0.1 g/l in a dose-dependent manner.Soy extract at a concentration of 0.05 g/lincreased alkaline phosphatase (ALP)activity (P<0.05) and collagen synthe-sis (P<0.05) of MC3T3-E1 cells. Theanti-estrogen tamoxifen eliminated thestimulation of MC3T3-E1 cells on pro-liferation, ALP activity and collagensynthesis by soy extract, indicatingthat the main action of soy extract onthe osteoblastic MC3T3-E1 cells issimilar to that of estrogen. Therefore,soy extract has a direct stimulatory ef-fect on bone formation in cultured os-

teoblastic cells in vitro.25 The total cou-marins from the fruits of Cnidium mon-nieri increased bone mineral densityof femur metaphysis of osteoporoticrats.26

A herbomineral formulation OST-6(osteocare) was evaluated for its in-hibitory effect on the progress of boneloss-induced ovariectomy in rats. Eachgram of OST-6 contains Terminalia ar-juna (bark 250 mg), Withania som-nifera (root 250 mg), Commiphoramukul (gum resin 280 mg) and pravalbhasma (220 mg). Ovariectomized ratswere administered with OST-6 at 250and 500mg/kg b.wt. orally, daily for 90days. On the 91st day, ovariectomizedrats showed reduced bone mineralcontent and increased serum alkalinephosphatase levels, excretion of uri-nary calcium and pyridinium crosslinks levels. Histologically, sections re-vealed narrowed and disappeared tra-beculae and widened medullary spac-es. The total numbers of tararate-re-sistant acid phosphatase (TRAP) pos-itive cells were significantly increasedboth in vivo and in vitro methods.

OST-6 at a dose of 500mg/kg, sig-nificantly improved bone mineral con-tents and serum alkaline phosphataselevels; reduced the elevated urinarycalcium and pyridinium cross links ex-cretion and the number of TRAP posi-tive cells; and reversed the histologi-cal features mentioned above.27

A Chinese herbal medicine, Hoe-hu ekki to (Bu-zong-yi-gi-tang), is com-posed of ten herbal medicines: a mix-ture consisting of 4.0 g of Astragalusroots (Ougi), 4.0 g of Atractylodeslanceae rhizome (soujyutsa), 4.0 g ofPanax ginseng roots (Ninjin), 3.0 g ofAngelica roots (Touki), 2.0 g of Bupleu-ri roots (Saiko) 2.0 g of Zyzyphus fruits(Taisou), 2.0 g of Aurantis nobilis peri-carp (Chinpi), 1.5 g of Glycyrrhiza roots(Kanzou), 1.0 g of Cimifugae rhizome(Shouma) and 0.5 g of Zingiberus rhi-zome (Shoukyou) was prepared, fromwhich 5.0 g ‘Hoehu ekki to’ was ex-tracted with hot water, filtered, lyo-philized, and stored at 4oC.

This medicine has been used forthe treatment of oligospermia and asa post operative medication in Japan,on bone loss in rats treated with a go-



nadotropin-releasing hormone (GnRH)agonist. The administration of GnRHagonist reduced the bone mineral den-sity in the whole femur to 91.0 per centof that in the control group. However,administration of conjugated estro-gens and Hoehu ekki to increased theserum concentrations of estradiol 16.8and 5.3 times respectively comparedwith the concentration in the GnRH ag-onist treated group, resulting in theaugmentation of the bone mineral den-sity to 110.3 per cent and 106.2 percent respectively. Hoehu ekki to en-hances the reduced BMD and causesa slight elevation of the serum estra-diol levels in the chemically castratedrats.28 The methanol extract of stemsof Sambucus sieboldiana inhibitedbone resorption in organ culture. Oraladministration of ethyl acetate fractionof methanolic extract (50, and 100mg/kg/d) to ovariectomized rats prevent-ed the decrease of bone mineral den-sity (BMD) of the lumbar (L2-4) vertebra,indicating that ethyl acetate fraction iseffective in vivo.29 The ethanol extractof the plant Cissus quadrangularis,commonly known as hadjod, for itsbone fracture healing property wasevaluated for its antiosteoporotic activ-ity in ovariectomized rat osteoporosisat two different dose levels - 500mg and750mg per kg/day. Healthy female al-bino rats were divided into five groupsof six animals each. The first group wassham operated and served as control.All the remaining groups were ovariec-tomized. Group 2 was fed with an equi-volume of saline and served as ova-riectomized control. Groups 3-5 wereorally treated with raloxifen (5.4 mg/kg)and with the ethanol extract of Cissusquadrangularis (500 and 750 mg/kg)respectively.

