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Safety and efficacy of diphetarsone in the treatment of amoebiasis, non-pathogenic amoebiasis and trichuriasis
84
TRANSACTIONS OFTHEROYA~.SOCIE~OFTROPICALMEDIC~NEANDHYGIENE,VOL.77,No. 1,84-86(1983)
Safety and efficacy of diphetarsone in the treatment of amoebiasis, non-pathogenic amoebiasis and trichuriasis J. S. KEYSTONE, E. PROCTOR, C. GLENN AND L. MCINTYRE Toronto General Hospital, and Departments of Medicine 0 Medical Microbiology, Universi& of Toronto, Toronto, Ontario, Canada
Tropical Disease Unit,
Abstract
Eighty-nine patients infected with Entamoeba histo&tica, non-pathogenic amoebae or Trichuris trichiura were studied prospectively to determine the safety and efficacy of diphetarsone therapy. An additional 75 patients were studied retrospectively to assessfurther the efficacy of diphetarsone in the treatment of E. histolytica cyst passers. Side effects were noted in 9% and included gastrointestinal upset, lightheadedness and headache. Transient liver function abnormalities were recorded in 5.6%. Diphetarsone was completely effective in the treatment of Dientamoeba fragilis, Entamoeba hartmanni, Iodamoeba buetschlii and Trichuris trichiura. 99% of the patients with E. hiswlytica, 97% of those with E. coli and 98% of those with Endolimax nana were cured.
Introduction
HAN & HUGOE-MATTHEWS, 1972). HO
HO \ O”/A NaO
*NH-
CH2-CH2
1972), few human safety studies have been conducted on this compound. The paucity of such data prompted us to study the safety of
MATTHEWS,
Diphetarsone (Bemarsal) has been widely used to treat intestinal amoebiasison the European continent since its efficacy against cysts of Entamoeba histolytica was first reuorted in 1953 (SCHNEIDER & DUPOUX, 1953). In 1965, Junod fortuitously observed that dibhetarsone -T-----.---~~~ was effective in the treatment of Trichuns trichiura (JUNOD, 1965). Other observers have confirmed the drug’s efficacy in the treatment of intestinal amoebiasis, both pathogenic and nonpathogenic. and in whipworm infection. Excellent drug tolerance has been repeatedly commented upon (BOYCEet al., 1974; DESSER& YANG, 1976; LIMBOS et al., 1968; SCHNEIDER,1957; LENCZNER,1972). In the 26 years that diphetarsone has been used in France and her former French-speaking colonies, chiefly for intestinal amoebiasis, no significant toxic effects have been reported in the literature (O’HOLO-
-NH a
$0 NaO
Structure of diphetarsone Diphetarsone (1, 2, di(4arsonophenylamino) ethane decahvdrate) (Fig. l), is a nolar nentavalent arsenical with mole&la; keight 460-l. -The exact mechanism of action of the drug is not known. It is thought to act directly on amoebic cysts, probably by conversion to an active arsenoxide which inhibits sulphydryl enzymes (SCHNEIDER,1957). Its anthelminthic effect is limited to mature Trichuris worms where diphetarsone has been observed to cause a break between the whip and body portions (JUNOD, 1965). Although diphetarsone has been generally reported as safe and efficacious with infrequent side effects listed as vomiting? gastro-intestinal distress, shin rash and transient rise in SGOT (SCHNEIDER, 1957; LENCZNER, 1972; O’HOLOHAN & HUGOE-
diohetarsone and to re-evaluate the efficacy of this
d&g iu the treatment of amoebic cyst -passers, non-pathogenic
atnoebiasis and trichuriasis.
Materials and Methods All patients attending the Tropical Disease Unit at the
Toronto General Hospital who were infected with T. trichiura, E. histolytica or non-pathogenic amoebiasisrequiring treatment were asked to participate, in a prospective
,studyto determinethe efficacyand sideeffectsof diphetarsone. Patients who were referred for treatment of these organisms had the diagnosis confirmed by the Unit laboratory before they could be considered for entry into the study. Volunteers were treated with 500 mg of diphetarsone, thrice daily for 10 days. No other drugs were administered concurrently. Ten laboratory parameters were followed on days 0 (before treatment), 7 and 14 (four days post-treatment). Haematological studies included haemoglobin, white blood count, differential and platelet count; urinalysis and BUN were measuresof renal function; blood sugars were drawn and SGOT, alkaline phosphatase and bilirubin determinations were carried out to evaluate possible hepatic toxicity.
