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PubMed1998

Treatment of antimony-unresponsive Indian visceral leishmaniasis with ultra-short courses of amphotericin-B-lipid complex.

High cost is the principal drawback of treating visceral leishmaniasis (VL; kala-azar) with any of the new lipid formulations of amphotericin B. The aim of the present study was to see if the costs of treatment with such drugs could be reduced by using ultra-short courses. Amphotericin-B-lipid complex (ABLC) was given to 77 Indian patients with antimony-unresponsive VL, either as a single infusion of 5 mg/kg (Group A) or two infusions, each of 5 mg/kg, given 5 days apart (Group B) or on consecutive days (Group C). Other than the anticipated higher fever and chills, treatment was well-tolerated. On day 19 after first infusion, 72 patients were considered apparent cures: 24 (89%) of the 27 in Group A; all 24 (100%) in Group B; and 24 (92%) of the 26 patients in Group C. Six months after treatment, 19 (70%) of 27 in Group A, 19 (79%) of 24 in Group B, and 21 (81%) of 26 in Group C were healthy, relapse-free and considered definitive cures. These cure rates were not statistically different. All 18 treatment failures (five initial non-responders and 13 relapses) were cured after treatment with a 5-day course of ABLC at a higher dose (10-15 mg/kg.day). In a related analysis of hospital plus drug costs for treating antimony-unresponsive VL, short-course ABLC (1-5 days) was compared with conventional amphotericin B (0.75-1.0 mg/kg on alternate days over 30-34 days). This analysis, which included the cost of re-treatment, identified one short-course ABLC regimen with an overall estimated expense which was only modestly higher than that of amphotericin B. Together, the present results provide further support for the use of ABLC in the management of VL patients who fail antimony therapy.

Adolescent↗
PubMed1998

Comparative efficacy of meglumine antimoniate and aminosidine sulphate, alone or in combination, in canine leishmaniasis.

Thirty-two domestic dogs naturally infected with Leishmania infantum and showing viscero-cutaneous signs of canine leishmaniasis were treated with aminosidine sulphate (11 dogs) meglumine antimoniate (10 dogs) or with a combination of the two drugs (11 dogs) for 21 consecutive days. Clinical and laboratory assessments, made on day 21 and at 2, 4 and 6 months after initiation of treatment, showed that the drug combination gave the best score in terms of clinical efficacy, incidences of early clinical relapse, any clinical relapse or apparent parasitological cure, and reduction in parasite densities in bone-marrow and lymphnode aspirates (even though a lower dose of antimonial was used in the combination than for antimonial monotherapy). For each of the above parameters, however, the higher efficacy of the drug combination was not statistically significant, probably because of the large variations caused by using naturally infected animals of various ages and breeds.

Animals↗
PubMed1982

Arterial pH monitoring with monocrystalline antimony sensors. A study of sensitivity for PO2 variations.

Monocrystalline antimony catheter electrodes were studied intra-arterially in non-heparinized dogs. The sensitivity for variations in arterial PO2 (PaO2) was evaluated for this kind of metal-metal oxide pH sensor. The influence of PaO2 compensation on a previous pH sensitivity estimate was calculated. When the mV signal from the antimony sensor, after compensation for pH and temperature variations, was expressed as a function of log10 PaO2, a non-linear relation was found for the PaO2 range studied, 2.9-50 kPa. After calculations this range was divided into a lower and a higher sub-range. A first-order linear approximation was applied for these subranges. The sensitivity for oxygen was 70 mV/log10 PaO2 in the range 2.9kPa less than PaO2 less than 10 kPa, and 20.7 mV/log10 PaO2 in the range 10 kPA less than PaO2 less than 50 kPa. The non-logarithmic sensitivity for intra-arterial oxygen is contradictory to results from in vitro studies in test solutions. The present study indicates that the monocrystalline antimony pH sensor has a sensitivity for PaO2 variations which is closely correlated to the haemoglobin-oxygen dissociation function. When compensation for PaO2 variations was performed on an earlier evaluated study over a wide pH range but limited PaO2 range, the pH sensitivity previously found was not influenced.

