The effects of a traditional drug, turmeric (Curcuma longa), and placebo on the healing of duodenal ulcer

The effects of a traditional drug, turmeric (Curcuma longa), and placebo on the healing of duodenal ulcer

Phytomedicine, Vol.5(1),pp 29-34

N Van Daul, N Ngoe Ham", D Huy Khac", N Thi Lam:', P Tong Son", N Thi Tan2

,

D Due Van4, S DahlgrenS, M Crabe", R johansson", G Lindgren" and N Stjernstrom" lFaculty of Chemistry, University of Hanoi, Vietnam

ZVietnam-Sweden General Hospital, Uong Bi, Vietnam

3National Institute for Drug Quality Control, Hanoi, Vietnam

"University Hospital of Viet Due, Hanoi, Vietnam

5University Hospital of Umea, Sweden

6University Hospital of Malmo, Sweden

7County Hospital of Pitea, Sweden

8Medical Products Agency, Uppsala, Sweden

Summary

In a joint Vietnam-Sweden prospective double-blind two-center study, the herbal remedy of Curcuma

long a (turmeric) - in a dosage of 6 g daily as suggested in the Vietnamese pharmacopoeia - was com-pared with an equal amount of placebo in 118 patients, suffering from duodenal ulcer The patients in the two groups were well matched prior to treatment

Clinical assessments were carried out weekly, while laboratory investigations were carried out before be-ginning of the treatment and after four and eight weeks: Only patients, having one duodenal ulcer with

a minimum diameter of 5 mm verified by endoscopy (Uong Bi General Hospital, UBGH) and/or radio-graphy (UBGH and Viet Due University Hospital, VDUH) not more than 4 days prior the study were included in the study No treatment with Hj-receptor antagonists, anticholinergics or other drugs used

in the treatment of ulcer disease during the preceding week were allowed Follow-up endoscopy and/or radiography were performed after 28 ±4 days and 56± 4 days

Turmeric was not superior to placebo in healing duodenal ulcer either after four or eight weeks of treat-ment After eight weeks the ulcer-healing rate of turmeric was 27% while placebo had healed 29% Both drugs were well tolerated

Key words: Curcuma longa, turmeric, duodenal ulcer, double-blind study

Introduction

Herbal remedies have been used for centuries in

Viet-nam in the treatment of common diseases in VietViet-nam

As the prices of modern drugs are high, the health

au-thorities encourage the use of traditional medicines

Thus it is of great interest to assess the curative efficacy

of commonly used traditional drugs by means of

mod-ern methodology

Patients with gastric and duodenal ulcers are

fre-quentlyencountered in Vietnam The diseases are

com-mon and have a considerable negative impact on the health situation in general and cause economic losses to both families and community As highly efficient drugs such as Hj-receptorblocking agents or proton pump-in-hibitors are rarely available for ordinary people in Viet-nam, surgical intervention is a treatment of first rank

As a medical alternative, however, turmeric (Curcuma longa, familia Zingiberaceae) is claimed to have heal-ing properties in the treatment of duodenal ulcer

30 N Van Dau et al.

Turmeric is a widely used plant Elder chemists may

recall the use of the extract of the plant as a colour

in-dicator in titrations and in some laboratories, the use of

turmeric paper was only surpassed by that of litmus

The plant material is still used as a dye in the textile

in-dustry, as well as in the preparation of lacquer and

var-nish, as food dye in curry powders and as a colour

in-gredient in cosmetics

Thechemical constituentsof the powder is curcumin

(0.3%), essential oil (1-5%), starch, oxalate calcium

and lipids Curcumin is a red brown crystal, nonsoluble

in water, soluble in alcohol, ether, chloroform, acid and

alkaline In the essential oil there is curcumen (C15H24 ) ,

paratolylmethylcarbinol and camphor

Concerning the pharmacological effect of curcuma

longa, paratolylmethylcarbinol stimulates the bile

se-cretion Curcumin causes contraction of the

gallblad-der, while the essential oil seems to have a fungicide

and a disinfecting effect against some bacteria A

solu-tion of curcuma gives in animal experiments

contrac-tion of uterus

The medical use of turmeric is also extensive The

dry, powdered root material of the Curcuma longa is

used in Indonesia as a choleretic and against insect

bites (Report on Activities on Standardization, 1987)

