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 © Gustav Fischer Verlag 1998 _ The effects of a traditional drug, turmeric (Curcuma longa), and placebo on the healing of duodenal ulcer N Van Daul, N Ngoe Ham", D Huy Khac", N Thi Lam:', P Tong Son", N Thi Tan , 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 g daily as suggested in the Vietnamese pharmacopoeia - was compared 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 beginning of the treatment and after four and eight weeks: Only patients, having one duodenal ulcer with a minimum diameter of mm verified by endoscopy (Uong Bi General Hospital, UBGH) and/or radiography (UBGH and Viet Due University Hospital, VDUH) not more than 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 ± days and 56 ± days Turmeric was not superior to placebo in healing duodenal ulcer either after four or eight weeks of treatment 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 Vietnam in the treatment of common diseases in Vietnam As the prices of modern drugs are high, the health authorities 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 modern methodology Patients with gastric and duodenal ulcers are frequently encountered 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-inhibitors are rarely available for ordinary people in Vietnam, surgical intervention is a treatment of first rank As a medical alternative, however, turmeric (Curcuma longa, familia Zingiberaceae) is claimed to have healing 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 indicator 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 industry, as well as in the preparation of lacquer and varnish, as food dye in curry powders and as a colour ingredient in cosmetics The chemical constituents of 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 (C 15H24 ) , paratolylmethylcarbinol and camphor Concerning the pharmacological effect of curcuma longa, paratolylmethylcarbinol stimulates the bile secretion Curcumin causes contraction of the gallbladder, while the essential oil seems to have a fungicide and a disinfecting effect against some bacteria A solution of curcuma gives in animal experiments contraction 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 Standardization, 1987) In Thailand, turmeric is used as an antipruritic, an antiinflammatoric and an antiallergic agent (Office of Primary Health Care, 1987) as well as against dyspepsia (Division of Medical Research, Department of Medical Sciences, 1989) In addition, extracts 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 traditional drug of choice in the treatment of duodenal ulcer The aim of the present study was to compare the healing efficacy of the single powder of the root of Curcuma longa on 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 mm verified by endoscopy (UBGH) and/or radiography (UBGH and VDUH) not more than 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 closure (raphi) - No pyloric stenosis of organic origin - No concurrent gastric or prepyloric ulcers - No concurrent disease or therapy that could confuse the assessments - No clinically significant abnormalities in the pretrial laboratory test battery, which included hematology (Hb, WBC, ESR and thrombocytes), serum creatinine, bilirubin, GOT, GPT, Na- K+ and in urine albumin and uropepsin (VDUH) Patients below 18 years and above 50 years were excluded, 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 randomized, using the method with closed envelopes, for an eight week treatment with either turmeric (2 g = 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 inpatients (UGBH) were carefully observed by the nursing 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 recorded: 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 Follow-up endoscopy (UBGH) and/or radiography (UBGH and VDUH), and laboratory tests were performed after 28 ± days and 56 ± days Patients were asked about adverse events, which were recorded in the patient record forms A special assessment team comprising two independent, 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 (Johansson), who acted as a non-decisionmaking secretary, assessed the validity of the pretrial diagnosis and the outcome ot the treatment (healed or not healed ulcers) of each patient The patients who were not healed were treated with cimetidine 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 specimen at the University of Hanoi and complied with the requirements of the Vietnamese pharmacopoeia (Ministry 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 Zanga tablets • Constituents of the Curcuma longa tablets Curcuma Zanga powder Gum arabicum Talc powder Tricalcium phosphate Manihot utilissima glue, 12 % Magnesium stearate 250mg mg 55 mg 25 mg 125 mg 4mg • Constituents of the placebo tablets Lactose Manihot utilissima glue, 12 % Talc powder Dextrin Manihot utilissima powder Lemon yellow Magnesium stearate 200 mg 60 mg 13 mg 1.3 mg 90mg 3.5 mg 3.7mg • The tablets were coated with: Talc powder Manihot starch Carboxymethyl cellulose Gelatin Saccarose Titanium dioxide Lemon yellow 31 0.3 mg 0.7mg • 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 for Curcuma Zanga powder and the TLC of the placebo must not show the same spots as the Curcuma tonga powder The methanolic extracts were used The stationary phase was silica gel G The mobile phase was chloroform:acetic acid, 9: 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 