Sideeffectswere recordedon day 14. When possible,test
results which were abnormal on day 14were repeated on day
21.
A minimum of two stools, and preferably three stools, concentratedby the MIF technique were examined one week apart beginning four days after drug therapy was completed. Stains were carried out on each specimen using iron haematoxylin. In order to obtain additional information on the efficacy of diphetarsone in the treatment of E. hisrolyricacyst passers, a retrospective chart review of adult out-patients whose charts were coded with a diagnosis of E. histolytica was conducted. In order to be included in the analysis, the diagnosis of E. histdytica cyst passage had to be confirmed by the Unit laboratory and a minimum of two stooI examinations had to be carried out one week apart beginning four or more days after treatment with a standard lo-day course of diphetarsone. In addition, no other drugs could have been adminis-
tered concurrently.
Statistical analysis was carried out by the Student’s t-test and Chi-square analysis.
J.
S.
KEYSTONE
Results
A. Efficacy Study 59 males and 30 females were treated for trichuriasis and a variety of intestinal protozoa. The mean age was 34 years. Two thirds of the patients were foreign-born and one third were returning Canadian travellers. Half of the patients were infected with more than one parasite. As outlined in Table I, a single course of diphetarsone was highly effective in eradicating amoebaeand T. trichiura from the intestinal tract. 38 of 39 patients treated for E. histolytica in the prospective study were cured while all 75 patients reviewed retrospectively were cleared of the parasite; with an over-all combined cure rate of 99%. 70% of patients in the prospective study submitted three stools for examination after treatment, with the remainder submitting two stools. In the retrospective analysis, 33% of the patients submitted three posttreatment stools with the remainder providing two stools for follow-up examination. B. Sgfety Study Side-effects were noted in 9% of 89 patients in the prospective study. Gastro-intestinal and C.N.S. effects predominated (Table I). None of these problems was severeenough to warrant the interruption of drug therapy. No abnormalities resulting from treatment were noted in haemoglobin, white count, BUN, blood sugar or bilirubin. 12% of patients whose platelet
Table
I-Efficacy
Parasite
of diphetarsone
No. of Isolates treated
% Cured
:;
98 100
E. histolytica
prospective retrospective E. nana E. coli E. hartmanni D . fragilis I. buetschlii T. trichiura
Table
III-Liver
44 a: z
7
function
98 97 100
100 100 100
cd.
Table
85
II-Side
Effects 9/89 (9%)
No. of Patients
Symptom Swelling of mouth Lightheadedness Nausea, flatulence Diarrhoea Headache
: 3 1
Total
9
counts were below 150,000 on days 7 or 14 were normal before treatment. Since 11% of patients had low platelet counts before treatment, thrombocytopenia was not associated statistically with drug therapy. A similar situation was noted with respect to proteinuria with three of 89 patients having l+ proteinuria on day 7 or 14, but not on day 0, and one patient having proteinuria on day 0. The only significant abnormalities noted were elevation of liver enzymes. Five patients or 5.6% had transient rises in SGOT and/or alkaline phosphatase.All patients were asymptomatic and had normal biochemical indices one week following the enzyme elevation (Table II). Discussion
We found diphetarsone to be very effective in the treatment of asymptomatic E. histolytica cyst passers, non-pathogenic amoebiasisand T. trichiura infection with cure rates of 97 to 100%. Mebendazole, though lesseffective, but which causesfewer side effects than diphetarsone, is the present drug of choice for trichuriasis. Dientamoeba fragilis and Endolimax nana are the two non-pathogenic amoebaeso far implicated as causesof gastro-intestinal symptoms. Tetracycline can be used to treat D. fragilis, but diphetarsone is currently the only drug available for the treatment of E. nana.
