Immunotherapy versus chemotherapy in localised cutaneous leishmaniasis. Efficacy of a short course (10 days) of high-dose meglumine antimonate with or without interferon-gamma in treating cutaneous leishmaniasis in Guatemala. Immunotherapy of localized, intermediate, and diffuse forms of American cutaneous leishmaniasis. Placebo-controlled clinical trial of meglumine antimonate (glucantime) vs. localized controlled heat in the treatment of cutaneous leishmaniasis in Guatemala. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. Treatment of cutaneous leishmaniasis with a topical antileishmanial drug (WR279396): phase 2 pilot study. Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Evaluating the efficacy of allopurinol for the treatment of cutaneous leishmaniasis. American cutaneous leishmaniasis: a comparison of three sodium stibogluconate treatment schedules. Efficacy of sodium stibogluconate alone and in combination with allopurinol for treatment of mucocutaneous leishmaniasis. Comparison of meglumine antimoniate and pentamidine for peruvian cutaneous leishmaniasis. Aminosidine (paromomycin) versus sodium stibogluconate for the treatment of American cutaneous leishmaniasis. Allopurinol in the treatment of American cutaneous leishmaniasis. Treatment of cutaneous leishmaniasis with allopurinol and stibogluconate. Randomized, double-blind study of stibogluconate plus human granulocyte macrophage colony-stimulating factor versus stibogluconate alone in the treatment of cutaneous Leishmaniasis. Miltefosine for new world cutaneous leishmaniasis. Comparison of generic to branded pentavalent antimony for treatment of new world cutaneous leishmaniasis. Randomized, double-blind clinical trial of topical imiquimod 5% with parenteral meglumine antimoniate in the treatment of cutaneous leishmaniasis in Peru. Inefficacy of allopurinol as monotherapy for Colombian cutaneous leishmaniasis. A randomized, controlled trial. [Evaluation of the effectiveness and toxicity of pentostam and glucantime in the treatment of cutaneous leishmaniasis]. Treatment of American cutaneous leishmaniasis: a comparison between low dosage (5 mg/kg/day) and high dosage (20 mg/kg/day) antimony regimens. Heat therapy for cutaneous leishmaniasis elicits a systemic cytokine response similar to that of antimonial (Glucantime) therapy. Immunochemotherapy for cutaneous leishmaniasis: a controlled trial using killed Leishmania (Leishmania) amazonensis vaccine plus antimonial. Comparison of the effectiveness of two topical paromomycin treatments versus meglumine antimoniate for New World cutaneous leishmaniasis. Efficacy of 28-day and 40-day regimens of sodium stibogluconate (Pentostam) in the treatment of mucosal leishmaniasis. Randomized, controlled, double-blind trial of topical treatment of cutaneous leishmaniasis with paromomycin plus methylbenzethonium chloride ointment in Guatemala. Placebo controlled treatment of Ecuadorian cutaneous leishmaniasis. Non-ulcerative cutaneous leishmaniasis in Honduras fails to respond to topical paromomycin. Limited efficacy of injectable aminosidine as single-agent therapy for Colombian cutaneous leishmaniasis. Oral pentoxifylline combined with pentavalent antimony: a randomized trial for mucosal leishmaniasis. Antimony plus recombinant human granulocyte-macrophage colony-stimulating factor applied topically in low doses enhances healing of cutaneous Leishmaniasis ulcers: a randomized, double-blind, placebo-controlled study. Topical paromomycin/methylbenzethonium chloride plus parenteral meglumine antimonate as treatment for American cutaneous leishmaniasis: controlled study. Parenteral aminosidine is not effective for Peruvian mucocutaneous leishmaniasis.
