The preparation and study of some thiazole derivatives of antimony.
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Patients suffering from American cutaneous leishmaniasis were studied before therapy (active lesion) and at the end of therapy (cured patients). Assays of lymphocyte proliferative responses of peripheral blood mononuclear cells induced in vitro by Leishmania braziliensis promastigote antigens (Lb) or by three proteins (A-2/P-2, P-4, and P-8) derived from Leishmania pifanoi amastigotes were performed. Antigen-stimulated cells were harvested for CD4 and CD8 phenotype analysis and the levels of gamma interferon (IFN-gamma), interleukin 2 (IL-2) and interleukin 4 (IL-4) produced were also determined. Results show two different patterns of Lb-induced T cell responses: (a) predominance of responding CD4+ cells and mixed type 1 and type 2 cytokine production (IFN-gamma, IL-2, and IL-4) during the active disease, (b) similar proportions of responding CD4+ and CD8+ cells and type 1 cytokine production (presence of IFN-gamma and IL-2 and very low IL-4) at the end of therapy (healed lesions). Thus, this last pattern is probably associated with a beneficial T cell response. The A-2/P-2 amastigote cysteine proteinase provided only marginal (s.i. approximately or = 2.5) T cell stimulation in 25% of patients studied; in contrast, the L. pifanoi P-4 and P-8 amastigote antigens induced significant stimulation (s.i. approximately or = 5) in approximately 50% of the patients. In comparison to Lb-stimulated cultures, lower proliferative responses of T lymphocytes to P-4 or P-8 were observed. However, the P-4- or P-8-stimulated cultures had similar percentages of reactive CD4+ and CD8+ cells, as well as type 1 cytokines (presence of IFN-gamma and IL-2, and low levels or absence of IL-4) in the supernatants both before and at the end of therapy. The consistent induction of apparently beneficial T cell responses by the P-4 and P-8 amastigote glycoproteins points to the possibility that these molecules be considered as candidates for future defined vaccines against leishmaniasis.
Flow cytometry (FC), combined with propidium iodide as supravital colorant, was used to study Leishmania(subgenus Viannia)panamensis [L (V) panamensis] complex strain susceptibility to meglumine antimoniate, sodium stibogluconate and pentamidine. Despite all drugs examined being leishmanicidal to axenic forms in in vitro trials (in the presence of macrophages), axenic amastigotes directly exposed to these drugs were highly resistant under our experimental conditions. A direct lethal effect on promastigotes, detectable by FC, was only obtained with pentamidine after in vitro treatment of both promastigotes and axenic amastigotes with the drugs. Pentamidine's rapid lethal effect, as detected by FC, could be further confirmed in short- and long-term parasite cultures after exposure to a drug. FC's suitability for measuring L (V) panamensis complex's promastigote susceptibility to pentamidine, shortly after in vitro drug exposure, might be useful in monitoring clinical trials with this drug and facilitating rapid pentamidine-resistant natural isolate identification.
Data on the efficacy and safety of pentavalent antimony in the treatment of visceral leishmaniasis during pregnancy are scanty. A case of visceral leishmaniasis in a 39-year-old woman in the second trimester of pregnancy is reported here. The patient was hospitalized in poor condition with high fever and pancytopenia which had lasted for 6 weeks. A bone marrow aspirate revealed numerous amastigotes and serodiagnosis for Leishmania was positive at a high titer. The patient was successfully treated with meglumine antimoniate at a daily dose of 850 mg of antimony for 20 days. She delivered at term a healthy female baby who remains in good condition at 18 months of age. Thus a dose of 850 mg of antimony, which is lower than that presently recommended, seems to be effective and non toxic to the fetus when administered at the second trimester of pregnancy.