Most North American physicians have shied away from using arsenicals in the treatment of amoebiasis becausethese compounds have been associatedwith encephalopathy, polyneuritis, visual disturbances and severe dermatitis. In spite of its membership in the arsenical family, none of these problems has been reported specifically with diphetarsone. In over
test results
Test Result (I.U./l.) Day
Patient
Age (Years)
Sex
No. 1
52
M
No. 2
;:
No. 43 No. 5 *Normal-less **Normal-less
et
55 71 than 55 I.U./l. than 90 I.U./l.
Test
0
7
14
21
34
30 94 E
-
64 129
iI
SGOT* Alk. Phos** SGOT
4:
194 162 41
M F
SGOT SGOT
49 22;
4: 29
6 22 36
86
DIPHETARSONE
TREATMENT
OF
10,000patients treated with diphetarsone in our Unit since 1971. we have twice observed drug rash which was in nd instance life threatening. Alteration in hepatic function in our study would suggest that diphetarsone be contraindicated in patients with severe liver disease. In recent years, increased concern about potential drug toxicity has led to rigid regulations governing the development and testing of pharmaceuticals for human consumption. Drug companies are unwilling to invest large sums of m&ey in the development and marketing of drugs which have limited demand. Clinician; involveiin the treatment of human intestinal parasites are hampered by their lack of accessto diphetarsone, a drug with excellent efficacy and tolerance for the treatment of non-pathogenic amoebiasis, amoebiasis and trichuriasis. References Boyce, J. M. H., Fitzgerald, T. C. & Gregg, R. (1974). Diphetarsone (‘Bemarsal’) and other anthehninthic drugs in the treatment of Trickuris trickiura (whipworm) infestation in a subnormality hospital. British 3ournal of Psychiatry, 124, 160-165. Desser, S. S. & Yang, J. Y. (1976). D&amoeba fia@is in
AMOEBIASIS
AND
TRICHURIASIS
idiopathic gastrointestinal disorders. Canadian Medical
Association Journal, 114, 290-291.
Junod, Ch. (1965). Essai de traitement de la trichocephalose par la diphetarsone. Bulletin de la Socie’te’ de Patkologie Exotiaue. 58. 653-660.
Lenczne;, hi. k. (1972). Treatment of trichuriasis. Transactions of the Royal Societyof Tropical Medicine and Hygiene, 66, sio-511: Limbos. I’.. De Muvnck. A. & Tanssens,P. G. (1968). T&em&t de la *tri&ocephal&e par ia diphetarsone. Acta Gastroenterologica Belgica, 31, 492-496.
O’Holohan, D. R. & Hugoe-Matthews, J. (1972). Diphetarsone (Bemarsal) in the treatment of Trickuris trickiura infe&ons. Sohkeast AsianJournal of Tropical Medicine and Public Health, 3, 576-579.
Schneider, J. & Dupoux, J. (1953). Traitement de l’amibiase intestiliale par le bis (p-arsonophenylamino) 1, 2 ethane. Bulletin de la So&% de Patkologie Exotique, 46, 550-561. Schneider, J. (1957). Le traitement de I’amibiase intestinale et des colites ambiennes. Semaine des H@itaux Tkhapeutique, 33, 610-612. Stauffer, J. W. & Levine, W. L. (1974). Chronic diarrhoea related to Endolimax nana. American 3ournal of Diseases, 19, 59-63.
Accepted for publication 9th June, 1982.
5th INTERNATIONAL SYMPOSIUM ON MEDICINAL PLANTS, CONFERENCE CENTRE, UNIVERSITY OF IFE, NIGERIA July 13 -
July 15, 1983
Theme: Anti-infective agents of higher plant origin Tonics to be covered include:
i. ii. iii. iv.
Antiprotozoan agents such as the antimalarials. Antimicrobial. funrricidal and antiviral agents. Molluscicides; anti&istosomal and anthilmintic agents. Drug development from plants.
You are cordially invited to participate in the Symposium. For further information, please contact: The Chairman, VISOMP 1983, Dr. C. 0. Adewunmi or the Secretary, Drug Research and Production Unit, Faculty of Pharmacy, University of Ife, Ile-Ife, Nigeria.