In a randomised trial a combination vaccine consisting of live BCG together with killed leishmania promastigotes was compared with a standard antimonial regimen in 94 patients with localised cutaneous leishmaniasis. Three vaccinations over 32 weeks gave a similar cure rate (94%) to three 20-day courses of meglumine antimonate. In the immunotherapy group side-effects were few (5.8%) and slight whereas in the chemotherapy group they were frequent (52.4%) and often serious. Immunotherapy is a low-cost, low-risk alternative to chemotherapy in localised cutaneous leishmaniasis, applicable by primary health services in rural areas. Sixty-six Guatemalan men with parasitologically confirmed cutaneous leishmaniasis, due most commonly to Leishmania braziliensis, were randomly assigned to receive one of three treatment regimens: meglumine antimonate (meglumine) for 20 days; meglumine for 10 days; and meglumine for 10 days plus alternate-day injections of interferon-gamma. In each group, meglumine was given intravenously as 20 mg of antimony/(kg of body weight.d). All treatment regimens were associated with similar response rates: the lesions of 19 (90%) of 21 patients who received meglumine for 20 days, 18 (90%) of 20 patients who received meglumine for 10 days, and all 22 patients who received meglumine plus interferon-gamma were completely reepithelialized by 13 weeks. In addition, for patients receiving all treatment regimens, test-of-cure cultures for Leishmania were negative and reactivation of lesions did not occur during 12 months of follow-up. The high efficacy of our 10-day course of meglumine indicates that the currently recommended duration of 20 days may be unnecessary for infections caused by L. braziliensis and suggests that a 10-day course of high-dose antimony should be tested as therapy for cutaneous leishmaniasis in other geographic areas. The clinical efficacy of immunotherapy for localized American cutaneous leishmaniasis with a combination of heat-killed Leishmania mexicana amazonensis promastigotes and viable BCG (bacille Calmette Guérin) has been compared with meglumine antimoniate chemotherapy and with BCG alone in a controlled clinical study in 217 patients. The results in the first two groups were comparable, with greater than 90% clinical cures with an average time of 16-18 w required for healing. The cure rate was considerably lower (42%) and more prolonged in the group receiving BCG alone. Secondary effects were observed in less than 5% of the patients receiving combined immunotherapy or BCG alone. In contrast, 49% of the patients receiving chemotherapy showed side effects. High therapeutic efficacy was also observed using combined immunotherapy in patients with intermediate and diffuse cutaneous leishmaniasis who were previously unresponsive to chemotherapy. Cure or clinical improvement was seen in all 11 patients with intermediate forms of the disease, and marked clinical improvement was observed in 9 of 10 patients with diffuse disease. The results on the efficacy of the combined vaccine in immunotherapy for American cutaneous leishmaniasis provide a strong rationale for studying its effectiveness in prophylactic trials. Sixty-six Guatemalans with parasitologically proven cutaneous leishmaniasis were randomly and equally divided into 3 treatment groups: those receiving meglumine antimonate (Glucantime), 850 mg antimony/day im for 15 days; those receiving localized controlled heat from a radio-frequency generator, 50 degrees C for 30 sec, 3 treatments at 7 day intervals; and those receiving treatment with a placebo. Of 53 isolates identified, 40 were Leishmania braziliensis braziliensis and 13 were L. mexicana mexicana. Thirteen weeks after beginning treatment, the number of patients from each group with completely healed and parasitologically negative lesions were as follows: meglumine antimonate, 16 (73%); localized heat, 16 (73%); and placebo, 6 (27%). The cure rate for those with infections due to L. b. braziliensis in each group was as follows: meglumine antimonate, 11 out of 14 (79%); controlled heat, 9 out of 14 (64%); and placebo, 0 out of 11. To determine the relative efficacy and toxicity of stibogluconate and ketoconazole for the treatment of cutaneous leishmaniasis, a comparative trial was conducted in which 120 Guatemalan men with parasitologically proven cutaneous leishmaniasis were randomly divided into three treatment groups: sodium stibogluconate (20 mg of antimony per kilogram per day intravenously for 20 days), ketoconazole (600 mg per day orally for 28 days), and placebo. Treatment outcome was influenced by species. Among patients infected with Leishmania braziliensis, 24 (96%) of 25 in the stibogluconate group but only 7 (30%) of 23 in the ketoconazole group responded. Among Leishmania mexicana-infected patients, only 4 (57%) of 7 in the stibogluconate group but 8 (89%) of 9 in the ketoconazole group responded. These differences emphasize the importance of speciation in the treatment of leishmaniasis. We studied the efficacy of WR279396, a topical formulation of aminoglycosides that cures 100% of cutaneous leishmaniasis lesions in mice. We conducted what is to our knowledge the first controlled study of WR279396 therapy for clinical cutaneous leishmaniasis. A total of 45 Colombian soldiers, all men, were randomly assigned to treatment with WR279396 (33 patients) or placebo (12 patients). Each lesion was treated twice daily for 20 days. Lesions were measured at the end of therapy and at 45, 90, and 180 days after treatment began. A total of 17 (61%) of 28 assessable WR279396-treated patients were cured, and 5 (55%) of 9 assessable placebo-treated patients were cured (P = 0.9). For the 36 lesions treated with WR279396 that were cured, cure took a mean of 35 days, whereas for the 6 lesions that were cured in the group of patients receiving placebo, cure time took a mean of 56 days (P = 0.04). WR279396 is a nontoxic topical formulation that significantly accelerated cure time in patients with Leishmania panamensis cutaneous leishmaniasis. The classic agent for cutaneous leishmaniasis is pentavalent antimony. However, there are no reports of the efficacy of antimony versus placebo or of the efficacy of any alternative therapy versus either antimony or placebo. In the present report, the oral antifungal agent ketoconazole (600 mg/day for 28 days) was compared to a recommended regimen of intramuscular Pentostam (20 mg antimony/kg, with a maximum of 850 mg antimony/day, for 20 days) in a randomized study of the treatment of Panamanian cutaneous leishmaniasis due to Leishmania braziliensis panamensis. A separate group of patients with this disease was administered placebo.