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A prospective descriptive study was designed to determine the impact of highly active antiretroviral therapy (HAART) in the evolution of visceral leishmaniasis (VL) in HIV-1 infected patients. Thirty-two patients were treated with meglumine antimoniate or amphotericin B in lipid formulations. Patients who had undergone previous HAART at study entry (n=17) continued with therapy while receiving treatment for VL. Patients who had never undergone HAART started it after VL treatment finished (n=15). Ten patients were lost to follow-up. All of the remaining patients (n=20) continued to receive HAART and were followed for an average of 441 days. Relapses were observed in 5 of 20 patients. These results indicate that HAART neither prevents the incidence of VL relapse nor modifies the clinical picture described in the pre-HAART era.
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Standard anti-leishmanial drugs were tested for their ability to inhibit the growth of intracellular amastigotes of Leishmania aethiopica, L. donovani and L. infantum in the human leukemia monocyte THP-1 cell line. Sodium stibogluconate and meglumine antimoniate were active against L. donovani with ED50 values of 8.9 micrograms SbV/ml and 2.9 micrograms SbV/ml, respectively. L. aethiopica was less sensitive to sodium stibogluconate with an ED50 value of 25.3 micrograms SbV/ml while pentamidine had an ED50 value of 0.6 microM. Both L. donovani (ED50, 9.3 microM), and L. aethiopica (ED50, 6.4 microM), were sensitive to aminosidine sulphate. An L. infantum isolate, clinically resistant to meglumine antimoniate treatment, had an ED50 of 22.2 micrograms SbV/ml. The toxic level of drugs on host cells was determined by colorimetric Methyl Tetrazolium (MTT) assay prior to activity tests. The results obtained with the THP-1 in vitro drug screening model were similar to those obtained in the mouse peritoneal macrophage model.
Relapse after chemotherapy using the pentavalent antimonials, sodium stibogluconate and meglumine antimoniate, was assessed in 135 patients diagnosed in the Aba Roba focus of south western Ethiopia during the period 1982-1991. Ten cases relapsed with a mean of 15.6 +/- 16.3 months following treatment. A 15-day course of 10 mg Sbv/kg b.wt. sodium stibogluconate used in 1982/1983 had a better outcome than a 15-day course of 17 mg Sbv/kg b.wt. of meglumine antimoniate used in 1990/1991. The relapse rate among patients treated with sodium stibogluconate 16-20 mg Sbv/kg b.wt. for 20 days in 1985-1990 was comparable to the relapse rate in patients treated with meglumine antimoniate 16-20 mg Sbv/kg b.wt. for 20 days in 1990/1991. Findings are discussed.
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We report a typical case of an oriental sore (cutaneous leishmaniasis) in a 28-year-old patient. The lesion was located on the upper lip, causing macrocheilia and an esthetic problem to the patient, who required urgent treatment. N-Methylglucamine antimonate proved to be an effective, well-tolerated drug.
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One of the more serious clinical forms of leishmaniasis occurs in espundia when the mucosae of the upper respiratory passages are inflamed. This complication is a metastasis from a skin lesion caused by Leishmania braziliensis braziliensis (Lbb) although cases have been described associated with other leishmanial species. Epidemiological data suggest that a detectable mucosal metastasis occurs in fewer than 5% of patients infected with Lbb in our study area. The determinants of this complication are still largely obscure. The granuloma usually commences on the nasal septum. In about two-thirds of our patients the lesion remained restricted to the nose. In the rest the pharynx, palate, larynx and lips were involved, in this order. It is often difficult to isolate the parasite and for routine diagnosis the leishmanin skin reaction and serological tests are helpful. Although a serious condition, with possible mutilation and even death as subsequent complications, treatment is still mainly with pentavalent antimonials, introduced 40 years ago. These are most unsatisfactory for field use, being given parenterally and relatively toxic. In mucosal leishmaniasis, if sufficient antimony can be administered in a regular daily dose, the relapse rate is small (3 of 42 patients followed for a mean of 5 years). Also, antimony treatment of the initial skin ulcer due to Lbb followed for a mean of 4 years of 83 patients resulted in subsequent mucosal metastasis in only 2. Since espundia is relatively rare, specific treatment targeted to this specific problem is the efficient short term solution. At present there is no satisfactory alternative drug to those in current use.