TRANSACTIONS OFTHEROYA~.SOCIE~OFTROPICALMEDIC~NEANDHYGIENE,VOL.77,No. 1,84-86(1983)
Safety and efficacy of diphetarsone in the treatment of amoebiasis, non-pathogenic amoebiasis and trichuriasis J. S. KEYSTONE, E. PROCTOR, C. GLENN AND L. MCINTYRE Toronto General Hospital, and Departments of Medicine 0 Medical Microbiology, Universi& of Toronto, Toronto, Ontario, Canada
Tropical Disease Unit,
Abstract
Eighty-nine patients infected with Entamoeba histo&tica, non-pathogenic amoebae or Trichuris trichiura were studied prospectively to determine the safety and efficacy of diphetarsone therapy. An additional 75 patients were studied retrospectively to assessfurther the efficacy of diphetarsone in the treatment of E. histolytica cyst passers. Side effects were noted in 9% and included gastrointestinal upset, lightheadedness and headache. Transient liver function abnormalities were recorded in 5.6%. Diphetarsone was completely effective in the treatment of Dientamoeba fragilis, Entamoeba hartmanni, Iodamoeba buetschlii and Trichuris trichiura. 99% of the patients with E. hiswlytica, 97% of those with E. coli and 98% of those with Endolimax nana were cured.
Introduction
HAN & HUGOE-MATTHEWS, 1972). HO
HO \ O”/A NaO
*NH-
CH2-CH2
1972), few human safety studies have been conducted on this compound. The paucity of such data prompted us to study the safety of
MATTHEWS,
Diphetarsone (Bemarsal) has been widely used to treat intestinal amoebiasison the European continent since its efficacy against cysts of Entamoeba histolytica was first reuorted in 1953 (SCHNEIDER & DUPOUX, 1953). In 1965, Junod fortuitously observed that dibhetarsone -T-----.---~~~ was effective in the treatment of Trichuns trichiura (JUNOD, 1965). Other observers have confirmed the drug’s efficacy in the treatment of intestinal amoebiasis, both pathogenic and nonpathogenic. and in whipworm infection. Excellent drug tolerance has been repeatedly commented upon (BOYCEet al., 1974; DESSER& YANG, 1976; LIMBOS et al., 1968; SCHNEIDER,1957; LENCZNER,1972). In the 26 years that diphetarsone has been used in France and her former French-speaking colonies, chiefly for intestinal amoebiasis, no significant toxic effects have been reported in the literature (O’HOLO-
-NH a
$0 NaO
Structure of diphetarsone Diphetarsone (1, 2, di(4arsonophenylamino) ethane decahvdrate) (Fig. l), is a nolar nentavalent arsenical with mole&la; keight 460-l. -The exact mechanism of action of the drug is not known. It is thought to act directly on amoebic cysts, probably by conversion to an active arsenoxide which inhibits sulphydryl enzymes (SCHNEIDER,1957). Its anthelminthic effect is limited to mature Trichuris worms where diphetarsone has been observed to cause a break between the whip and body portions (JUNOD, 1965). Although diphetarsone has been generally reported as safe and efficacious with infrequent side effects listed as vomiting? gastro-intestinal distress, shin rash and transient rise in SGOT (SCHNEIDER, 1957; LENCZNER, 1972; O’HOLOHAN & HUGOE-
diohetarsone and to re-evaluate the efficacy of this
d&g iu the treatment of amoebic cyst -passers, non-pathogenic
atnoebiasis and trichuriasis.
Materials and Methods All patients attending the Tropical Disease Unit at the
Toronto General Hospital who were infected with T. trichiura, E. histolytica or non-pathogenic amoebiasisrequiring treatment were asked to participate, in a prospective
,studyto determinethe efficacyand sideeffectsof diphetarsone. Patients who were referred for treatment of these organisms had the diagnosis confirmed by the Unit laboratory before they could be considered for entry into the study. Volunteers were treated with 500 mg of diphetarsone, thrice daily for 10 days. No other drugs were administered concurrently. Ten laboratory parameters were followed on days 0 (before treatment), 7 and 14 (four days post-treatment). Haematological studies included haemoglobin, white blood count, differential and platelet count; urinalysis and BUN were measuresof renal function; blood sugars were drawn and SGOT, alkaline phosphatase and bilirubin determinations were carried out to evaluate possible hepatic toxicity.