                Ketoconazole clinically cured 16 of 21 (76%) patients. The lesions on nine patients healed by 1 month after therapy, and the lesions healed by 3 months after therapy on the other seven patients. Side effects were limited to a 27% incidence of mild, reversible hepatocellular enzyme elevation and an asymptomatic, reversible, approximately 70% decrease in serum testosterone in all patients. Pentostam cured 13 of 19 (68%) patients; the lesions on seven patients healed by the end of therapy, and the lesions on four other patients healed by 1 month after the end of therapy. Side effects were a 47% incidence of mild, reversible hepatocellular enzyme elevation and the morbidity due to 20 intramuscular injections in almost all patients. The placebo group of 11 patients had a 0% cure rate. By 1 month after therapy, all placebo-treated patients demonstrated new lesions or one lesion that was 23% to 875% larger than before therapy.
                Both ketoconazole and Pentostam were more effective than placebo against L. braziliensis panamensis cutaneous leishmaniasis. Oral ketoconazole is comparable in efficacy to this parenteral Pentostam regimen and can be recommended as initial treatment for this disease. nan Thirty-six patients with American cutaneous leishmaniasis were randomized to receive intravenous sodium stibogluconate for 10 days at a dose of 600 mg antimony (Sb) per day by one of three schedules: once daily by rapid infusion (A), by continuous 24 hr infusion (B), or in divided doses every eight hours by rapid infusion (C). Patients not cured after initial treatment were rerandomized to one of the other treatment schedules. An additional 19 patients who were not part of the randomized study received standard (STD) sodium stibogluconate treatment (600 mg Sb once daily by rapid infusion for 10 days, identical with schedule A). In the randomized study, the overall cure rate after the first course of treatment was 64%, but was higher for schedule A (100%) than for B (50%) or C (42%) (P less than 0.01). Considering all courses of treatment, schedule A was more effective (94%) than B (53%) or C (43%) (P less than 0.01). Paradoxically, patients in group A had a higher cure rate than patients in group STD (42% after the first course of treatment and 51% when all courses of treatment were considered). Side effects were mild and well tolerated. Total side effects were more frequent in groups B + C (52%) than A + STD (23%) due to an increased incidence of subjective complaints (26% vs. 10%, P less than 0.05) in patients receiving other than once daily rapid infusion. We conclude that giving the same total amount of sodium stibogluconate in three divided doses or by continuous infusion offers no advantage over standard, once daily treatment of American cutaneous leishmaniasis. A randomized, open, controlled clinical trial was designed to evaluate the efficacy, tolerance, and safety of sodium stibogluconate plus allopurinol and sodium stibogluconate alone as treatment of patients with mucocutaneous leishmaniasis. In phase 1 of the study, all 22 patients with severe disease had improvement of their lesions, but only two had clinical cure (both of these patients received sodium stibogluconate alone). In phase 2, which included 59 patients with moderate disease, the cure rate among sodium stibogluconate recipients was 75% (21 of 28) compared with 63.6% (14 of 22) among the sodium stibogluconate plus allopurinol recipients. The rates of clinical adverse events were similar among both groups. Thrombocytopenia was more frequent in the sodium stibogluconate plus allopurinol recipients, but the difference was not statistically significant. Eight patients (two sodium stibogluconate recipients and six sodium stibogluconate plus allopurinol recipients) withdrew from the study because of severe thrombocytopenia. In this study, the addition of allopurinol to sodium stibogluconate provided no clinical benefit as treatment of mucocutaneous leishmaniasis. Pentamidine was compared with meglumine antimoniate (Glucantime) for 80 patients with cutaneous leishmaniasis due to Leishmania braziliensis in Peru. Of the 40 patients administered Glucantime (20 mg of antimony [Sb]/kg/day intravenously for 20 days), 31 cured (78%), 6 failed (15%), of which 5 were due to relapse, and 3 were lost to follow-up (7%). Of the 40 patients administered pentamidine (2 mg/kg every other day for seven injections), 14 were cured (35%), 23 failed (58%), and 3 were lost to follow-up (7%). Five pentamidine failures were due to relapse, and 14 failures were due to the presence of parasites two weeks after therapy. Both regimens were well tolerated. Gastrointestinal, musculoskeletal, and total adverse events were not statistically different in either group. Elevations in levels of liver