Drugs 15 (Suppl. 1): 16-18 (1978) © ADIS Press 1978
Treatment of Symptomatic Intestinal Amoebiasis with Tinidazole Edito G. Garcia Department of Parasitology. Institute of Public Health. University of the Philippines System. Manila. Philippines
Summary
Tinidazole was given in a Single dose of 2g a day for 2 days to 17 adults. and in a single dose of 50mg/ kg bodyweight daily for 3 days to 4 children. with symptomatic. but not severe. intestinal amoebiasis. A II 21 patients showed clinical improvement but only 20 (95 %) were parasitologically cured as evinced by failure to demonstrate Entamoeba histolytica in 3 stool samples collected on the 4th. 15th and 22nd day after treatment. Two subjects had mild nausea within a few hours of taking the first dose. while 8 had constipation of 3 to 5 days duration after treatment. I patient had nausea and constipation and another had palpitations.
Although a large number of amoebicidal drugs are now in use, a highly effective and well tolerated compound requiring only I dose a day, rather than multiple daily doses, is still wanting. Such a therapeutic agent should be readily absorbed after oral administration, have a long half-life and its minimum effective plasma concentration should persist for at least 24 hours, if not longer. Tinidazole may fill this need. This compound is 1-[2-(ethylsulfonyI)ethyl]-2methyl-5-nitroimidazole, a derivative of the substituted imidazole group of compounds; like metronidazole, another member of the group, it has antitrichomonal and amoebicidal activity. It was shown to be amoebicidal in guinea-pigs (Garcia, 1969) and later demonstrated to be effective in clinical
amoebiasis (Ahmad, 1973; Soh and Min, 1974) either in small repeated, or single large, daily doses. The results of a study comparing human blood levels of metronidazole and tinidazole after oral administration of 2g showed that higher plasma concentrations were reached with tinidazole. The half-life of tinidazole was 12.7h while that of metronidazole was 6.2h and the serum concentration of tinidazole after 48h was 4.2)lg/ml while that of metronidazole was 1.3)lg/ml (Monro, 1974). These observations indicate that tinidazole has a longer period of effective concentration in the patient than metronidazole. Since a single dose of 2g was well tolerated it is feasible, in view of the pharmacokinetics, to give this dose once a day for 2 or 3 days for the treatment of amoebiasis
Tinidazole in Symptomatic Intestinal Amoebiasis
and this paper reports our experience with this dose in this disease.
1. Methods
17
Table I. Results of treatment with tinidazole of 21 cases of symptomatic intestinal amoebiasis
Number treated
Clinically improved no. (%)
Parasitological cure no. (%)
The patients selected for this study were 17 adults and 4 children. All complained of diarrhoea or dysen4 (100) 4 (100) 4 Children 17 (100) 16 (94) tery and were subsequently, on stool examination, 17 Adults found to have hematophagous Entamoeba histo[ytica trophozoites. Pregnant women, patients with significant haematological fmdings, patients with known or Table II. Nature and frequency of side-effects in 21 cases suspected liver or renal insufficiency, cases of fulof amoebiasis treated with tinidazole minating or very severe amoebic dysentery requiring fluid replacement and asymptomatic E. histo[ytica Side-effects No. cyst passers were excluded from the study. 8 Pre-treatment examinations included blood count, Constipation urine examination and a physical examination. The Nausea 2 blood count was repeated once after treatment and the Palpitations urine examination was repeated on the 4th and 15th Nausea and constipation day after treatment. Post-treatment stools were collected on the 4th, 15th and 22nd day after treatment and examined by formalin-ether concentration technique. All 21 patients had clinical improvement and 20 All adult patients were given a single dose of 2g (95 %) were parasitologically cured as evinced by daily for 2 days while children were given a dose of failure to demonstrate E. histo[ytica in 3 stool ex50mg/kg bodyweight daily for 3 days. The patients aminations on the 4th, 15th and 22nd day after treatreceived the drug as tablets in the morning, and were ment. The subject who was not considered kept in the laboratory for 2 hours under observation parasitologically cured was negative for E. histolytica in case of immediate drug reactions. Each patient reon the 4th and 15th day after treatment but was posiported for the next 2 days after completion of treattive on the 22nd day. Clinical improvement, such as ment for clinical observation, and on the designated decrease in frequency of bowel movements and days, for examination of post-treatment stools. The diminution of the intensity of abdominal pain results were classified as clinical cure (with improvesuffered by the patient, was observed after the first ment or disappearance of symptoms) and parasitoday of treatment. logical cure (negative for E. histo[ytica by formalinA number of mild side-effects were observed. 8 ether concentration examination of post-treatment patients had constipation lasting from 3 to 5 days stools). after treatment while 2 patients had nausea. The nausea was mild and lasted for about an hour. 1 of 2. Results the patients who had nausea had palpitations on the fIrst day after treatment. Whether the palpitations The results of treatment are presented in table I were due to tinidazole is unknown. No abnormalities while the nature and frequency of side-effects ob- in the post-treatment blood counts and urine exserved among the patients are summarised in table II. aminations were observed.