Sideeffectswere recordedon day 14. When possible,test
results which were abnormal on day 14were repeated on day
21.
A minimum of two stools, and preferably three stools, concentratedby the MIF technique were examined one week apart beginning four days after drug therapy was completed. Stains were carried out on each specimen using iron haematoxylin. In order to obtain additional information on the efficacy of diphetarsone in the treatment of E. hisrolyricacyst passers, a retrospective chart review of adult out-patients whose charts were coded with a diagnosis of E. histolytica was conducted. In order to be included in the analysis, the diagnosis of E. histdytica cyst passage had to be confirmed by the Unit laboratory and a minimum of two stooI examinations had to be carried out one week apart beginning four or more days after treatment with a standard lo-day course of diphetarsone. In addition, no other drugs could have been adminis-
tered concurrently.
Statistical analysis was carried out by the Student’s t-test and Chi-square analysis.
J.
S.
KEYSTONE
Results
A. Efficacy Study 59 males and 30 females were treated for trichuriasis and a variety of intestinal protozoa. The mean age was 34 years. Two thirds of the patients were foreign-born and one third were returning Canadian travellers. Half of the patients were infected with more than one parasite. As outlined in Table I, a single course of diphetarsone was highly effective in eradicating amoebaeand T. trichiura from the intestinal tract. 38 of 39 patients treated for E. histolytica in the prospective study were cured while all 75 patients reviewed retrospectively were cleared of the parasite; with an over-all combined cure rate of 99%. 70% of patients in the prospective study submitted three stools for examination after treatment, with the remainder submitting two stools. In the retrospective analysis, 33% of the patients submitted three posttreatment stools with the remainder providing two stools for follow-up examination. B. Sgfety Study Side-effects were noted in 9% of 89 patients in the prospective study. Gastro-intestinal and C.N.S. effects predominated (Table I). None of these problems was severeenough to warrant the interruption of drug therapy. No abnormalities resulting from treatment were noted in haemoglobin, white count, BUN, blood sugar or bilirubin. 12% of patients whose platelet
Table
I-Efficacy
Parasite
of diphetarsone
No. of Isolates treated
% Cured
:;
98 100
E. histolytica
prospective retrospective E. nana E. coli E. hartmanni D . fragilis I. buetschlii T. trichiura
Table
III-Liver
44 a: z
7
function
98 97 100
100 100 100
cd.
Table
85
II-Side
Effects 9/89 (9%)
No. of Patients
Symptom Swelling of mouth Lightheadedness Nausea, flatulence Diarrhoea Headache
: 3 1
Total
9
counts were below 150,000 on days 7 or 14 were normal before treatment. Since 11% of patients had low platelet counts before treatment, thrombocytopenia was not associated statistically with drug therapy. A similar situation was noted with respect to proteinuria with three of 89 patients having l+ proteinuria on day 7 or 14, but not on day 0, and one patient having proteinuria on day 0. The only significant abnormalities noted were elevation of liver enzymes. Five patients or 5.6% had transient rises in SGOT and/or alkaline phosphatase.All patients were asymptomatic and had normal biochemical indices one week following the enzyme elevation (Table II). Discussion
We found diphetarsone to be very effective in the treatment of asymptomatic E. histolytica cyst passers, non-pathogenic amoebiasisand T. trichiura infection with cure rates of 97 to 100%. Mebendazole, though lesseffective, but which causesfewer side effects than diphetarsone, is the present drug of choice for trichuriasis. Dientamoeba fragilis and Endolimax nana are the two non-pathogenic amoebaeso far implicated as causesof gastro-intestinal symptoms. Tetracycline can be used to treat D. fragilis, but diphetarsone is currently the only drug available for the treatment of E. nana.
