Ad do aod aa wee The Korean Journal of Parasitoloay Vol. 12, No. 2, 135-140, 1974 — 135 — Clinical Trial of Tinidazole (Fasigyn) in Acute and Chronic Intestinal Amoebiasis Jung-Kyoo Lim Department of Pharmacology, College of Medicine, Seoul National University A large number of amoebicides have been used in the treatment of amoebiasis, but none are completely satisfactory. Until re- cently there is no single drug for the treat- ment of all forms of amoebiasis, However the introduction of metronidazole was a sig~ in the chemotherapy of when Powell et al. (1966) used this drug in the treatment of amoel Metronidazole has been reported to be effe~ ctive in both intestinal and extraintestinal amoebiasis (Powell et al, 1967; Khambatta, 1969: Antani and Srinivas, 1970; Scott and Miller, 1970 Tinidazole nificant advance amoebiasis, Fasigyn) is a new drug which is active in vivo against Entamoeba histolytica and could compete account of its lower side effects and its higher anti-protozoan activity against Tri- with metronidazole on chomonas vaginalis (Augusto Diez et al, 19 72) and Giardia lamblia (Andersson et al, 19 72) infestations at lower doses. Tinidazole, ethyl [2-(2-methyl-3-nitro-1- imidazoly!) ethyl) sulphone was introduced as an antitrichomonal drug produced by Pfizer Research Laboratories, Sandwich England. ‘The structural formula is as follows The author is most grateful to Dr. Han-Jong Rim, Professor of Parasitology, Korea University Medical College for his technical assistance and helpful com. ments given to this manuscript, On: cH, Ny? CH, «CH: « $0, » CHa » CH, ‘The purpose of the study was to determine the optimal dose and treatment period for the use of tinidazole in two dosage regimes and determine efficacy and tolerance of the drug in the treatment of symptomatic inte- stinal amoebiasis. PATIENTS AND METHODS A total number of 30 patients (18 males and 12 females) ranging in age from 14 to 68 years with acute and chronic intestinal amoebiasis were selected for this study. Ten Table 1. Incidence of intestinal protozoa on a group of 370 rural inhabitants in Korea, No, Percent ‘Total number of examinations 370 Total number positive 75 20.3 Parasites Entamoeba histolytica 50 13.5 Entanneba coli 7 10.0 Endolimax nana wm 46 Giardia lamblia 8 22 Todamocba bittschlti 1 03— 136 — had uncomplicated acute amocbic dysentery, 20 had chronic intestinal amoebiasis. ‘Ten pati dysentery were studied at the out-patient clinic of the 51st Evacuation ROK Army Hospital. The diagnosis was based on gastro~ intestinal symptoms of diarrhea with blood and mucus in the stool, abdominal discomfort and the finding of trophozoites on stool exa ts suffering from acute amoebic ation. All were treated ambulatorily with 150mg q.i.d. daily for 10 successive days. A stool examination by a direct smear method using a warm saline solution and a concentration method was carried out on every on the day following the end of therapy and on days 30 and 45 following commencement of therapy. A general was undertaken before treatment, on the day following the end of therapy and on days 30 and 45 following the commencement of the~ rapy. In chronic intestinal amoebiasis, the pati- ents were selected among 370 inhabitants residing in the village of Cholla Puk Do. Diagnosis was by means of a concentration method for the presence of E. histolytica (Table 1). ‘The study was of the double blind type. A total of 20 patients suffering from bulky stools, flatulence, abdominal discomfort and vague abdominal pains increased by dietary or alcoholic excess was chosen for the treat- ment, Tinidazole was given orally in two treatment t 10 patients received 150mg q.i.d. for 10 days, and re- maining 10 patients were given a regimen of 300mg q.i.d. for 7 days. The stool exami- nations and general clinical examination car- on the day following end of therapy and on days 30 foll: owing the commencement of therapy. patient daily during the first week, clinical examination regimens: the ried out before starting therapy, ‘The following clinical laboratory tests in both acute and chronic intestinal amoebiasis were performed in the pretreatment period, on the day following