In the Philippines, turmeric serves as an antiseptic and

as an antiflatulent (Report on Activities on

Standard-ization, 1987) In Thailand, turmeric is used as an

anti-pruritic, an antiinflammatoric and an antiallergic agent

(Office of Primary Health Care, 1987) as well as

against dyspepsia (Division of Medical Research,

De-partment of Medical Sciences, 1989) In addition,

ex-tracts of Curcuma longa have been reported to have

antifertility activity in the rat and the rabbit (Garg

1971, Garg 1974, Garg et al., 1978) and spasmolytic

activity on the isolated guinea pig ileum (Gryral et al.,

1953)

Sesquiterpenes, curcumin, desmethoxycurcumins,

starch and lower carbohydrates, fatty acids and lipids

have been isolated from the material, but the alleged

active principle is not known

In Vietnam, turmeric is considered to be the

tradi-tional drug of choice in the treatment of duodenal

ul-cer The aim of the present study was to compare the

healing efficacy of the single powder of the root of

Cur-cuma longaon duodenal ulcer with placebo

Materials and methods

Patients

Out-patients from the Viet Due University Hospital

(VDUH) in Hanoi and in patients from the Uong Bi

Hospital (UBGH), who fulfilled the following criteria,

were enrolled into the study:

- The patient should have one duodenal ulcer with a minimum diameter of 5 mm verified by endoscopy (UBGH) and/or radiography (UBGH and VDUH) not more than 4 days prior to inclusion

- No treatment with Hy-receptor antagonists or anticholinergics or other drugs used in the treatment of ulcer disease during the preceding week

- No history of gastric surgery, except for simple clo-sure (raphi)

- No pyloric stenosis of organic origin

- No concurrent gastric or prepyloric ulcers

- No concurrent disease or therapy that could con-fuse the assessments

- No clinically significant abnormalities in the pre-trial laboratory test battery, which included

hematolo-gy (Hb, WBC, ESR and thrombocytes), serum creati-nine, bilirubin, GOT, GPT,Na-. K+ and in urine albu-min and uropepsin (VDUH)

Patients below 18 years and above 50 years were ex-cluded, as were pregnant women Each patient gave his

or her written consent The trial was approved by the Ministry of Health in Vietnam, the Ethical Committee

of the University of Umea and the Medical Products Agency in Uppsala, Sweden

Study design

The patients fulfilling the inclusion criteria were ran-domized, using the method with closed envelopes, for

an eight week treatment with either turmeric (2 g = 8 tablets - given three times a day) or an equal amount of placebo To ensure "blindness" the intervention drug, turmeric, and the tablets of placebo were coated with the same outershell to have the same appearance in size, form, weight and taste All patients took the same number of tablets, of identical appearance, at the same time of the day To ensure patient compliance, the in-patients (UGBH) were carefully observed by the nurs-ing team and the out-patients (VDUH) were regularly visited by a team of medical students

Before the trial and then weekly during the trial, the patients were asked about the presence or absence and, if present, about the intensity of the symptoms listed below The symptoms were assigned a point value (within brackets) and, thus, the reduction of symptoms during the treatment period could be re-corded:

a Epigastric pain (0,5)

b Constipation (0,5) (In Vietnam this is considered important)

c Pain at night (0,5)

d Reduction of pain when eating (0,5)

e Nausea/vomiting (0,5)

f Haematemesis or melena (4)

g Season periodicity pain (3)

The effects of a traditional drug, turmeric (Curcuma Zanga),on the healing of duodenal ulcer 31

Preparation of the Curcuma longa powder

The rhizomes of Curcuma Zanga were collected in the

province of Hai Hung, Vietnam The plant material

was identified by a comparison with a voucher

speci-men at the University of Hanoi and complied with the

requirements of the Vietnamese pharmacopoeia

(Min-istry of Health, 1983)