Animals↗
PubMed1999

Evidence that the high incidence of treatment failures in Indian kala-azar is due to the emergence of antimony-resistant strains of Leishmania donovani.

The possibility that the high frequency of treatment failures in Indian kala-azar might be due to infection with antimony-resistant strains of Leishmania donovani has not been experimentally addressed. L. donovani isolates were obtained from splenic aspiration smears of 24 patients in Bihar, India, who either did not respond (15) or did respond (9) to 1 or more full courses of treatment with sodium antimony gluconate (SAG). A strong correlation (P<.001) between clinical response and SAG sensitivity in vitro was observed only when strains were assayed as intracellular amastigotes: responsive isolates ED50=2.4+/-2.6, ED90=6.4+/-7.8 microgram SAG/mL; unresponsive isolates ED50=7.4+/-3.7 microgram SAG/mL, ED90=29.1+/-11.1 SAG/mL. No correlation with clinical response was found by use of extracellular promastigotes (ED50=48+/-22 vs. 52+/-29 microgram/mL). The emergence of antimony-resistant L. donovani strains appears to be a cause of treatment failures in India.

Adolescent↗
PubMed1996

Cure of antimony-unresponsive Indian visceral leishmaniasis with amphotericin B lipid complex.

Twenty-one Indian patients with visceral leishmaniasis who did not respond to or relapsed after 28-60 days of pentavalent antimony therapy were treated with amphotericin B lipid complex (ABLC). Five infusions (3 mg/kg each) given every second day over 9 days (total dose, 15 mg/kg) resulted in a 100% apparent cure response. In 4 other patients who had not responded to antimony, apparent cure was also induced by ABLC given 3 mg/kg a day 5 consecutive days (total dose, 15 mg/kg). Fever and chills developed routinely during the initial 2-h infusions; these reactions were tolerated and diminished with successive infusions. Six months after treatment, all 25 patients were healthy, had parasite-free bone marrow aspirates, and were considered cured. ABLC is effective short-course therapy for kala-azar patients who do not respond to conventional antimony treatment.

Adolescent↗
PubMed1997

Efficacy of aminosidine administered alone or in combination with meglumine antimoniate for the treatment of experimental visceral leishmaniasis caused by Leishmania infantum.

BALB/c mice with an experimental visceral leishmaniasis produced by Leishmania infantum were treated with aminosidine sulphate alone or combined with meglumine antimoniate. Parasite burdens in the liver and spleen were determined by subculturings using a sensitive microtitration method. Treatments with aminosidine alone decreased the parasite burdens compared with those observed in the untreated mice, but were less efficacious than meglumine antimoniate. Aminosidine combined with meglumine antimoniate resulted in an increased efficacy compared with either drug given alone. However, these regimens were associated with toxicities and with persistence of hepatic and splenic leishmanial foci after drug administrations.

Animals↗
PubMed2001

Successful treatment of visceral leishmaniasis with allopurinol plus ketoconazole in an infant who developed pancreatitis caused by meglumine antimoniate.

Pentavalent antimony is still the drug of choice in the treatment of visceral leishmaniasis. Pantavalent antimony can cause a wide range of adverse effects, the most serious of which are cardiotoxicity and hepatotoxicity. Acute pancreatitis is a rarely reported adverse effect. An infant who developed pancreatitis during meglumine antimoniate treatment for visceral leishmaniasis and who was successfully treated with a combination of allopurinol and ketoconazole is reported.

Acute Disease↗
PubMed2006

Successful internal mammary visualization with periareolar injections of Tc-99m antimony sulfur colloid in sentinel node breast lymphoscintigraphy.