The findings assessed on thebasis of biomechanical, biochemicaland histopathological parametersshowed that the ethanol extract of theplant had a definite antiosteoporoticeffect.30 The preventive effect of a herb-al formulation Dae-Bo-Won-Chun(DBWC), on the progress of bone lossinduced by ovariectomy (OVX) wasstudied in rats. From light microscopeanalyses, porous or erosive appear-ances were observed on the surface

of the trabecular bone of the tibia inovariectomized rats, whereas those ofthe same bone in sham-operated ratswere composed of fine particles. Thetrabecular bone area and the trabec-ular thickness in ovariectomized rats,decreased by 50 per cent from thosein sham-operated rats; these decreas-es were completely inhibited by theadministration of DBWC at a concen-tration of 10mg/kg per day for 7 weeks.The mechanical strength of the neckof the femur was decreased by ova-riectomy, and this was significantlysuppressed by the administration ofDBWC. Serum phosphorus, alkalinephosphatase and thyroxine levels inovariectomized rats increased com-pared with those in sham operatedrats, and the increases were com-pletely inhibited by the administrationof DBWC. These results strongly sug-gest that DBWC is effective in prevent-ing the development of bone loss in-duced by ovariectomy in rats.31

DiabetesDiabetes mellitus is a group of meta-bolic disorders in the endocrine sys-tem. The disease is found in all parts ofthe world and is rapidly increasing.People suffering from diabetes are notable to produce or properly use insulinin the body, so they have a high con-tent of blood glucose.

There are two type of diabetes,Type 1 and Type 2. Type 1, or insulin-dependent diabetes mellitus (IDDM),in which the body does not produceany insulin, most often occurs in chil-dren and young adults. People withType 1 diabetes must take a daily insu-lin injection to stay alive. Type 1 diabe-tes accounts for 5-10 per cent of diabe-tes. Type 2, or noninsulin-dependent di-abetes mellitus (NIDDM), in which thebody does not produce enough, ordoes not properly use insulin, is themost common form of the disease, ac-counting for 90-95 per cent of diabetes.Type 2 diabetes is nearing epidemic pro-portions, due to an increased numberof elderly people, and a greater preva-lence of obesity and sedentary life-styles. As a very common chronic dis-ease, diabetes is becoming the thirdmost lethal disease of mankind.32

Plants have always been an ex-emplary source of drugs and many ofthe currently available drugs havebeen derived directly or indirectly fromthem. Several plants and isolated com-pounds have been demonstrated tohave anti-diabetic potential in NID-DM.33, 34 Some Indian plants that havebeen pharmacologically tested andshown to be of some value in diabe-tes mellitus are described below.

Aegle marmeloseAn aqueous extract of the leaves (1gm/kg for 30 days) significantly con-trolled blood glucose, urea, bodyweight, liver glycogen and serum cho-lesterol of alloxanized (60 mg/kg IV)rats as compared to controls and thiseffect was similar to insulin treatment.35

The aqueous extract of leaves, whenfed (1 gm/kg/ day) to STZ (45 mg/kgIV) diabetic rats for 2 weeks, de-creased malate dehydrogenase lev-els (an enzyme known to increase indiabetes) in comparison to diabeticcontrols. 36 A further aqueous extractof leaves, administered orally for 28days, also normalized STZ (45 mg/kgbody weight) induced histo-patholog-ical alterations in the pancreatic andkidney tissues of rats.37

Coccinia indica is used in theAyurvedic and Unani systems of med-icine for the treatment of diabetes.38

Oral administration of 500 mg/kg of C.indica leaves showed significant hy-poglycemia in alloxan-diabetic dogs(45 mg/kg IV) and increased glucosetolerance in normal and diabetic dogs(OGTT and IVGT), respectively.39 Theoral feeding of an ethanol extract ofthe leaves (200 mg/kg) to 18 h fastedrats and STZ diabetic rats led to low-ering of blood sugar by 23 and 27 percent respectively, hepatic glucose-6-phosphatase by 19 and 32 per centrespectively, and hepatic fructose-1,6-bisphosphatase by 20 and 30 per centrespectively, as compared to con-trols.40

The beneficial effects of leaves ofC. indica have also been shown in adouble-blind control trial enrolling 16patients with uncontrolled maturity on-set diabetes and 16 controls. Treat-ment was given for 6 weeks and 10



patients showed marked improvementin their glucose tolerance.41 In a clini-cal study (n-30), an oral administra-tion of dried extract of C. indica (500mg/kg for 6 weeks) significantly re-stored the raised activity of lipoproteinlipase and the levels of G-6 phos-phatase and LDH, which otherwiseincrease in severe diabetics.42 As asingle oral dose, the plant extract hasbeen shown to exert a beneficial hy-poglycemic effect in experimental an-imals and human diabetic subjects.43