The fresh rhizomes were washed with water, sliced

and then dried at a temperature below 70 DC until the

weight was unchanged by further drying for at least 15

minutes The dried slices were ground and the powder

which could pass through a no 22 sieve was used in the

Curcuma Zangatablets

Follow-up endoscopy (UBGH) and/or radiography

(UBGH and VDUH), and laboratory tests were

per-formed after 28 ± 4 days and 56 ± 4 days Patients

were asked about adverse events, which were recorded

in the patient record forms

A special assessment team comprising two

indepen-dent, objective, well-known Vietnamese specialists (one

radiologist and one gastroenterologist) of the Bach Mai

University Hospital, Hanoi, not participating in the

study, - Professor Duong Tu Ky and Professor Nguyen

Khanh Trach - and one of the Swedish authors

(Jo-hansson), who acted as a non-decisionmaking

secre-tary, assessed the validity of the pretrial diagnosis and

the outcome ot the treatment (healed or not healed

ul-cers) of each patient

The patients who were not healed were treated with

cimetidine

0.3 mg 0.7mg

• Constituents of the Curcuma longa tablets

Curcuma Zangapowder

Gum arabicum

Talc powder

Tricalcium phosphate

Manihot utilissima glue, 12%

Magnesium stearate

• Constituents of the placebo tablets

Lactose

Manihot utilissima glue, 12%

Talc powder

Dextrin

Manihot utilissima powder

Lemon yellow

Magnesium stearate

• The tablets were coated with:

Talc powder

Manihot starch

Carboxymethyl cellulose

Gelatin

Saccarose

250mg

8 mg

55 mg

25 mg

125 mg 4mg

200 mg

60 mg

13 mg 1.3 mg 90mg 3.5 mg 3.7mg

44mg 4mg 0.2 mg 1.5 mg

185 mg

Titanium dioxide Lemon yellow

• Specification of the tablet Appearance: circular, odorless, lemon Diameter: 11 mm± 5%

Weight: 0.5 mg± 5%

Disintegration time: not more than 0.5 hour Identification test: The thin layer chromatography (TLC) of the Curcuma Zanga tablets must show spots forCurcuma Zangapowder and the TLC of the placebo must not show the same spots as the Curcuma tonga

powder The methanolic extracts were used The sta-tionary phase was silica gel G The mobile phase was chloroform:acetic acid, 9:1

The ash contents of the Curcuma Zanga tablets was not more than 22%, of the placebo tablets not more than 9.6%

The acid neutralizing capacity of the Curcuma Zanga

tablet was approximately 0.5 mmole Hel and for the placebo tablets approximately 0.02 mmole HCl

Statistical considerations

No relevant background information as far as the heal-ing efficacy of turmeric was available when preparheal-ing the study The sample size had, consequently, to be roughly estimated and was set in the order to detect (one-sided) a difference in healing rate of 25 - 30 per cent, that is an expected healing rate of 55 per cent for the intervention drug and a spontaneous healing rate within the placebo group of 30 per cent for an overall significance level of five per cent and a statistical

pow-er of 90% Thus at least 60 patients had to be enrolled

in each group An interim analysis was planned in the study to be done at one year after the start of the study when it was anticipated that approximately 50 patients would have been enrolled in each group In actuality,

130 patients had at that time been randomized and the inclusion of patients was stopped

The healing rate of duodenal ulcer and the frequency

of side effects were compared with the chi-square test

at five per cent level of significance The size of duod-enal ulcer and the reduction of symptom score were tested by means of the t-test and compared at the 95 per cent confidence interval

Results Patient characteristics

A total of 130 patients were randomized in the study,

65 to the Curcuma Zangagroup and 65 to the placebo group Seven patients, six in the Curcuma Zangagroup and one in the placebo group, were at the assessment point excluded from the study Five of the patients in

32 N Van Oau et al.

100

80

60

%

40

20

o

Fig 1 The weekly reduction

weeks of symptoms expressed in

percentage of the pre-entry

• Placebo • Curcuma longa symptoms

Table2 Duodenal ulcer healing rates

Ulcer healing

Ta ble2shows th at the ulcer-healing rate a fter4weeks

of treatment wa s2percent in the Curcuma longagroup and15percent in th e placebo group Afte r8weeks27 per cent and29 per cent were healed, respectively

the turmeric group could at the final assessment not be

incl uded as their diagnosis was uncertain an d one pa

-tient in each group had two ulcers, one of which was

prepylor ic The characteristics of the rem aining 123

pa tients are given in Table 1.Another five pa tients had

to be withdrawn from the study because of concurrent

disease (2 pat.) an d lost for follow-up (3pat.), leaving

a total of 118 pa tients for the fina l evaluation

Curcuma longa Placebo Table 1 Characteristics of patients

Curcuma longa

(n=59)