PURPOSE: The subareolar and periareolar injection techniques result in higher detection rates and do not require tumor localization in impalpable lesions when compared with the peritumoral technique. One of the main criticisms, however, is the widely reported inability to detect internal mammary nodes. This contrasts with our clinical experience using Tc-99m antimony sulfur colloid, in which internal mammary nodes are commonly seen. METHODS: A retrospective analysis of 241 patients over 38 months was performed to investigate the ability of our periareolar injection technique to detect internal mammary lymph node drainage in breast cancer sentinel node lymphoscintigraphy. Four injections of 5 to 10 MBq (0.14-0.27 mCi) Tc-99m antimony sulfur colloid were administered on the day of surgery followed by massage and imaging. The radioisotope was suspended in 0.1 mL with a 0.5-mL air lock. Each injection was performed over 2 seconds with a 25-gauge needle at a depth of 1.1 to 1.3 cm. Patients whose records could not be retrieved or who underwent an injection technique apart from periareolar or peritumoral were removed from the analysis. RESULTS: One hundred thirty-three patients underwent the periareolar technique, 72 patients underwent the peritumoral technique, and 36 patients were excluded from the analysis. Internal mammary drainage was seen in 24 of 133 (18.0%) patients, of which 12 (9%) were seen only in the internal mammary chain. This is much higher than previous studies quoting 0.0% to 4.3% and is similar to previously reported rates using the peritumoral technique. CONCLUSIONS: Our periareolar injection technique using Tc-99m antimony sulfur colloid is able to detect internal mammary lymph nodes in at least 18.0% of patients.

Antimony↗
PubMed1969

Uptake of antimony potassium tartrate by mouse liver slices.

1. The uptake of (124)Sb-antimony potassium tartrate by isolated mouse liver slices has been measured and found to establish high tissue: medium concentration ratios.2. Uptake was not influenced by oxygen lack, potassium, ouabain, dinitrophenol or sodium arsenate. It was inhibited by dimercaprol and reduced at low temperature. No evidence was found of counter-transport. After subcellular fractionation, most of the radioactivity was recovered from particulate fractions.3. Kinetic studies of uptake from media containing different concentrations of antimony suggest that uptake is due partly to diffusion and partly to a saturable binding mechanism, probably involving chelation by non-diffusible thiol groups. Saturation studies suggest that only a small proportion of thiol groups bind antimony, the remainder undergoing catalytic oxidation.

Animals↗
PubMed1972

Pharmacokinetic and toxicological studies of antimony dextran glycoside (RL-712).

1. The absorption, tissue distribution and excretion of antimony dextran glycoside (RL-712) has been studied in normal rodents.2. Some organs in the body, especially liver and spleen, retain large amounts of antimony for considerable periods of time. Excretion of antimony in the urine was low and only about 10-12% of the dose administered was excreted within the first 48 hours.3. Blood levels were maintained for at least 3 days after a single intramuscular dose to rabbits, corresponding to 14 mg Sb/kg body weight.4. Toxicity studies and tests on foetal toxicity in mice and rats, respectively, showed no abnormalities.5. The possible value of RL-712 in the prophylaxis and treatment of leishmaniasis is discussed.

Abnormalities, Drug-Induced↗
PubMed2001

Antimonial-mediated DNA fragmentation in Leishmania infantum amastigotes.

The basic treatment of leishmaniasis consists in the administration of pentavalent antimonials. The mechanisms that contribute to pentavalent antimonial toxicity against the intracellular stage of the parasite (i.e., amastigote) are still unknown. In this study, the combined use of several techniques including DNA fragmentation assay and in situ and cytofluorometry terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling methods and YOPRO-1 staining allowed us to demonstrate that potassium antimonyl tartrate, an Sb(III)-containing drug, was able to induce cell death associated with DNA fragmentation in axenic amastigotes of Leishmania infantum at low concentrations (10 microg/ml). This observation was in close correlation with the toxicity of Sb(III) species against axenic amastigotes (50% inhibitory concentration of 4.75 microg/ml). Despite some similarities to apoptosis, nuclease activation was not a consequence of caspase-1, caspase-3, calpain, cysteine protease, or proteasome activation. Altogether, our results demonstrate that the antileishmanial toxicity of Sb(III) antimonials is associated with parasite oligonucleosomal DNA fragmentation, indicative of the occurrence of late events in the overall process of apoptosis. The elucidation of the biochemical pathways leading to cell death could allow the isolation of new therapeutic targets.