Feeding of water-soluble alkaloidfractions of alcohol extract (1 gm/kg)of Coccinia indica leaves to normalfasting guinea pigs showed hypogly-cemic activity.44 The oral administra-tion of bark extract Ficus bengalene-sis showed a significant antihypergly-cemic effect in STZ diabetic rats byraising serum insulin levels or inhibit-ing insulinase activity in the liver andkidney.45 Oral administration of pelar-gonidin and leucopelarogonidin de-rivative (100 mg/kg) isolated from thebark of F. bengalenesis exerts signifi-cant hypoglycemic activity in normaland moderately alloxanized diabeticdogs (60 mg/kg IV injection).46-49

Gymnema sylvestreThe anti-hyperglycemic effect of driedleaf powder of Gymnema sylvestre wasseen in alloxanized rabbits along witha decrease in the activity of gluconeo-genic enzymes and reversal of patho-logical changes in the liver initiatedduring the hyperglycemic phase.50 Theoral feeding of powdered leaves of G.sylvestre (500 mg/rat) for 10 days sig-nificantly prevented intravenous beryl-lium nitrate-induced hyperglycemia inrats and normalized it in 4 days in com-parison to 10 days in untreated rats.

However, no significant hypogly-cemia was seen in normal rats whowere daily fed with the leaves of G.sylvestre for 25 days.51 Oral adminis-tration of aqueous extracts of leavesof G. sylvestre (20 mg/day) for 20-60days normalized blood sugar levelsof STZ diabetic rats through b cell re-generation.52,53 Gymnemic acid isolat-ed from G. sylvestre54,55 and triterpeneglycosides isolated from plant inhibit-

ed glucose utilization in muscles.56

Oral treatment of G. sylvestre leavesextract (400 mg) for 18-20 months plusconventional treatment showed ben-eficial effects in 22 NIDDM patients.57

In a clinical observation, an aque-ous decoction of G. sylvestre leaves(2 gm thrice daily) to 10 healthy per-sons (10 days) and 6 diabetic patients(15 days) significantly reduced thefasting and OGTT glucose level in allthe groups except OGTT in healthygroup.58

Momordica charantiaThis is the most popular herbal re-source and is often used to treat dia-betes.59,60 The anti-diabetic potentialof Momordica charantia is well estab-lished in streptozocin- or alloxan-in-duced diabetic rats, mice and rabbit61-

63, genetically diabetic mice64 and inhumans with Type 2 diabetes.65 Aque-ous extracts of M. charantia improvedOGTT after eight hours in normal miceand reduced hyperglycemia by 50 percent after five hours in STZ diabeticmice.66 Ethanolic and acetone extractof M. charantia fruits (250 mg/kg dosePO) significantly lowered blood sugarin fasted as well as glucose loadednon-diabetic rats.67,68 A homogenizedsuspension of the vegetable pulp ofM. charantia to 100 cases of moderateNIDDM subjects caused a significantreduction of postprandial serum glu-cose in 86 per cent cases and fastingglucose in 5 per cent cases.69 Theaqueous juice of M. charantia fruit ex-erted anti-hyperglycemic and antioxi-dant effect in the pancreas of STZ-di-abetic mice.70 Oral supplementation(0.5, 1 and 3 per cent) with freeze-dried powder of M. charantia for 14days with and without 0.5 per cent cho-lesterol and 0.15 per cent bile acid inthe diet resulted in a consistent de-crease in serum glucose levels in nor-mal rats only in the former group.71 Theaqueous extract of unripe fruits of M.charantia has also been shown to par-tially stimulate insulin release from iso-lated beta-cell of obese-hyperglyce-mic mice.72

In a clinical trial, water-soluble ex-tract of the fruits of M. charantia signifi-

cantly reduced blood glucose con-centrations in the nine NIDDM diabet-ics on OGTT (50 gm). Fried karela fruitsconsumed as a daily supplement tothe diet produced a small but signifi-cant improvement in glucose toler-ance in diabetic subjects without anyincrease in serum insulin levels.73

Pterocarpus marsupium studies con-ducted by various authors have shownhypoglycemic activity of the wood ex-tract in different animal models.74-77

Pterostilbene isolated from Pterocar-pus marsupium heart wood causedhypoglycemia in dogs (at the dose of10 mg/kg IV). Higher doses (20, 30 and50 mg/kg) caused initial hyperglyce-mia followed by hypoglycemia lastingfor nearly five hours.78-79