Placebo (n=64)

4weeks

8weeks

(1/55) 2 % (15/56) 27 %

(9/62 ) 15 % (18/62) 29 %

Sex(M/F)

Meanagee SO

Smokers/non-smokers

Mean length of history

Mean endoscopy size (mm)

of ulcer - UBGH

Mean x-ray size (mm)

of ulcer - UBGH

Mean x-ray size of ulcer

-VOUH

Mean x-ray size (mm)

of ulcer - both

49/10 36,S :!: 10,8 43/12 7,5years 7,0 (SD:!: 1,2) 7,2 (SD :!: 3,3 ) 5,7 (SO:!: 0,9 ) 6,3 (SD :!: 2,3)

47 /17 36,S :!: 9,1 41/20 7,3years 6,9 (SO:!: 1,0) 6,0 (SO :!: 2,7) 5,6 (SO:!: 0,9) 5,8 (SO:!: 1,7)

Symptom relief

All patients in the trial had a clear relief of symptoms after the first week During the following weeks, the symptoms in bot h groups slowly decreased Although

it was possible to observe a slight difference between the 2gro ups (Fig 1), the discrepancy was not statisti-cally significant

The effects of a traditional drug, turmeric (Curcuma longa),on the healing of duodenal ulcer 33

Side effects

Laboratory findings

There were no differences between the 2 groups

con-cerning laboratory analyses

The adverse events reported after questioning are

pre-sented in Table 3 A total of 20 patients (36%) in the

Curcuma longa group and 12 patients (20%) in the

Placebo group reported side effects (p>O.05) However,

most of these symptoms can be related to the ulcer

dis-ease

With modern drugs it is fairly easy to heal duodenal

ul-cer Hy-receprorblocking drugs have been wellknown

for some years (Wormsley, 1988) and proton

pump-in-hibitors heal both duodenal and gastric ulcer in a very

short time (Dahlgren et al., 1988) Sucralfate

(Garcia-Paredes et aI., 1991, Lam et al., 1985) have also been

used with good effect and antacids are known to heal

ulcer in up to 78% (Berstad and Weberg, 1986)

Erad-ication of Helicobacter pylori with a combination of

three antibiotics (Hosking, Ling et aI., 1994) or

antibi-otic and proton pump-inhibitors (e.g Bayerdorffer,

Mannes et al., 1993) have now also been used with

good healing effects on duodenal ulcer and much less

relapses

Duodenal ulcer is frequently diagnosed in Vietnam

and partial gastric resection is a very common

opera-tion performed in Vietnamese hospitals The economic

impact on health of duodenal ulcer in terms of health

expenditures and reduction of working capacity as well

as the cost of surgical treatment, can at present time

not be estimated in a developing country like Vietnam

After many years of fighting for independence, war and

tough economic constraints, Vietnam is still unable to

import modern drugs The country must, consequently,

partly rely on drugs that can be manufactured in

Viet-nam and partly on traditional prescriptions which have

been transferred from generation to generation

through folk healers Under such conditions, it is

understandable that practice of traditional medicine

Acknowledgement

The authors are indebted to the staff of the Vietnam-Sweden General Hospital, Uong Bi, and the University Hospital of Viet Due, Hanoi, for active and enthusiastic participation in the trials We are also thankful to Pharmacists Britt-Marie Hornell and Lena Sahlstrorn as well as Doctor Georg Dahlen for essential coordination and administrative work The study was supported by grants from the Swedish Agency for Research Cooperation with Developing Countries (SAREC)

We thank Smith Kline Beecham for a generous gift of cimeti-dine and CEA AB, Strangnas, Sweden, for X-ray films

has been integrated into the official health care system and that the assessment of old practice is officially en -couraged

The aim of the study was to assess the healing

effica-cy of duodenal ulcer of turmeric (Curcuma tonga),

which has been used for a long time in Vietnam in the medical treatment of epigastric pain and ulcer disease

We opted to compare in the treatment of duodenal ul-cer the inte rven tion drug with a placebo in order to gather bas e line information in the Vietnamese context and because most of the above mentioned modern drugs are usually not available No statistical difference could be observed, which means that the recommended dose of six grams of the powder of the root of