end of therapy and o1. days 30 or 45 following the commencement of therapy with tinidazole: serum bilirubin, SGOT, SGPT, alkaline phosphatase, blood urea, WBC and differential count, RBC, hemoglobin, hematocrit, urinalysis for sugar, protein, urobilinogen and microscopy of the centrifuged deposit. The criteria of cure in this investigation were as follows: (1) prompt relief of abdo- minal pain and other acute or chronic _com- plaints of the patients, (2) improvement and cessation of diarrhea with complete return of the stools to normal consistency, (3) disapp- earance of F. histolytica, trophozoites by the direct smear and cysts by the concentration techniques, and of blood and mucus during treatment and in the follow-up period at the 30th and 45th days after treatment, and at least 5 post-therapy microscopical exami nations were negative, Sigmoidoscopic examination, for cultivation and ECG were not performed. During and after therapy the patients were questioned carefully and examined for any le side effect of the drug. rectal swab RESULTS 1) Acute intestinal amoebiasis In each of the ten patients with acute in- testinal amoebiasis, trophozoites of EZ. histo~ iytica were present in the feces before the beginning of therapy. Each patient was given tinidazole 150mg q.i.d. for 10 days, 8 were completely cured clinically and parasitologi cally. In two of the 10 patients who remained parasitic failure, symptomless one was converted to a st passing state at the end of— 137 - Table 2, Results of treatment with tinidazole, ae eee No, of Clinical Parasitic Percent of Form of amoebiasis Dosage ieee cure —_‘iinical reent Acute amoebic dysentery 150 mg q.i.d. 10 8 9 80.0 for 10 days Chronic intestinal 150mg 4.i.d. 10 6 8 4 60.0 amoebiasis for 10 day Chronic intestinal 300 mg q.i-d. 10 8 9 2 80.0 "amoebiasis for 7 ays the 10-day period of therapy, and another case had relapsed with acute symptoms at the 20th day after treatment. ‘The latter case was given a second course of 150mg q.i.d. for 10 days, after which his stool negative, and he responded clinically prom- ptly and completely to the second course, In patients showing complete cure, abdominal pains were relieved within 24-48 hours, diarrhoea, the end of the 4th day and the stools became became and blood and mucus disappeared by normal. Subjective improvement was felt by within four to six days and was usually complete by the end of the ten day period of therapy. Therefore a regime of 150mg q.i.d. for 10 days in acute intestinal amoebiasis was effective, yielding cure rate of 80 per cent (Table 2). The tolerance of the drug was entirely satisfactory in all the most patients cases. 2) Chronic intestinal amoebiasis Cysts of E, histolytica were found in the stools of 20 patients prior to therapy. ‘The patients were divided into two group of ten patients receiving tinidazole 150 mg q.i.d. for 10 days, the other group of ten patients receiving 300mg q.i.d. for 7 days. Final assessment was made at 30 days immediately after treatment and the results are summari zed in Table 2. Parasitological cure was obtained in 6 out of 10 patients (60 per cent) given the 150mg q.id. for 10 days regimen and 8 out of 10 patients (80.0%) given the 300mg q.i.d. for 7 days regimen. The high dosage schedule showed a higher cure rate in chronic intes- tinal amoebiasis, however, in these cases of parasitological failure, microscopical exami- nation showed a marked reduction in the number of the cysts in their stools. An im: provement in the clinical picture and subje- ctive symptoms of almost all the cases were observed by the 10th day after commencing treatment, Giardia lamblia and nonpathogenic com- mensal Entamoeba colt were found frequently However tinidazole has been held by some to be effective against G. lam blia and E. coli infections. in this study. 