enzymes and pancreatic enzymes were statistically higher in the Glucantime group, but no patient terminated therapy prematurely. In this study, Glucantime was more effective than pentamidine for treatment of L. braziliensis cutaneous leishmaniasis in Peru based on parasitologic as well as clinical criteria. The efficacy of aminosidine was compared with sodium stibogluconate in an open, randomized study of parasitologically-proven cutaneous leishmaniasis in Belize. Aminosidine, 14 mg/kg/d (max. 1 g daily) for 20 d, healed 10 of 17 lesions and sodium stibogluconate, 20 mg/kg/d for 20 d, healed 15 of 17 lesions. Lesions caused by Leishmania braziliensis were relatively unresponsive to aminosidine. Aminosidine was well tolerated and toxicity was not observed. Sodium stibogluconate was not well tolerated and treatment was associated with bone marrow suppression and elevation of serum aminotransferases. Pentavalent antimony, the generally accepted treatment for leishmaniasis, is given parenterally, and it is expensive and not readily available in developing countries. An inexpensive, orally administered compound would be a substantial advance in treatment. Previous studies in vitro have shown synergism between allopurinol and pentavalent antimony in tissue-culture systems. We designed this clinical study to determine whether synergism could be demonstrated in patients.
                We performed a randomized, controlled study of the efficacy of allopurinol plus meglumine antimoniate (Glucantime), as compared with meglumine antimoniate alone, in patients with cutaneous leishmaniasis, who were recruited from a village in southeastern Colombia. In addition, those who declined injections were treated with allopurinol alone, and those who declined any treatment were considered controls. All the patients were followed for one year after the completion of treatment. Lesions that healed completely at three months and remained healed during follow-up were considered to be cured.
                The cure rate for patients treated with meglumine antimoniate was 36 percent; the addition of allopurinol increased the rate to 74 percent (P less than 0.001). Treatment with allopurinol alone yielded a cure rate of 80 percent (P less than 0.001). There were no cures among the untreated patients. There was no significant difference between the cure rate with allopurinol plus meglumine antimoniate and that with allopurinol alone. No major toxic effects were observed.
                For the treatment of American cutaneous leishmaniasis, the combination of allopurinol and meglumine antimoniate is significantly more effective than meglumine antimoniate alone, probably because of the efficacy of allopurinol alone, which appears to be as good as the combination. We conducted a randomized, controlled study in southern Colombia to determine if the addition of allopurinol to stibogluconate was superior to stibogluconate alone in the treatment of cutaneous leishmaniasis. Lesions that healed after a 3-month course of therapy and remained so during a 1-year period of follow-up were considered cured. The cure rate for patients treated with stibogluconate was 39%; the addition of allopurinol increased this rate to 71% (P = .005). For the treatment of cutaneous leishmaniasis, the combination of allopurinol and stibogluconate is significantly more effective than is stibogluconate alone. These results support those of other clinical studies in which allopurinol and stibogluconate were shown to be superior to stibogluconate alone. The aggregate data support the use of allopurinol as an inexpensive, orally administered agent that can be used as an adjunct to stibogluconate or, perhaps, other oral agents in the treatment of cutaneous leishmaniasis. The response to recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) in the treatment of cutaneous leishmaniasis was evaluated. Twenty patients with cutaneous leishmaniasis who had lesions for 60 days were enrolled in a double-blind placebo trial of GM-CSF with standard parenteral sodium stibogluconate (20 mg/kg-1/day-1) for 20 days. Ten patients were randomized to receive intralesionally injected GM-CSF (200 microgram) at enrollment and 1 week after, and 10 patients received saline as placebo. GM-CSF- and antimony-treated patients healed faster than patients who received antimony alone (49+/-32.8 vs. 110+/-61.6 days, P<.05). Seven of 10 patients were healed of their lesions before 40 days after therapy in the GM-CSF group, compared with only 1 of 10 patients in the placebo group (relative risk, 7; 95% confidence interval, 1.04-47.00). Thus, GM-CSF plus antimony significantly increased the chance of lesion healing in 40 days. The oral agent miltefosine has demonstrated a >95% cure rate in Indian visceral leishmaniasis. We performed a