This hypoglycemic effect was at-tributed to the presence of tannates inthe extract. An orally administed waterdecoction of the bark (1 gm/100 gmbody weight for 10 days) showed ahypoglycemic action in alloxanized di-abetic rats.80 A chronic administrationof the infusion of wood powder for fivedays inhibited the rise in blood glucoselevel in rats after glucose loading.81

Epicatechin, a pure flavonoid, iso-lated from the ethanol extract of P.marsupium bark has also been shownto possess a significant anti-diabeticeffect.82-85 Epicatechin has been shownto enhance insulin release and theconversion of proinsulin to insulin invitro.85 Marsupin and pterostilbeneconstituents significantly loweredblood glucose level in STZ diabeticrats and the effect was comparable tometformin.86

An Indian, open, multicentric studyassessing vijayasar in the treatment ofnewly-diagnosed or untreated NIDDMshowed that the extract controlled fast-ing and post-prandial blood glucoselevels in 67 out of 97 patients (69 percent) by the twelfth week at doses of2, 3 and 4 g in 73, 16 and 10 per centpatients respectively. Four patientswere withdrawn from treatment due toexcessively high post-prandial bloodglucose levels. No significant changewas observed in the mean levels oflipids. Other laboratory parameters re-mained stable during the designatedtreatment period of 12 weeks.87



Syzigium cumini is widely distrib-uted throughout India, and Indian folkmedicine mentions its use for the treat-ment of DM.2 Preliminary studies onSyzigium cumini seeds and leaveshave shown a hypoglycemic effect.88,

89 Oral feeding of S. cumini (170, 240and 510 mg/rat for 15 days) caused50 per cent reduction in blood glucoseof normal, fasted rats while chlorpro-pamide showed 52 per cent reduc-tion.90 In oral administration of theaqueous extract of seeds of S. cumini(2.5 and 5.0 gm/kg for 6 weeks), thehypoglycemic effect was most promi-nent at a dosage of 5.0 gm/kg.91 Thedaily administration of lyophilizedpowder of S. cumini (200 mg/kg)showed maximum reductions of73.51, 55.62 and 48.81 as comparedto their basal values in mild (plasmasugar-180 mg/dl, duration 21 days),moderate (plasma sugar 280 mg/dl,duration 120 days) and severe (plas-ma sugar-400 mg/dl, duration 60 days)diabetic rats.92

CancerCancer is the second leading causeof death in the world - one out of ev-ery four deaths is from cancer. TheNational Institute of Health (NIH) hasestimated costs relating to cancer tobe US$ 156.7 billion. It is also impor-tant to note that 77 per cent of all can-cers diagnosed people are 55 yearsof age or older.93 With cancer takingsuch a toll on the population, both inlives and costs, the discovery of anti-cancer drugs has become very im-portant.

Some of the most effective cancertreatments to date are natural productsor compounds derived from naturalproducts. The Catharanthus roseus(rosy periwinkle) was used in Cuba,The Philippines and South Africa forthe treatment of inflammation, rheuma-tism and diabetes. The active principles,vinblastine and vincristine94-96 showedsignificant clinical anti-tumour activityagainst Hodgkins’s and non-Hodgkins’s lymphomas, acute lympho-blastic leukaemia, breast carcinomaWilms’ tumour, Ewing’s sarcoma, neu-roblastoma, heptoblastoma and smallcell lung cancer, thus achieving a prom-

inent role in modern cancer chemother-apy.97, 98

The most significant anti-cancerdrug discovered and developed istaxol, isolated in 1969 from the barkof the Pacific yew tree (Taxus brevi-folia).99 In early clinical trials in 1989,it was found to be effective in ovariancancers and breast cancers, andsince that time it has shown signifi-cant therapeutic benefits for otheradvanced malignancies. As a natu-ral source of supply could not be re-lied upon, taxol and other taxoidshave been produced by semi-syn-thetic conversions of a precursorcompound, 10-deacetyl baccatin,found in renewable yew tree needles.The paclitaxel (taxol) story illustratesthe great importance of conservingnatural resources.

The resin podophyllin obtainedfrom the Podophyllum peltatum root,is toxic and is used clinically to removewarts. The major constituent of the res-in is the lignan, podophyllotoxin. Twosemi-synthetic derivatives of podo-phyllotoxin, viz. etoposide and tenipo-side, were developed as chemicallyactive agents.100

Camptothecin is an anti-cancerdrug, which was isolated from the Chi-nese ornamental tree, Camptothecaacuminate.101, 102 Camptothecin (as itssodium salt) was clinically approvedby the NCI in the 1970s, but was laterdropped because of severe bladdertoxicity. Yet extensive research to-wards lead development or more ef-fective derivatives was continued, andresulted in two effective derivatives,topotecan and irinotecan. Topotecanis used for the treatment of ovarian andsmall cell lung cancers, while irinote-can is used for the treatment of colo-rectal cancers.