3) Side effects and toxicity of the drug Tinidazole is well tolerated and is free from serious toxicity. In this study of 30 patients treated with tinidazole, only 6 pati ents complained of slight gastrointestinal discomfort which did not warrant withdrawal from treatment, and disappeared immediately after stopping the treatment. There was no significant alteration in blood count, liver function tests and urine analysis of any of the patients treated with tinidazole. DISCUSSION Tinidazole has been widely used since 1975— 138 — for the treatment of urogenital trichomoniasis (Catizone and Bianchi, 1970; Daels, et al 19 70; Dubois et al., 1970: Diwald, 1971; and Rios and Becker, 1972) and more recently 1972). he toxicity of tinidazole was studied in rats, mice, monkeys and rabbits. shown that even with high doses there were no pathological changes in the blood or in the internal organs due to tinidazole, and mice the LDeo is 4,000 mg/kg body weight orally and 2,300mg/kg body weight intrap- eritonealy (Catizone and Bianchi 1970) against giardiasis (Andersson et al, It was In rat It has been found effective in experimental amoebiasis in albino rats. ‘The #n vitro acti vity of the tinidazole was shown by Prakash et al (1970) to be equivalent to that of di- iodohydroxyquinoline, slightly less than that of metronidazole, and greater than that of chloroquine phosphate or oxytetracycline. On the other hand, a pilot evaluation in human with intestinal amoebiasis demonstrate effi- cacy and id. for 10 days. The effect of metronidazole was assessed by Powell et al (1966) for the first time in 53 adult male African patients with acute amoebic dysentery. In the highest dosage of 800 mg thrice daily for 10 days, 22 out of 25 patients (88%) were apparently cured, How- ever, in the lower dosage of 200mg thrice daily for 10days, 5 out of 11 patients (45.5 %) were cured and 11 (55%) out of 20 pa ients who received 400mg of metronidazole thrice daily for 10 days were cured. Chhetri and Chakravarty (1969) treated 21 patients suffering from intestinal amoebiasis with metronidazole (6 tablets, each of 200mg daily for 5~10 days). ‘There were three pa- tolerance at 150mg 4. rasitic failur and 1 clinical failure, giving a cure of 81%. Side effects included nausea, tremulousness, giddiness and abdominal pain Zuberi and Ibrahim (1973) reported that a cure rate of 8.7% (26 out of 30 cases) was obtained in acute amoebic dysentery given tinidazole orally in doses of 450~1, 200 mg daily for 5 days. In acute intestinal amocbiasis, the 10 pati ents treated in the present trial, 8(80%) were made free from F. histolytica following tini- dazole 150mg q.i.d. for 10 days. This result is similar to that obtained by the above authors, However in chronic intestinal amoebiasis, parasitological cure was obtained in only 6 (60%) out of 10 patients who received 150 mg q.i.d. for 10 days, On the other hand a cure rate of 80% in 10 chronic cases given 300mg q.i.d. for 7 days. These findings suggest that higher doses are required to obtain para amoebiasis. obtained cure in chronic intestinal Similar results have shown with other drugs. O'Holohan and Hugoe-Matthews (19 72) reported that in acute amoebic dysentery even the lowest regimen of metronidazole (2.0m) in a single dose gave excellent results in symptomatic amoebiasis, but in cyst passers the cure rate dropped to about 57% at the highest dosage regimen of 2.4 gm. In the use of dehydroemetine, et al (1968) reported cure rates of 86% for acute dysentery, 100% for acute hepatic and only 34% of chronic cyst Salem amoebiasis passers. ‘The present study suggests that tinidazole will also be less effective in cases of chronic cyst passers of E. histolytica than in symp- tomatic acute amoebic further using different dosage schedules and durations of therapy may show an optimal effective dose for this condition. Park et al (1973) made clinical observation dysentery. However extensive trialson 41 cases. of amoebiasis, including 30 cases of Intestinal amoebiasis, 6 case of amoebic liver abscess and 5 cases of amoebic hepatitis in Wonju, Korea. They reported that all cases were cured with tinidazole at the dose of 450~1, 000 mg/day for 7~10 days in intes~ tinal amoebiasis, and 1, 200 mg/day for 7 days in the cases of amoebic hepatitis. The side effects were mild, nausea and dizziness occurring in only 2 cases. liver abscess and Further large-scale trials are necessary but tinidazole is a single direct acting amoebicide equally effective in both