healing efficacy of turmeric was available when preparing 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 power 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 duodenal 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 44mg 4mg 0.2 mg 1.5 mg 185 mg A total of 130 patients were randomized in the study, 65 to the Curcuma Zanga group and 65 to the placebo group Seven patients, six in the Curcuma Zanga group 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 o weeks • Placebo • Curcuma longa 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 Another five pa tients had to be withdrawn from the study because of concurrent disease (2 pat.) an d lost for follow-up (3 pat.), leaving a total of 118 pa tients for the fina l evaluation Table Characteristics of patients Curcuma longa Placebo (n = 59) (n = 64) Sex (M/F) Mean age e 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 7,5 years 7,0 (SD:!: 1,2) 47 /17 36,S :!: 9,1 41/20 7,3 years 6,9 (SO:!: 1,0) 7,2 (SD :!: 3,3 ) 6,0 (SO :!: 2,7) 5,7 (SO:!: 0,9 ) 5,6 (SO:!: 0,9) 6,3 (SD :!: 2,3) 5,8 (SO:!: 1,7) Fig The weekly reduction of symptoms expressed in percentage of the pre-entry symptoms Ulcer healing Ta ble shows that the ulcer-healing rate a fter weeks of treatment was percent in the Curcuma longa group and 15 percent in th e placebo group Afte r weeks 27 per cent and 29 per cent were healed, respectively Table Duodenal ulcer healing rates weeks weeks Curcuma longa Placebo (1/55) % (15/56) 27% (9/62) 15 % (18/62) 29 % 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 groups (Fig 1), the discrepancy was not statistically significant The effects of a traditional drug, turmeric (Curcuma longa), on the healing of duodenal ulcer Laboratory findings There were no differences between the groups concerning laboratory analyses Side effects The adverse events reported after questioning are presented in Table 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 disease Table Frequency of side effects Curcuma longa Placebo Constipation Burning sensation Gas Hunger sensation 15 Total side effects 20 (36.9 %) o o 12 (20%) Discussion With modern drugs it is fairly easy to heal duodenal ulcer Hy-receprorblocking drugs have been wellknown for some years (Wormsley, 1988) and proton pump-inhibitors heal both duodenal and gastric ulcer in a very short time (Dahlgren et al., 1988) Sucralfate (GarciaParedes 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) Eradication of Helicobacter pylori with a combination of three antibiotics (Hosking, Ling et aI., 1994) or antibiotic 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 operation 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 Vietnam 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 33 has been integrated into the official health care system and that the assessment of old practice is officially encouraged The aim of the study was to assess the healing efficacy 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 ulcer the inte rvention 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 Curcuma 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 It also illustrates the need for further studies and that traditional prescriptions should be compared with drugs that can be manufactured 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 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 cimetidine and CEA AB, Strangnas, Sweden, for X-ray films II References Bayerdorffer, E., Mannes, G A., Sommer, A., Hochrer, W., Weingart , J., Hatz, R., Lehn, N., Ruckdeschel, G., Dirschedl, P and Stolte, M : Scand j Gastroenterol 28: Suppl 196: 19 - 25, 1993 Berstad, A and Weberg, R.: Antacid in the treatment of gastroduodenal ulcer Scand.] Gastroenterol 21: 385, 1986 Dahlgren, S., Dornellof, L., Hradsky, M., Norryd, c., Brunkvall, J., Svensson, G., Svensson, J 0., Karlsson, J" Knutsson, U., Gasslander, T., Lindhagen, J., Arbman, G., Jansson, R., Sandstrom, R., Huldt, B., Pettersson, B.-G., janunger, 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 34 N Van Dau et al Division of Med ical Research, Department of Medical Sciences: Manual of medicin al plants for primary health care Curcuma domestica Val., 2nd ed Bangkok, pp 19 - 20, 198 Do Tat Loi, The medicinal plants and drugs of Vietnam Science and Technical Publi shing 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 the treatment of duodenal ulcers Amer.] Med 91: (Suppl 2A), 64, 1991 Gar g, S K.: Effect of Curcuma longa Linn on fertility in female albino rats Bull P G I., 5: 178, 1971 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 Indian plants for antifertility activity Indian] Exp Bio!' 16: 1077, 1978 Gryral, M L., Choudhury, N K and Saxena, P N.: The effect of certain indigenous remedies on the healing of wounds and ulcers.] Indian Med Assoc 22 (7): 2,1953 Hosking, S W., Ling T 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 sucralfare in corpus, prepylor ic and du odenal ulcerassociated gastric ulcers A double-bl ind , placebo-controlled study Amer J Med.: 79 (Suppl 2C); 24 - 31 , 1985 Mini str y of Health, Pharmacopoea Vietnamica (Part II): Science and Technical Publishing H ou se, Hanoi, 1983 Office of the Primary Health Care: Medical Plants in Primary Health 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 Wormsley, K G.: Long-term treatment of duodenal ulcer Postgrad Med.] 64 (Suppl 1): 47, 1988 11 Address S Dahlgren, Borjegatan lOB, S-75313 Uppsala , Sweden