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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

Endpoint:
direct observations: clinical cases, poisoning incidents and other
Type of information:
other: human data
Adequacy of study:
weight of evidence
Study period:
January 1994 - December 1996
Reliability:
other: high
Rationale for reliability incl. deficiencies:
other: The publication has a high reliability. Comment: Very detailed description of responses and adverse effects.

Data source

Reference
Reference Type:
publication
Title:
Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral lesihmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases.
Author:
Thakur, C.P. et al.
Year:
1998
Bibliographic source:
Annals of Tropical Medicine & parasitology, 92 (5): 561 - 569.

Materials and methods

Study type:
clinical case study
Endpoint addressed:
not applicable
Test guideline
Qualifier:
no guideline required
Principles of method if other than guideline:
Eighty parasitologically confirmed cases of visceral leishmaniasis (kala-azar) in Bihar, India, were treated daily with 20 mg sodium stibogluconate/kg for 30 days, to assess the current efficacy and toxicity of this 30-day regimen. The test substance was administered intramuscular.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
sodium stibogluconate (SSG)
IUPAC Name:
sodium stibogluconate (SSG)
Details on test material:
- Name of test material (as cited in study report): Sodium stibogluconate (SSG)
No further information on the test material was stated.

Method

Type of population:
general
Subjects:
- Number of subjects exposed: 80 patients
- Sex: 67 males / 13 females
- Age: 6-10 years: 17 patients (21%); 11-20 years: 17 patients (21%); 21 -30 years: 18 patients (23 %); 31 -40 years: 15 patients (19%); 41 - 50 years: 10 patients (13%); 51 - 60 patients: 3 patients (4%)
- Race: the race was not stated.
The study was conducted in Patna medical College Hospital and Balaji Utthan Sansthan, both in Patna, Bihar, India. Patients with visceral leishmaniasis (VL; kala-azar) (confirmed by demonstration of amastigotes in Giemsa-stained smears of splenic aspirates) were admitted to the study if : they had no history of treatment with any antileishmanial drug; the y were between 6 and 60 years old; they had no serious concurrent illness (such as HIV infection, tuberculosis, pneumonia, or cardiac, renal or hepatic disease); and they were not pregnant. informed consent to participate was obtained and the study was cleared by the local ethical committee.
Ethical approval:
confirmed and informed consent free of coercion received
Route of exposure:
other: intramuscular injection
Reason of exposure:
intentional
Exposure assessment:
measured
Details on exposure:
See "Medical treatment" below
Examinations:
Initial assessment of those enrolled included the following:
- Urine analysis
- Haematological testing: Counts of leucocytes and platelets, estimation of prothrombin time and haemoglobin concentration
- Biochemical testing: Serum concentration of sodium, potassium, creatinine, asparate and aniline aminotransferase, and albumin.
- Physical exammination: Measurement of spleen and liver size and body weight
- Other: Electrocardiograms (ECG) and chest X-rays

Appropriate investigations were repeated at the end of treatment (day 30) and at follow-up (days 60, 90, 120, 150 and 180).
The spleen of each patient was aspirated on days 0, 30 and 180. the aspirates were stained with Giemsa and checked for amistigotes, independently, by two experienced parasitologists.

Clinical cure was defined as absence of fever and reduction in the size of spleen at the end of treatment, parasitological cure as absence of parasites in splenic aspirates recovered at the end of treatment, and ultimate cure as the absence of clinical or parasitological relapse within 6 months of initiating treatment.Patients were followed monthly for 6 months.

Intercurrent infections were treated as appropriate. Unresponsive patients, relapsing patients, and patients who were withdran from the study were treated with amphotericin B deoxycholate, administered at a dose of 1 mg/kg.day for 20 days.

Adverse events were monitored daily.
Medical treatment:
Each patient was given an intramuscular injection of SSG, at a dose of 20 mg/kg body weight (to a maximum daily dose of 850 mg), daily for 30 days, in one of both buttocks.

Results and discussion

Clinical signs:
In the study the patients that were admitted to the study showed as the main presenting features intermittent fever, shivering, and diminution in appitite. Several patients had clinical features of malnutrition (hair loss in 11 patients, leg oedema in five, angular stomatitis in two).
The 30-day regimen of SSG commonly caused adverse effects. There was considerable evidence of gastro-intestinal toxicity. Severe loss of appetite (i.e. complete aversion to food) occurred in one patient, who was withdrawn from the study on day 24. His liver, pancreatic and renal functions were within normal limits. He was parasitologically positive at the time of withdrawal, started having fever 3 weeks later and was then treted with amphotericin B and cured.
Furthermore, minor side effects of sodium stibogluconate were pain at the site of injection (2 patients), mild diminution in appetite (12 patients) metallic taste in mouth (6 patients), and joint pain (2 patients).
Results of examinations:
- Urine analysis: no data
- Haematological examination: In the study the patients that were admitted to the study showed as the main presenting features anaemia (all patients) and leucopenia. At the end of treatment (day 30) and throughout follow-up, the mean leucocyte count and haemoglobin concentration were all significantly higher.
- Biochemical examination: In patients that were admitted to the study, the mean concentration of serum albumin (3.0g/dl) was less than the normal range(3.6 - 4.7 g/dl). At the end of treatment (day 30) and throughout follow-up, the serum albumin concentration was significantly higher. There were no significant changes in the concentrations of serum creatinine, asparate aminotransferase, alanine aminotransferase, sodium or potassium, or blood urea at the end of treatment.
- Physical examination: In the study the patients that were admitted to the study showed as the main presenting features loss of weight and splenohepatomegaly. Every patient complained of weight loss. At the end of treatment the mean spleen and liver sizes were significantly smaller than pre-treatment (day 0).
- Electrocardiograms and chest X-rays: The 30-day regimen of SSG commonly caused adverse effects. Electrocardiographic changes occurred in many of the patients, diminution in the height of the T wave in 32 (40 %) patients, inversion of the T wave in 7 (9 %), elevation of the ST segment in 3 (4 %), prolonged QT interval in 6 (8 %) and diminution in the height of P, R and T waves in 2 (3 %). Cardiac arrhythmia occurred in 5 (6 %) patients, supraventricular arrhythmia in one and ventricular tachycardia, ventricular fibrillation, torsade de pointes and multifocal ventricular ecotopics occurred in the 4 patients who died.
Effectivity of medical treatment:
In this case the test substance is the medical treatment. For effectiveness see "Outcome of incidence" below.
Outcome of incidence:
The 30-day regimen of SSG failed in 34 (46%) of the patients.
Curing rate: Clinical and parasitological cure was obtained for 48 (60 %) patients, however 26 (33 %) patients did not respond to the first course of treatment.

Applicant's summary and conclusion

Conclusions:
Curing rate:
Clinical and parasitological cure was obtained for 48 (60 %) patients, however 26 (33 %) patients did not respond to the first course of treatment.

Adverse effects:
Electrocardiographic changes occurred in many of the patients, diminution in the height of the T wave in 32 (40 %) patients, inversion of the T wave in 7 (9 %), elevation of the ST segment in 3 (4 %), prolonged QT interval in 6 (8 %) and diminution in the height of P, R and T waves in 2 (3 %). Cardiac arrhythmia occurred in 5 (6 %) patients, supraventricular arrhythmia in one and ventricular tachycardia, ventricular fibrillation, torsade de pointes and multifocal ventricular ecotopics occurred in the 4 patients who died. Minor side effects were pain at the site of injection (2), mild diminution in appetite (12) metallic taste in mouth (6), and joint pain (2).

Tentative LOAEL:
not assignable