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Original Articles
Comparative Double Blind Trials of Tiberal Compared with Metronidazole and Oral Dehydroemetine in Oligosymptomatie Amoebiasis
Chong-Hwee Chun, Pil-Won Park, O-Jeung Lee, Soo-Young Pak
Dept. Internal Medicine, St. Mary's Hospital, Catholic Medical College
Vol.6 Num.1 (p97~104)
New and better substances are still being sought for the treatment of amoebiasis. The aim of this trial is to assess the effectiveness and tolerance of Tiberal and oral dehydroemetine in patients with oligosymptomatic (or mild) intestinal amoebiasis comparing with that of metronidazole which are known to be an active amoebicide.
Selection of cases.
Lately, classical symptomatic amoebiasis accompanying mucus-bloody stool and tenesmus could be seldom experienced at urban areas in this country. At here the majority of intestinal amebiasis is manifested by loose stools containing mucus, pus or blood (rare), and also by a rapid response to antibiotics, but with frequent episods of recurrence caused by diet-failure or alcohol drinking.
Among 187 cases of mild enterocolitis which were suspected as being mild intestinal amoebiasis clinically, authors selected amoeba-positive 60 cases and additional 7 cases which were included later in this clinical trial study. The 7 drop-outs in the original study were replaced by these additional 7 cases.
The clinical trials were carried out at the St. Mary's Hospital, Catholic Medical College, Seoul, Republic of Korea. During 12 month (April 25, 1973-May 17, 1974), we treated 60 cases of so-called oligosymptomatic amoebiasis with above mentioned three amoebicides. 60 ambulatory cases suffering from mild GI troubles were admitted into the trial (liable to recurrent diarrhoeal stools including mucus, or pus with tenesmus, and also to lower abdominal discomfort or mild pain) those were suspected clinically as having intestinal amoebiasis with carriers of E. histolytica (trophozoits and/or cysts in the feces). Oligosymptomatic amoebiasis group, in this clinical trial study, consisted of 34 males and 26 females ranging from 17 to 62 years of age. All were adolecents or adults and their age distribution was shown in Table 1.
Methodology on this clinical trials.
We have carried out so-called the comparative double blind traials with Tiberal versus Metronidazole versus oral Dehydroemetine in symptomatic amoebiasis of mild grade. The trial drugs were given also without the knowledge of either the one who gave it or the one who got it in this comparative double blind study. Both (drug examiner) doctor and (drug examined) patients have had no knowledg of each drug. Pharmacist responded to doctor's prescription with code numbers. After the completion of the study the exact name of a drug were publically drawn from the code numbers and the purpose of double blind study was attained. In this study an arrangement for a drug administration schedule was set by a pharmacist exclusively.
60 patients were assigned to one of the three drugs by proper randomization so that 20 patients received tiberal and 20 metronidazole and 20 oral dehydroemetine.
After the trial, code numbers of the drugs were identified; nos 1, 6, 10, 14, 19, 23, 25, 27, 28, 29, 33, 34,35, 36, 44, 45, 47, 51, 53, and 54 were tiberal; 8, 9, 11, 12, 13, 15, 16, 18, 20, 22, 32, 39, 41, 48, 49, 50, 52, 55, 56, and 57 were metronidazole, and nos. 2, 3, 4, 5, 7, 17, 21, 24, 26, 30, 31, 37, 38, 40, 42, 43, 46, 58, 59 and 60 were oral dehydroemetine.
The therapeutic effects were assessed by the clinical evalution and by stool parasitology (direct examination and concentration method) performed on day 3 and 6 on treatment, and then at the end of treatment (8~10 day) and one month after the initial treatment. This made a total 4 to 5 parasitological examination per patient, including one examination required for diagnosis prior to treatment. At the same time aspect and consistency of the stool were regisered, the effect of the drugs on other protozoa found in the stools were also reported.
The tolerance were assessed by clinical findings and laboratory studies made in limited cases at least before and after treatment unless otherwise stated. Blood count, BUN, Alkaline phosphatase, SGP, TECG and urinalysis were performed as laboratory controls.
Authors have establi shed following evaluation criteria for this clinical study.