18
Tinidazole in Symptomatic Intestinal Amoebiasis
3. Discussion The results indicate that tinidazole is an effective and well tolerated chemotherapeutic agent for the treatment of symptomatic intestinal amoebiasis as a single daily dose of 2g for 2 days for adults and at a dose of 50mg/kg bodyweight once a day for 3 days in children. One patient found not to be cured parasitologically showed a complete clinical recovery. This patient was cyst positive for E. histo[ytica on the 22nd day after treatment but was negative on the 4th and 15th day after treatment. The fact that the patient was negative on two stool examinations suggests reinfection occurred rather than a failure of treatment. Side-effects were all mild indicating that a single daily dose of 2g for 2 days is well tolerated. The posttreatment constipation experienced by some patients cleared without treatment. It is possible that the constipation may be due to the effect of tinidazole on the anaerobic bacterial flora of the intestine. Although the pharmacokinetics of metronidazole and tinidazole (Monro, 1974) indicate that tinidazole
may be a better chemotherapeutic agent for amoebiasis in view of the higher and longer maintenance of blood levels, a properly designed and controlled study should be undertaken to evaluate this point.
References Ahmad, I.: Clinical trial of tinidazole (Fasigyn) in amoebic liver abscess. Abstracts, 12th SEAMEO-TROPMED Seminar, Seoul, Korea, May 29-June 2, 1973. Garcia, E.G.: Compound CP-12,574 in the treatment of experimental amoebiasis. Report to PfIZer (1969). Monro, A.M.: Blood levels of chemotherapeutic drugs and the pharmacokinetics of tinidazole and metronidazole. Current Medical Research and Opinion 2: 130-13 7 (t 974). Soh, C.T. and Min, H.K.: The use oftinidazole on the treatment of amebiasis. Korean Central Journal of Medicine 26: I (t 974).
Author's address: Professor Edilo G. Garcia. Department of Parasitology, Institute of Public Health, University of the Philippines System, Manila. Philippines.
Treatment of Symptomatic Intestinal Amoebiasis with Tinidazole Edito G. Garcia Department of Parasitology. Institute of Public Health. University of the Philippines System. Manila. Philippines
Summary
Tinidazole was given in a Single dose of 2g a day for 2 days to 17 adults. and in a single dose of 50mg/ kg bodyweight daily for 3 days to 4 children. with symptomatic. but not severe. intestinal amoebiasis. A II 21 patients showed clinical improvement but only 20 (95 %) were parasitologically cured as evinced by failure to demonstrate Entamoeba histolytica in 3 stool samples collected on the 4th. 15th and 22nd day after treatment. Two subjects had mild nausea within a few hours of taking the first dose. while 8 had constipation of 3 to 5 days duration after treatment. I patient had nausea and constipation and another had palpitations.
Although a large number of amoebicidal drugs are now in use, a highly effective and well tolerated compound requiring only I dose a day, rather than multiple daily doses, is still wanting. Such a therapeutic agent should be readily absorbed after oral administration, have a long half-life and its minimum effective plasma concentration should persist for at least 24 hours, if not longer. Tinidazole may fill this need. This compound is 1-[2-(ethylsulfonyI)ethyl]-2methyl-5-nitroimidazole, a derivative of the substituted imidazole group of compounds; like metronidazole, another member of the group, it has antitrichomonal and amoebicidal activity. It was shown to be amoebicidal in guinea-pigs (Garcia, 1969) and later demonstrated to be effective in clinical
amoebiasis (Ahmad, 1973; Soh and Min, 1974) either in small repeated, or single large, daily doses. The results of a study comparing human blood levels of metronidazole and tinidazole after oral administration of 2g showed that higher plasma concentrations were reached with tinidazole. The half-life of tinidazole was 12.7h while that of metronidazole was 6.2h and the serum concentration of tinidazole after 48h was 4.2)lg/ml while that of metronidazole was 1.3)lg/ml (Monro, 1974). These observations indicate that tinidazole has a longer period of effective concentration in the patient than metronidazole. Since a single dose of 2g was well tolerated it is feasible, in view of the pharmacokinetics, to give this dose once a day for 2 or 3 days for the treatment of amoebiasis
Tinidazole in Symptomatic Intestinal Amoebiasis
and this paper reports our experience with this dose in this disease.