Curcu-ma longa was not efficient It can be argued that the dosage was inadequate and should have been higher because traditionally people suffering epigastric pain would mix (undefined) quantities of turmeric in their food

Nevertheless, this study shows that turmeric alone is hardly the drug of choice.Italso illustrates the need for further studies and that traditional prescriptions should be compared with drugs that can be manufac-tured and widely distributed in a developing country, e.g an efficient antacid The availability of a better medical treatment could eventually reduce the rather high frequency of operation for duodenal ulcer

Bayerdorffer, E., Mannes, G A., Sommer, A., Hochrer, W., Weingart , J., Hatz, R., Lehn, N., Ruckdeschel, G.,

Dir-schedl, P and Stolte, M : Scand j Gastroenterol.28: Suppl 196: 19 - 25, 1993

Berstad, A and Weberg, R.: Antacid in the treatment of

gas-troduodenal ulcer Scand.] Gastroenterol 21: 385, 1986.

Dahlgren, S., Dornellof, L., Hradsky, M., Norryd,c., Brunk-vall,J.,Svensson, G., Svensson,J.0., Karlsson,J"

Knuts-son, U., Gasslander, T.,Lindhagen, J., Arbman, G., Jans-son, R., Sandstrom, R., Huldt, B., PettersJans-son, B.-G., janun-ger, K.-G., Sjolund, B and Hernqvist, H : The effects of omeprazole and cimetidine on duodenal ulcer healing and

the relief of symptoms Aliment Pbarmacol Therap , 2:

483 - 492 , 1988

II References

Placebo 3 8

o

1

12 (20%)

Curcuma longa

4 15 1

o

20 (36.9 %)

Discussion

Constipation

Burning sensation

Gas

Hunger sensation

Table 3 Frequency of side effects

Total side effects

34 N Van Dau et al.

Division of Med ical Research, Department of Medical

Sci-ences: M anual of medicin al plants for primary health care

Curcuma domestica Val., 2nd ed Bangkok, pp 19 - 20,

198 9

Do Tat Loi, The medicinal plants and drugs of Vietnam

Sci-ence and Technical Publi shin g Hou se, Hanoi, Vietnam

Garc ia-Paredes, ] , Rubio, M D., L1enas, F., Taxonera, c.,

and Pardo, L.: Comparison of sucra lfate and ran itidine in

th e treatment of duodenal ulcers Amer.] Med 91: (Suppl.

2A), 64, 1991

Gar g, S K.: Effect of Curcuma longa Linn on fertility in

fe-male albino rats Bull P G I., 5: 178, 19 71

Garg , S K.: Effect of Curcuma longa (rhizome) on fertilit y in

experimental animals Planta Med 26: 225, 1971.

Garg, S K., Mathur, V S and Chaudhury, R R.: Screening of

Indi an plants for antifertility activity Indian] Exp Bio!'

16: 10 77, 1978

Gryral, M L., Choudhury, N K and Saxena, P N.: The

ef-fect of certain indigenous remedies on the healing of

wounds and ulcers.] Indian Med Assoc 22 (7): 2,1953.

Hosking, S W., LingT.K W., Chung, S C S., Yung, M Y.,

Cheng, A F B., Sung, ] j Y., Li, A K C.: Lancet 343 :

508 - 510 , 1994

Lam S K.: Efficacy of sucra lfare in corpus, prepylor ic a nd

du od enal ulcerassociated gastric ulcers A double-bl ind ,

placebo-controlled study Ame rJ. Med.: 79 (Suppl 2C);

24 - 31 , 1985

Mini str y of Health, Pharmacopoea Vietnamica (Part II): Sci-ence and Technical Publi shin g H ou se, Hanoi, 1983 Office of the Primary Health Ca re: M edical Plants in Primary

H ealth Care, p 67, Bangk ok , 1987

Report on Activities on Standardizati on : Selected crude drugs for ASEAN common use in pr imary health care (ANNEX 1): Quality Control and Utilizat ion of Herbal Medicines in ASEAN Countries, Ind one sia, 1987

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11 Address

S Dahlgren, Borjegatan lOB, S-75313 Uppsala , Swe-den