MalariaMalaria is undoubtedly one of the mostserious and widespread human dis-eases. It is caused by a protozoan par-asite (Plasmodium spp). Anophelesmosquitoes are the vectors that carrythe malaria parasite, and the insecti-cide DDT was extensively used to killmosquitoes in the 1950s. Thereafter,

due to resistance to DDT amongAnopheles spp. and serious side-ef-fects for human health and the envi-ronment, the use of DDT was stopped.

The isolation of the anti-malarialdrug, quinine, from the bark of Cincho-na species (C. officinalis), was reportedin 1820 by Caventou and Pelletier. Thebark had long been used by indigenouspeople of the Amazon region for thetreatment of fevers, and was introducedinto Europe to treat malaria.103

Using the structure as a lead,chemists synthesized the anti-malari-al drugs, chloroquine and mefloquine.Another plant used in the treatment offevers for more than 2,000 years in tra-ditional Chinese medicine is Artemi-sia annua (Quinhaosu), which yields theantimalarial agent artemisinin.104, 105 Itsderivatives, artemether and artether,are currently in use against strains ofmalaria that are increasingly resistantto first line treatments (chloroquine andsulphadoxine in combination with py-rimethamine) and are considered tobe the most effective anti-malarialagents on the market today.106

AnalgesicsIn the ancient world, pain was one ofthe major ailments. The use of medic-inal plants for the cure of pain possi-bly began with treatment by use of thecrude extract of the poppy (Papaversomniferum), dating from around 6,000years ago in Sumeria. Traditionallyopium has been used as an astringent,an antispasmodic, an aphrodisiac, adiaphoretic, an expectorant, a hypnot-ic, a narcotic, and a sedative. But theeffectiveness of the opium poppy asan analgesic is well known. Opium andits derivatives are used in the phar-maceutical industry as narcotic anal-gesics, hypnotics, and sedatives.

Morphine was isolated by Ser-turner in 1806, codeine by Robiquetin 1832 and the non-morphine alka-loid papaverine by Merck in 1848.107

Ironically, heroin is a compound thathas probably been most abused andhas caused the most human anguish.A close relative, dextromethorphan is,in fact, used in most cough syrups to-day, but lacks the abuse potential ofits chemical cousin.



Central DrugResearch InstituteThe following case study analyzes aTM product for technology transfer topharmaceuticals. The case study de-scribes Central Drug Research Insti-tute (CDRI) experience from the intro-duction of Ayurvedic knowledge to thesuccessful launch of its own new drugin the market. The case study demon-strates the process of developmentand the commercialization of ad-vanced technology in the country.

Drugs developedThe development of new drugs fromnatural products has been the avowedobjective of the CDRI since its incep-tion. The main thrust of the Institute’sresearch programme has been on thediscovery and development of drugsfor reproductive health research (fertil-ity regulation, breast cancer, prostatehyperplasia), tropical and infectiousdiseases (malaria, tuberculosis, leish-maniasis, filariasis) and aging-relateddisorders (diabetes and dyslipidemia,osteoporosis, thrombosis, stroke, de-mentia).

The major focus has been to ob-tain novel lead molecules from medic-inal plants and to develop them asmodern drugs, but the Institute is al-ways open to alternative approachesto develop a standardized plant ex-tract into a viable herbal preparationafter judging its marketing potential asa ‘herbal medicine’. Folkloric, tradition-al and indigenous plants are taken upfor investigation.

All the plant samples are botani-cally authenticated and voucher spec-imens are preserved in the BotanyDivision. Repeat collections are madefrom the same location during thesame season so as to minimize varia-tion. Initially 95 per cent ethanolic ex-

S. No. Drugs Source Use Licensee

1. Isaptent Seed husk of Plantago ovata Cervical dilatation (MPT) Unichem Labs

2. Gugulipid Gum of Commiphora mukul Hypolipidemic Cipla Nicholas Piramal Ind. Ltd.

3. ProMind Whole plant of Bacopa monniera Memory improvement Lumen Marketing Co.

4. Consap Nuts of Sapindus mukorossi Spermicidal Hindustan Latex Ltd.

Table 1: Products developed by Central Drug Research Institute

tracts of the plants are prepared forbiological screening. Wide ranges ofbiological test systems are reorga-nized so as to enable screening of thesame plant extracts for a large varietyof biological activities.