intestinal and extra intestinal amoebiasis once without significant toxicity. SUMMARY Tinidazole (Fasigyn), a new drug which is active tm vitro and in vivo against Entamoeba histolytica, was used in 30 Korean patients with acute and chronic intestinal amoebiasis. In acute amoebic dysentry cight of ten pati- ents given tinidazole 150mg q.i.d. for 10 days were cured clinically and parasitologi- cally. parasitological cure was obtained 6 out of 10 patients given 150mg q.i.d. for 10 days and 8 out of 10 in patients given 300mg qid. for 7 days. Tinidazole is well tolerated and is free from serious toxicity. There was no cant alteration in blood count, liver function tests and urine analysis of any of the pati- ents treated with tinidazole. In chronic intestinal amoebiasis, the mnifi- REFERENCES, Andersson, T., Forssell, J., and Sterner, G. (1972) Outbreak of iasis: Effect of a New Anti- flagellate Drug, 2: 449-451 inidazole. British Med. Jour. — 139 ~ Antani, J. and Srinivas, H.V. (1970). Clinical eval~ uation of metronidazole in hepatic amebiasis, Am. J. Trop. Med. & Hyg. 19(5): 762-766. Augusto Diez, T., Antonio Sucre, A., Arcia Rom ero, F. and Haydee de Sanchez (1972). A comparative study of metronidazole and a new compound-tinidazole, Reunion Nac de Obstetricay Ginecologia Merida, Ven Enero 19-22. Catizone, F. and Bianchi, 1. (1970). Controlled eli nical experiments with a new drug active on Trichomonas vaginalis. Gazz. Int. Med, Chir. 75 (17): 1318-1320. Chhetri, M.K., Chakarvarty, N.C, B, and Sarkar, 8.K. (1969). Further experience Bhattacharya, with metronidazole in the treatment of intestinal and hepatic amoebiasis, J. Indian Med. Ass. 61 21-281. J, Janssens, D. and Stroobants, W. (1970). ‘Trichomonas vaginitis. Modern therapeutic app- roach, ‘Tijdschr. voor Geneeskunde 15: 747-756. (Text by Belgian) Diwald, J. (1971). ‘Trichomoniasis-Behandlung der Frau mit Tinidazole. Wiener Med. Wochensehrift. 121: (24) 492-494, Dubois, P., Lambotte, R. Therapeutic clinical Daels, German text) » and Plompteux, G. (1970). trials with Fasigyn in vaginal trichomoniasis, Rev, Medicale de Liege. 25(18): 686-590. Khambatta, R.B. (1969). Metronidazole in chronic intestinal amoebiasis. Ann, Trop, Med. & Parasit, 62(2): 139-142. O'Holohan, D.R., and Hugoe- Matthews, J. (1972). Single-dose and short course regimens of Metro~ nidazole in the treatment of amoobiasis in Malay- sia, Ann, Trop. Med. & Parasit, 66(2): 181- 186. Park, JL, Lee, S.W., Choi, MoH, Kim, Y.S, and Jen, T.H. (1973). The use of (Fasigyn) on the treatment of intestinal and he- Intern. Med. 16 tinidazole patic amocbiasis (3): 213-216. (Korean text) Powell, S.J., Macleod, L, Wilmot, A, J. and Elsdon. Dew, R. (1966). tery and amoebic liver abscess. 1331. Korean J. Metronidazole in amoebic dysen- Lancet 2:1329-— 140 — Powell, S.J., Wilmot, A.J., and Elsdon-Dew, R. Salem, H.H., Hayatec, Z.G., Awaness, A.M. and (1967). Further trials of metronidazole in amo: Alallaf, G. (1968). Oral dehydroemetine dihyd~ ebic dysentry and amoebic liver abscess. Ann rochloride in intestinal and hepatic amocbie dis ‘Trop. Med. & Parasitol. 61: 511-514. ease, Trans, Roy. Soc. Trop, Med & Hyg. 62 Prakash, O., Joshi, D.V., Vinayak, V.K., Dhin~ (3): 406-412. gra, P.N. & Tarachand, A. (1970). The in Scott, F. and Miller, M.J, (1970). ‘Trials with me- vitro activity of tinidazole and other amoebicidal tronidazole in amebic dysentery. J. Am. Med. drugs on locally isolated strains of Entamoeba Assoc. 211: 118-120. histolytica. Indian J. Med. Res. $8(7): 845-5. Zuberi, S.J. and Ibrahim, M (1973). Clinical eval- Rios, E.R. and Becker, azole) in the treatment of Trichomoniasis. Se asis, (Communication) mana Med, 140: 183-185. (1972). Fasigyn (Tinid- uation of a new compound-tinidazole in amoebi- Mie Stk GL MAEM OO UEGEO Y01449) Tinidazole(Fasigyn) | jagR AR ABKE BRIE RUBE ik a fe Tinidazole Fasigyn) 2 ethyl{2-(2-methyl-5-nitro-1-imidazolyl) ethyl) sulphone © 2.4 Qe Trichomonas vagi- nalis | S61. LoL AMMA Entamoeba histolytica ol w3}1.S. in vitro 3) én vivo s. Ashe] Ve Slt. HAE AWD HERA 1083} BREW obT EBA 20%01 a sho] Tinidazole s| MARE gteeebal ct. 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