Radical cure: free of symptoms with no vegetative or cystic forms of E. histolytica in stool on 3 successive tests.
Biological cure: no cystic forms of E. histolytica in stool on 3 successive tests, but persistence of some intestinal disturbances.
Relapse: apparent cure or improvement (with negative of 3 successive tests, but persistence of some intestinal disturbances.
Relapse: apparent cure or improvement (with negative of 3 successive tests) followed by recurrence with vegetative amoeba on direct smear within 30 days. (re-infection may be included)
Failure: the trophozoites or cystic form of E. histolytica has persisted for treatment periods, with some intestinal troubles.
Methods of treatment and parasitologic examination
In each group one third of the patients received 2 capsnles of 250mg. Tiberal thrice daily for 7 days, one third received 2 tablets of 250 mgmetronidazole thrice daily for 7 days, and on third received 2 tablets of 10 mgdehydrometine thrice daily for 7 days as the only specific drug. No associated drugs were given together for symptomatic relief in all cases.
The reason why fixed 7 days dose were delivered to every cases was based on convinience of stool examination and equalizing the number of days for therapy. The therapeutic drugs were delivered usually for 2 days dose (1st prescription), 3 days dose and 2 days dose (3rd prescription) successively, therefore stool examination had been done on 3rd, 6th and 8~10th day of therapy.
Clinical results
In oligosymptomatic amoebiasis, 20 cases each were treated with doses of 1,500mg/day of Tiberal and metronidozole for 7 days respectively, and 20 cases were treated with doses of 60mg/day of dehydrometine for 7 days. The total doses administered were 10, 5g, and 420mg respectively in a period of 7 days.
Among tiberal group 19 cases were found to be negative after therapy whereas there was 1 with parasitological failure. The clinical effect was fast in 95% of the cases. Effective cure was achieved in 17 whereas symptoms persist in 3 patients among 20 cases. There were 1 failure and 2 late relapse. Comparing data of therapeutic results with that of metronidazole and dehydroemetine were shown in Table 2 & 3.
Table 3 shows the negativity rate of trophozoits or cystic form of E. histolytica in stools according to therapeutic periods of trial drugs received. The data would indicated that 5 days dose could not be enough to eradicate the parasites even in the susceptible cases. The result data of clinical improvement and clearance of E. histolytica in patient stool among drug trial groups were shown in Table 4. The cases treated with Tiberal showed no clinical signs on average 4.9days and negative amoeba in stool on average 4.1 days of therapeutic periods, comparing with on average 5.8 days and 4.1 days in metronidazole-treated group, and on average 6.3 days and average 4.5 days in dehydroemetine-treated group respectively.
Authors put in order the therapeutic procedures and their result of failed or relapsed cases with unplanned measures in Table 5.
These data could be obtained after the completion of the comparative double blind study by the code numbers which were publically drawn afterwards. These therapeutic procedures had been made just incidentally, not by prior plan. 2 cases, 4 cases and 3 cases could get finally effective cure by doubling doses of 7 days course of Tiberal, metronidazole and dehydroemetine respectively. 1 failed case treated with dehydroemetine and 1 another failed case with tiberal could get effective cure by additionally receiving metronidazole and dehydroemetine respectively. 2 failed cases treated with metroinidazole could be cleared of parasites by adding tiberal effectively.
Adverse reactions were noticed in 20% each of the patients treated with Tiberal and also with metronidazole, and 25% of those treated with dehydroemetine. They were all transient and never severs. There was not a single case who was discontinued on therapy owing to its side-effects. No significant change of laboratory data was noticed by the administration of trial drugs.
Brief summary
Tiberal, metronidazole and dehydroemetine (oral) were all recognized as highly efficacious anti-amoebic drugs in this clinical studies. On account of following standpoints 1) clearance of parasites in stool 2) clinical symptomatic relieving 3) drug tolerance 4) rate of relapse and failure 5) side-effects, Tiberal could be received much more recognition than metronidazole and dehydroemetine did.
Authors has experienced other 10 cases of amoebiasis among in patients (5 moderate severe intestinal amoebiasis, 4 liver abscesses and 1 lung abscess) treated with Tiberal and metronidazole with excellent therapeutic results, without any sequelae or relapse.
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