Animals↗
PubMed2006

Sodium antimony gluconate induces generation of reactive oxygen species and nitric oxide via phosphoinositide 3-kinase and mitogen-activated protein kinase activation in Leishmania donovani-infected macrophages.

Pentavalent antimony complexes, such as sodium stibogluconate and sodium antimony gluconate (SAG), are still the first choice for chemotherapy against various forms of leishmaniasis, including visceral leishmaniasis, or kala-azar. Although the requirement of a somewhat functional immune system for the antileishmanial action of antimony was reported previously, the cellular and molecular mechanism of action of SAG was not clear. Herein, we show that SAG induces extracellular signal-regulated kinase 1 (ERK-1) and ERK-2 phosphorylation through phosphoinositide 3-kinase (PI3K), protein kinase C, and Ras activation and p38 mitogen-activated protein kinase (MAPK) phosphorylation through PI3K and Akt activation. ERK-1 and ERK-2 activation results in an increase in the production of reactive oxygen species (ROS) 3 to 6 h after SAG treatment, while p38 MAPK activation and subsequent tumor necrosis factor alpha release result in the production of nitric oxide (NO) 24 h after SAG treatment. Thus, this study has provided the first evidence that SAG treatment induces activation of some important components of the intracellular signaling pathway, which results in an early wave of ROS-dependent parasite killing and a stronger late wave of NO-dependent parasite killing. This opens up the possibility of this metalloid chelate being used in the treatment of various diseases either alone or in combination with other drugs and vaccines.

Animals↗
PubMedDate not supplied

Nephrotoxicity attributed to meglumine antimoniate (Glucantime) in the treatment of generalized cutaneous leishmaniasis.

BACKGROUND: Pentavalent antimonials have became of basic importance for the treatment of leishmaniasis. Their most severe side effects have been reported to be increased hepatic enzyme levels and electrocardiographic abnormalities. Nephrotoxicity has been rarely related. OBSERVATIONS: We report a case of generalized cutaneous leishmaniasis involving a 50-year old male patient who was submitted to treatment with meglumine antimoniate (Glucantime). He developed acute renal failure (ARF) due to acute tubular necrosis (ATN), followed by death after receiving a total of 53 ampoules of Glucantime. CONCLUSIONS: The treatment with Glucantime was responsible by ARF diagnosed in this patient. The previous urine osmolarity and serum creatinine levels were normal and the autopsy showed ATN. It should be pointed out if ARF may also be explained by massive deposits of immunocomplexes by leishmania antibodies and antigens due to the antigenic break by the antimonial compound, since our patient presented countless lesions covering the entire tegument, similar to the Hexheimer phenomenon, but at the autopsy no glomerular alterations were seen.

Antiprotozoal Agents↗
PubMed2006

[Factors associated with treatment failure of cutaneous leishmaniasis with meglumine antimoniate].

We investigated factors associated with treatment failure in the treatment of cutaneous leishmaniasis with meglumine antimony in a reference service in Mato Grosso State. A retrospective cohort of 151 patients with cutaneous leishmaniasis was built using medical records. The incidence of therapeutic failure was 47% (IC95%=39.2%-55%). Antimoniate doses below 10 mg/kg/day (RR=1.8; IC95: 1.1-3.0), previous leishmaniasis treatment (RR=1.7; IC95: 1.3-2.4), 3 or more skin lesions (RR=1.9; IC95: 1.4-2.5), incomplete treatment (RR=1.9; IC95: 1.3-2.6) and body weight above 68 kg (RR=1.7; IC95: 1.1-2.5) were associated with therapeutic failure. After adjustment, therapeutic failure was associated with having 3 or more cutaneous lesions (OR=4.6; IC95%=1.2-17.4), reports of previous leishmaniasis treatment (OR=4.5; IC95%=1.1-17.5), body weight above 68 kg (OR=4.3; IC95=1.5-11.9) and incomplete treatment schedule (OR=12.5; IC95%=2.1-75.4), although body weight is possibly associated with treatment failure due to the limitation of the maximum daily dose. These results help to identify patients at risk of treatment failure of cutaneous leishmaniasis with antimony therapy.