1. Methods
17
Table I. Results of treatment with tinidazole of 21 cases of symptomatic intestinal amoebiasis
Number treated
Clinically improved no. (%)
Parasitological cure no. (%)
The patients selected for this study were 17 adults and 4 children. All complained of diarrhoea or dysen4 (100) 4 (100) 4 Children 17 (100) 16 (94) tery and were subsequently, on stool examination, 17 Adults found to have hematophagous Entamoeba histo[ytica trophozoites. Pregnant women, patients with significant haematological fmdings, patients with known or Table II. Nature and frequency of side-effects in 21 cases suspected liver or renal insufficiency, cases of fulof amoebiasis treated with tinidazole minating or very severe amoebic dysentery requiring fluid replacement and asymptomatic E. histo[ytica Side-effects No. cyst passers were excluded from the study. 8 Pre-treatment examinations included blood count, Constipation urine examination and a physical examination. The Nausea 2 blood count was repeated once after treatment and the Palpitations urine examination was repeated on the 4th and 15th Nausea and constipation day after treatment. Post-treatment stools were collected on the 4th, 15th and 22nd day after treatment and examined by formalin-ether concentration technique. All 21 patients had clinical improvement and 20 All adult patients were given a single dose of 2g (95 %) were parasitologically cured as evinced by daily for 2 days while children were given a dose of failure to demonstrate E. histo[ytica in 3 stool ex50mg/kg bodyweight daily for 3 days. The patients aminations on the 4th, 15th and 22nd day after treatreceived the drug as tablets in the morning, and were ment. The subject who was not considered kept in the laboratory for 2 hours under observation parasitologically cured was negative for E. histolytica in case of immediate drug reactions. Each patient reon the 4th and 15th day after treatment but was posiported for the next 2 days after completion of treattive on the 22nd day. Clinical improvement, such as ment for clinical observation, and on the designated decrease in frequency of bowel movements and days, for examination of post-treatment stools. The diminution of the intensity of abdominal pain results were classified as clinical cure (with improvesuffered by the patient, was observed after the first ment or disappearance of symptoms) and parasitoday of treatment. logical cure (negative for E. histo[ytica by formalinA number of mild side-effects were observed. 8 ether concentration examination of post-treatment patients had constipation lasting from 3 to 5 days stools). after treatment while 2 patients had nausea. The nausea was mild and lasted for about an hour. 1 of 2. Results the patients who had nausea had palpitations on the fIrst day after treatment. Whether the palpitations The results of treatment are presented in table I were due to tinidazole is unknown. No abnormalities while the nature and frequency of side-effects ob- in the post-treatment blood counts and urine exserved among the patients are summarised in table II. aminations were observed.
18
Tinidazole in Symptomatic Intestinal Amoebiasis
3. Discussion The results indicate that tinidazole is an effective and well tolerated chemotherapeutic agent for the treatment of symptomatic intestinal amoebiasis as a single daily dose of 2g for 2 days for adults and at a dose of 50mg/kg bodyweight once a day for 3 days in children. One patient found not to be cured parasitologically showed a complete clinical recovery. This patient was cyst positive for E. histo[ytica on the 22nd day after treatment but was negative on the 4th and 15th day after treatment. The fact that the patient was negative on two stool examinations suggests reinfection occurred rather than a failure of treatment. Side-effects were all mild indicating that a single daily dose of 2g for 2 days is well tolerated. The posttreatment constipation experienced by some patients cleared without treatment. It is possible that the constipation may be due to the effect of tinidazole on the anaerobic bacterial flora of the intestine. Although the pharmacokinetics of metronidazole and tinidazole (Monro, 1974) indicate that tinidazole
may be a better chemotherapeutic agent for amoebiasis in view of the higher and longer maintenance of blood levels, a properly designed and controlled study should be undertaken to evaluate this point.
References Ahmad, I.: Clinical trial of tinidazole (Fasigyn) in amoebic liver abscess. Abstracts, 12th SEAMEO-TROPMED Seminar, Seoul, Korea, May 29-June 2, 1973. Garcia, E.G.: Compound CP-12,574 in the treatment of experimental amoebiasis. Report to PfIZer (1969). Monro, A.M.: Blood levels of chemotherapeutic drugs and the pharmacokinetics of tinidazole and metronidazole. Current Medical Research and Opinion 2: 130-13 7 (t 974). Soh, C.T. and Min, H.K.: The use oftinidazole on the treatment of amebiasis. Korean Central Journal of Medicine 26: I (t 974).
Author's address: Professor Edilo G. Garcia. Department of Parasitology, Institute of Public Health, University of the Philippines System, Manila. Philippines.