The Institute has acquired a com-puter-assisted robotic High Through-put Screening (HTS) system capableof screening 96 tests samples in vitrowithin a short time. So far, more than6,000 samples of terrestrial plantshave been screened. Bio-assay-linkedchemical investigations on the identi-fied active plants have been under-taken, resulting in the identification ofsome active constituents whose struc-tures have been established.

All the herbal medicines followthe required development studies, in-cluding regulatory studies coveringpharmacology, pharmacokinetics, tox-icology and clinical trials, in order toensure their safety and efficacy. As aresult several herbal medicines havebeen developed and successfullycommercialized (Table 1) and othersare in various stages of development.

Case study: Gugulipid

Ayurvedic knowledge and JointResearchIndia recently increased research ontraditional Ayurvedic herbal medicinesafter observing that they are effective forconditions to which they have tradition-ally been applied. For example, the an-cient Sanskrit text on Ayurveda, the Sus-hruta Samhita, noted that Commiphoramukul was useful in treating obesity andconditions equivalent to hyperlipidemia,or increased concentrations of choles-terol in the body. The plant has beenused by Ayurvedic practitioners for atleast 200 years and may have been inuse since the writing of the Sushruta

Samhita more than 2,000 years ago.108

In the study, the crude gum from Com-miphora mukul significantly lowered se-rum cholesterol in rabbits with high cho-lesterol levels.109

The plant substance also protect-ed rabbits from cholesterol-inducedatherosclerosis (hardening of the ar-teries). This finding led to pharmaco-logical and toxicological studies thatshowed this herbal remedy to be ef-fective in humans, with no adverse sideeffects.110 On the basis of availabletherapeutic information, gum guggulwas taken up for detailed investiga-tions for hypolipidaemic agents (in col-laboration with Dr. Sukh Dev, NationalChemical Laboratory, Pune).

While Dr. Sukh Dev identified thechemical components of the variousfraction of gum guggul of C. mukul, Dr.S. Nityanand and co-workers at CDRIwere engaged in evaluating the bio-logical efficacy of different fractionsand their toxicity profile. By treating thegum guggul with ethyl acetate, solu-ble and insoluble fractions were ob-tained. The activity was found in theethyl acetate soluble fraction designat-ed as guggulipid, while the insolublefraction had no activity, instead itshowed hepatotoxicity.111-113

E and Z- GuggulsteronesAmongst the many compounds isolat-ed from guggulresin were two steroids:E and Z- guggulsterones.114, 115 Thisethyl acetate soluble fraction wasnamed gugulipid. A joint patent involv-ing Sukh Dev, then Director of Malti-Chem Research Centre, Baroda, andCDRI was filed. The lipid lowering ac-tion of guggulsterone was shown tobe mediated through activation oflecitin cholesterol acyltransferase(LCAT) and tissue lipolytic enzymes,enhanced catabolism of LDL, in-creased faecal bile acid excretion, in-



hibition of cholesterol biosynthesis inhyperlipidaemia without causing anyadverse effect of plasma HDL.116

Guggulsterone has been report-ed to possess mild antioxidant activitytogether with lipid lowering action. Theprotection provided by guggulsteronesagainst oxidative changes in humanLDL is due to its free radical scaveng-ing property, as this compound signif-icantly inhibits the generation of hy-droxyl radicals. Guggulsterones stim-ulated receptor medicated catabolismof LDL in treated rats.

H

O

O

H

O

O

E-guggul sterone Z-guggul sterone

Because the order of activity ofthe gugulipid fraction and that of thepure E and Z- guggulsterones is al-most the same, although the propor-tion of these guggulsterones in the ex-tractive was only about 4.4 per cent, itwas therefore, decided to develop aguggulipid fraction itself into a hypo-lipidaemic agent.

After considerable study, both abio-assay and chemical assay meth-ods were developed. The bioassaywas based on testing the hypolipi-daemic activity in triton-induced hyper-lipidaemic and alcohol-induced hyper-triglyceridaemia in rats, while chemi-

Figure 1: Guglip, a commerciallystandardized herbalpreparation

cal assays were based on TLC sepa-ration and UV spectrophotometric de-termination and HPLC estimationmethod for E and Z- guggulsterones.A large number of samples of gumguggul collected from different regionsof the country and stored for varyingperiods were investigated to standard-ize the drug gugulipid.