Most North American physicians have shied away from using arsenicals in the treatment of amoebiasis becausethese compounds have been associatedwith encephalopathy, polyneuritis, visual disturbances and severe dermatitis. In spite of its membership in the arsenical family, none of these problems has been reported specifically with diphetarsone. In over
test results
Test Result (I.U./l.) Day
Patient
Age (Years)
Sex
No. 1
52
M
No. 2
;:
No. 43 No. 5 *Normal-less **Normal-less
et
55 71 than 55 I.U./l. than 90 I.U./l.
Test
0
7
14
21
34
30 94 E
-
64 129
iI
SGOT* Alk. Phos** SGOT
4:
194 162 41
M F
SGOT SGOT
49 22;
4: 29
6 22 36
86
DIPHETARSONE
TREATMENT
OF
10,000patients treated with diphetarsone in our Unit since 1971. we have twice observed drug rash which was in nd instance life threatening. Alteration in hepatic function in our study would suggest that diphetarsone be contraindicated in patients with severe liver disease. In recent years, increased concern about potential drug toxicity has led to rigid regulations governing the development and testing of pharmaceuticals for human consumption. Drug companies are unwilling to invest large sums of m&ey in the development and marketing of drugs which have limited demand. Clinician; involveiin the treatment of human intestinal parasites are hampered by their lack of accessto diphetarsone, a drug with excellent efficacy and tolerance for the treatment of non-pathogenic amoebiasis, amoebiasis and trichuriasis. References Boyce, J. M. H., Fitzgerald, T. C. & Gregg, R. (1974). Diphetarsone (‘Bemarsal’) and other anthehninthic drugs in the treatment of Trickuris trickiura (whipworm) infestation in a subnormality hospital. British 3ournal of Psychiatry, 124, 160-165. Desser, S. S. & Yang, J. Y. (1976). D&amoeba fia@is in
AMOEBIASIS
AND
TRICHURIASIS
idiopathic gastrointestinal disorders. Canadian Medical
Association Journal, 114, 290-291.
Junod, Ch. (1965). Essai de traitement de la trichocephalose par la diphetarsone. Bulletin de la Socie’te’ de Patkologie Exotiaue. 58. 653-660.
Lenczne;, hi. k. (1972). Treatment of trichuriasis. Transactions of the Royal Societyof Tropical Medicine and Hygiene, 66, sio-511: Limbos. I’.. De Muvnck. A. & Tanssens,P. G. (1968). T&em&t de la *tri&ocephal&e par ia diphetarsone. Acta Gastroenterologica Belgica, 31, 492-496.
O’Holohan, D. R. & Hugoe-Matthews, J. (1972). Diphetarsone (Bemarsal) in the treatment of Trickuris trickiura infe&ons. Sohkeast AsianJournal of Tropical Medicine and Public Health, 3, 576-579.
Schneider, J. & Dupoux, J. (1953). Traitement de l’amibiase intestiliale par le bis (p-arsonophenylamino) 1, 2 ethane. Bulletin de la So&% de Patkologie Exotique, 46, 550-561. Schneider, J. (1957). Le traitement de I’amibiase intestinale et des colites ambiennes. Semaine des H@itaux Tkhapeutique, 33, 610-612. Stauffer, J. W. & Levine, W. L. (1974). Chronic diarrhoea related to Endolimax nana. American 3ournal of Diseases, 19, 59-63.
Accepted for publication 9th June, 1982.
5th INTERNATIONAL SYMPOSIUM ON MEDICINAL PLANTS, CONFERENCE CENTRE, UNIVERSITY OF IFE, NIGERIA July 13 -
July 15, 1983
Theme: Anti-infective agents of higher plant origin Tonics to be covered include:
i. ii. iii. iv.
Antiprotozoan agents such as the antimalarials. Antimicrobial. funrricidal and antiviral agents. Molluscicides; anti&istosomal and anthilmintic agents. Drug development from plants.
You are cordially invited to participate in the Symposium. For further information, please contact: The Chairman, VISOMP 1983, Dr. C. 0. Adewunmi or the Secretary, Drug Research and Production Unit, Faculty of Pharmacy, University of Ife, Ile-Ife, Nigeria.