Adolescent↗
PubMedDate not supplied

Successful therapeutic response of resistant cases of mucocutaneous leishmaniasis to a very low dose of antimony.

Two mucocutaneous leishmaniasis cases resistant to therapy are reported here. After the failure of initial therapies (antimony, amphotericin B and/or pentamidine) patients received a low-dose schedule: one ampoule of meglumine antimoniate (405 mg of pentavalent antimony [Sb v]) by intramuscular injection, three times a week until complete healing of the lesions. One patient was cured with a total of 30 ampoules in 10 weeks and the other received 36 ampoules in 12 weeks. Both remain clinically cured after one year of follow-up.

Adult↗
PubMed2003

High frequency of skin reactions in patients with leishmaniasis treated with meglumine antimoniate contaminated with heavy metals: a comparative approach using historical controls.

We analyzed data from historical controls treated with meglumine antimoniate to compare the frequency of adverse events observed in patients with cutaneous leishmaniasis treated with the same dose of meglumine antimoniate contaminated with heavy metals in an endemic area of the State of Bahia, Brazil. Group A patients were treated in 2000 with the drug produced by Eurofarma Laborat rios Ltda., S o Paulo, Brazil (lot A) and group B patients were treated in 1996 with the reference drug produced by Rhodia Farma Ltda., S o Paulo, Brazil (lot B). We observed an unusual higher frequency of skin reactions in group A patients. However, all type of adverse events observed in group A were also observed in group B. The physico-chemical analysis of these lots revealed that lot A had lower pH and higher concentration of total and trivalent antimony, lead, cadmium, and arsenic. Our findings suggest that the skin reactions could be attributed to heavy metal contamination of lot A.

Antiprotozoal Agents↗
PubMed1989

Gastric aspiration versus antimony and glass pH electrodes. A simultaneous comparative in vivo study.

To carry out a simultaneous comparison of the 24-h in vivo performance of antimony and glass electrodes and the findings of intermittent gastric aspiration, a triple-probe system with closely adjacent tips was positioned in the gastric corpus of 10 subjects representing different clinical and pharmacologic conditions. We showed that pH values measured with the antimony and the glass units were well correlated to those assessed in gastric aspirates (rs = 0.87; b = 1.079; a = -0.33; and rs = 0.85; b = 1.121; a = -0.38, respectively). A proportional correlation (rs = 0.86; b = 0.97; a = 0.02) was also found between the two intraluminal pH measurements. With regard to the error frequency distributions obtained by comparing the three measuring systems two at a time, the pH pairs differed by no more than 1 pH unit in most cases (greater than 90%). It can be concluded that antimony and glass pH electrodes can be used interchangeably in 24-h intragastric acidity studies in man.

Adolescent↗
PubMed2003

Dendritic cell-based immunotherapy combined with antimony-based chemotherapy cures established murine visceral leishmaniasis.

Dendritic cells (DCs) have been proposed to play a critical role as adjuvants in vaccination and immunotherapy. In this study we evaluated the combined effect of soluble Leishmania donovani Ag (SLDA)-pulsed syngeneic bone marrow-derived DC-based immunotherapy and antimony-based chemotherapy for the treatment of established murine visceral leishmaniasis. Three weekly injections of SLDA-pulsed DCs into L. donovani-infected mice reduced liver and splenic parasite burden significantly, but could not clear parasite load from these organs completely. Strikingly, the conventional antileishmanial chemotherapy (sodium antimony gluconate) along with injections of SLDA-pulsed DCs resulted in complete clearance of parasites from both these organs. Repetitive in vitro stimulation of splenocytes from uninfected or L. donovani-infected mice with SLDA-pulsed DCs led to the emergence of CD4(+) T cells with characteristics of Th1 cells. Our data indicate that DC-based immunotherapy enhances the in vivo antileishmanial potential of antimony or vice versa.

Adoptive Transfer↗