Clinical trialsClinical trials conducted by CDRI sci-entists showed that gugulipid reducedserum cholesterol and triglycerides byan average 24 per cent and 22 percent, respectively, and that some 260of a group of 330 hyperlipidaemic pa-tients responded to treatment. The re-sults clearly indicated the efficacy ofgugulipid and that it was toleratedbetter than clofibrate, the alternativeavailable drug. Based on these results,in 1986, the Drugs Controller of Indiagave permission to market gugulipidas a new drug.

Transfer of technologyAn agreement for licensing the prod-uct to Cipla Ltd., Bombay, was signedin January 1987, and the technologywas formally released to the companyby the former Prime Minister, Mr RajivGandhi. Commercial production of gu-gulipid began in October 1987. It wasmarketed in the form of tablets andgranules under the trade name Guglip(Figure 1) and also exported.

Since the preparation is a stan-dardized extract of an Ayurvedic med-icine and has been developed as amodern medicine, it was designatedby the licensee firm as an “allovedic”drug, that is, a combination therapy in-corporating concepts of modern med-icine and Ayurveda. The drug was wellreceived; and the demand shortly af-ter its release showed an upwardtrend.

Gugulipid was commercialized at10 tonnes per annum and from 1996to 1997 its annual sales value was es-timated at about US$ 80,000. Basedon the proceeds from these sales,CDRI received a good financial returnin terms of royalty payments. Howev-er, owing to the unavailability of thegum guggul raw material, demand for

the drug could not be met and its pro-duction was discontinued in July 1997.Since then, CDRI has developed atechnique for manufacturing the activeguggulsterones. This technology hasnow been licensed to a company forcommercialization.

Case study: ProMind

Traditional knowledge and re-searchBacopa monniera (Linn) Pennel, Syn:Herpestis monniera (Linn) HB&K (Ver-nacular: Brahmi, Aindri, Jal Neem), isa perennial creeper found throughoutIndia in wet, damp and marshy areas.In the folklore of Indian medicine, Ba-copa monnieri is used as brain ornerve tonics.

This plant has been mentionedin India since the time of Athar-Veda(c.800 BC). The first, clear referenceto its effect on the intellect and thememory is to be found in Caraka Sam-hita, written in the first century AD. It iscommonly given to infants to boostmemory power intelligence and men-tal health. Bacopa moniera ethanolicextract exhibited facilitatory effects onthe mental retention capacity in exper-imental models.117,118

ChemistryEvaluation of the traditional claims ofBrahmi was initiated by investigatingthe effect of the ethanolic extract onthe acquisition, consolidation and re-tention of three newly acquired behav-ioral responses in albino rats.119 Theactivity was localized in a fraction con-taining dammarane type triterpenoidsaponins, designated as bacosides Aand B. Both bacosides A and B showeda single spot on TLC over silica gel. Lat-er investigations revealed that baco-side A was a mixture of three com-pounds, which were designated A2,A2’ and A3. The sugar moiety consist-ed of glucose and arabinose. Repeat-ed chromatography of bacoside A overnormal and reverse phases yieldedtwo saponins, A2 and A3, in pure form.The structures of bacosides A2 andA3 were established.120,121 Bacoside Bwas found to be a triglycoside havingthe same aglycone as A2 and two units



of glucose and an arabinose as sugarmoiety.

Seasonal variationof bacosidesMethods have been developed for aquantitative determination of bacosideA content in the extract by UV spectro-photometry122 and HPLC.123 To moni-tor seasonal variations of bacosides,fresh plant material was collected ev-ery month, extracted with ethanol andfractionated. This was carried out overa period of 14 months commencingMarch 1993. The TLC of the n-butanolfraction of the ethanolic extractives ofthe plant was used to monitor baco-sides. From this study it was conclud-ed that bacoside A (mixture of baco-sides A2, A2’ and A3) predominatesin March and April whereas both ba-cosides A and B are available in May.In the remaining months, other com-pounds appear and disappear.

Pharmacological evaluationBoth the crude extract and the baco-sides were evaluated for their nootro-pic activity. In adult male rats, the ex-tract (40 mg/kg.p.s) was given 3 hoursbefore the test in acute studies andevery third day in chronic experiments.A labile test utilized brightness dis-crimination reaction in a semi-auto-matic Y-maze. In this test significanteffects were observed on all the threetempero-spatial parameters - acquisi-tion, consolidation and retention.

The initial test for stable behav-iour was an active conditioned flightreaction using a sound cue. In this testalso the animal learnt to escape footshock quickly (6 days versus 10 daysin control) and the reaction time wassignificantly lower from day 4 onwards.

The final test was the continuousavoidance test. A stable baseline be-haviour was achieved by day 20 in thistest but did not happen in the controlanimals.119 Detailed studies were car-ried out with bacosides A and a mix-ture of bacosides A and B.124

The labile test was the brightnessdiscrimination reaction for the Y-mazetest as was done with the extract. Thestable test included the active condi-tioned avoidance test used earlier and

a conditioned aversion test employ-ing aversion to lithium chloride in awater-deprived rat as the cue. The ba-cosides produced a dose-related ef-fect similar to that of the extracts in allthe three tests. The effect of 10 mg/kgbacosides was equal to that of 40mg.kg of extract. A dose of 10 mg/kg ofbacosides given orally 60 minutes pri-or to testing was able to abolish boththe deficits of the W-shaped curve.125

These results suggested that thefacilitatory effect of bacosides is main-ly due to their ability to consolidate theretention of learnt behaviour of theearliest form, i.e. short term memory.This facilitatory effect persisted whenthe other two longer lasting forms ofmemory were getting consolidated.The anti-amnestic activity of bacosidewas also evaluated. A significantlyhigher dose (20 mg/kg.p.c. for 3 days)was needed to prevent retrograde am-nesia caused by electro-convulsiveseizure, immobilization or scopola-mine in the Y-maze test.126 The baco-sides on the other hand exhibited sig-nificant anti-stress activity.

Safety evaluationThe LD50 of the ethanolic extract hasbeen determined in rats and mice by

the oral and IP routes. It was greaterthan 3g/kg by the oral route in the spe-cies. The LD50 by the IP route was 205mg.kg (range 230-182) in rats and 224mg/kg (range 260-135) in mice. Theoral LD50 of bacosides in mice was774 mg/kg. It was evident that the ex-tract had less acute toxicity bacosides.

Further studies have thereforebeen performed with the standardizedpreparation. Chronic toxicity studieshave been performed following oraladministration of 2.5, 5 and 10 timesthe effective nootropic dose of thepreparation in a rodent (rat) and anon-rodent species for 90 days. Vari-ous hematological, biochemical andgross behavioral changes were regu-larly recoded. Terminal autopsy wasfollowed by gross and microscopicexamination of all viscera as per reg-ulatory requirements. The preparationwas found to be safe and devoid ofany teratological effects in 2 species(rat and rabbit) and mutagenicity in invitro and in vivo tests.

Pre-clinical neuropharmacologi-cal studies demonstrated that bothBrahmi extract and bacosides im-proved short term and intermediatememory, thus improving long-termmemory. Based on these wide-rang-

O

OH

O

OOH

OHOO

OH

OHO

HO

O

OH

OHO

HO

Bacoside A2

O

OH

O

O

Bacoside A3

OHO

OO

OH

OHO

HOOH

OH

OH

OHO

HO



ing studies, the Drugs Controller of In-dia granted CDRI permission to con-duct Phase I clinical trials in healthyhuman volunteers.

The Institute has assessed thesafety and tolerability of the standardpreparation in 51 healthy human vol-unteers.127 Single oral doses of 20-200mg or 100 and 200 mg once daily forfour weeks were found to be safe, anddid not produce any reaction or sideeffects. Subsequently a placebo-con-trolled double-blind phase II clinicaltrial in 36 children of Attention DeficitHyperactivity Disorder (ADHD) wasconducted. The children received ei-ther a placebo or 50 mg of the prepa-ration twice daily for 12 weeks. Thechildren receiving the preparationshowed significant improvement inscores in several test systems andthere were no side effects.

Transfer of technologyAs the trials did not reveal any unde-sirable effects, a decision was takento market a standardized fraction of theplant extract as a herbal drug. Thepreparation containing a standardizedextract of B. monniera was licensed toa private company, which commercial-ized the product under the trade nameMemory Plus. The product was formal-ly launched in February 1996 by thethen Prime Minister, Mr. Narsimha Rao,and was successfully marketed andexported to several countries. In 2001,the product was licensed to anothercompany, Lumen Marketing, Chennai,India, which commercialized the prod-uct in 2002 under the name ProMind(Figure 2).

ConclusionCDRI provides a leading role in de-veloping India’s science and technol-ogy capability in drug research anddevelopment; undertaking frontline re-search; and providing specialized sci-ence and technology services and hu-man resource development. Indeed,the CDRI drug development pro-gramme relies heavily on traditionalknowledge of herbal remedies- a prac-tice now vigorously followed by inter-national pharmaceutical companies.The two case studies, selected from aset of several cases of a CDRI re-search project on technology transfer,present a successful implementationof technology transfer initiative.

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Figure 2: ProMind - a commerciallyavailable standardizedherbal preparation



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