large, placebo-controlled study of miltefosine therapy (2.5 mg/kg per day orally for 28 days) against cutaneous leishmaniasis in Colombia and Guatemala. In regions in Colombia where Leishmania vianna panamensis is common, the per-protocol cure rates for miltefosine and placebo were 91% (40 of 44 patients) and 38% (9 of 24). These values are similar to historic values for the antimony standard of care and placebo. In regions in Guatemala where L. v. braziliensis and L. mexicana mexicana are common, the per-protocol cure rates were 53% (20 of 38) for miltefosine and 21% (4 of 19) for placebo. The miltefosine rate was lower than historic antimony cure rates of >90%. Miltefosine was well tolerated. Miltefosine is a useful oral agent against cutaneous leishmaniasis due to L. v. panamensis in Colombia but not against leishmaniasis due to L. v. braziliensis in Guatemala. The cost of generic pentavalent antimony (generic stibogluconate) is approximately one-sixth that of branded pentavalent antimony (stibogluconate in the form of Pentostam or meglumine antimoniate in the form of Glucantime. We compared generic stibogluconate to Pentostam and Glucantime for the treatment of cutaneous leishmaniasis patients in Bolivia and Colombia. For all 114 patients, the per-protocol cure rates were 83-91% and the intent-to-treat cure rates were 75-83%. The highest values were in the generic stibogluconate group. The incidence of pancreatic enzyme abnormalities was 48-88% and the incidence of liver enzyme abnormalities was 48-87%. The lowest incidences were in the generic stibogluconate group. The efficacy and tolerance of inexpensive generic stibogluconate appears comparable to branded formulations for the treatment of cutaneous leishmaniasis in these endemic regions. Current treatments for cutaneous leishmaniasis are limited by their toxicity, high cost, and discomfort and the emergence of drug resistance. New approaches, including combination therapies, are urgently needed. We performed a double-blind, randomized trial of therapy with parenteral antimony plus topical imiquimod, an innate immune-response modulator, versus therapy with antimony alone, in subjects with cutaneous leishmaniasis for whom an initial course of antimony therapy had failed.
                Forty subjects with clinical resistance to antimony were recruited in Lima, Peru, between February 2001 and December 2002. All subjects received meglumine antimoniate (20 mg/kg/day im or iv) and were randomized to receive either topical imiquimod 5% cream (Aldara; 3M Pharmaceuticals) or vehicle control every other day for 20 days. Lesions and adverse events were evaluated during treatment and at 1, 2, 3, 6, and 12 months after the treatment period.
                The mean number of lesions was 1.2 per person; 71% of the lesions were facial and 76% were ulcerative. There were no major differences between the groups, and all but 2 subjects completed therapy. Mild adverse events were reported by 73% of the subjects, but only erythema occurred more commonly in the imiquimod group (P < or = .02). Lesions resolved more rapidly in the imiquimod group: 50% of the imiquimod group achieved cure at 1 month after the treatment period versus 15% of the vehicle cream group (P < or = .02); 61% of the imiquimod group at 2 months versus 25% of the vehicle cream group (P < or = .03); and 72% of the imiquimod group at 3 months versus 35% of the vehicle cream group (P < or = .02). Residual scarring in the imiquimod group was less prominent than in the vehicle cream group.
                Combined antimony plus imiquimod treatment was well tolerated, accelerated healing of lesions, and improved scar quality. This therapy may have particular advantages for subjects with facial lesions. Hundreds of thousands of cases of cutaneous leishmaniasis occur each year worldwide. Available therapies are parenteral, moderately toxic, and costly.
                To determine the efficacy of and tolerance for oral allopurinol as monotherapy for cutaneous leishmaniasis.
                Randomized, controlled trial.
                Outpatient clinics in 11 regions of Colombia in which cutaneous leishmaniasis is endemic.
                187 otherwise healthy adults with cutaneous leishmaniasis. Eighty-four percent of patients were infected with or were from regions with Leishmania panamensis; 16% were infected or were from regions with L. braziliensis.
                Patients were randomly assigned to one of three treatment groups. The first group received allopurinol, three 100-mg tablets four times daily (20 mg/kg of body weight per day) for 28 days. The second group received three placebo tablets four times daily for 28 days. The third group received Glucantime, 20 mg of intramuscular antimony/kg per day for 20 days.
                Complete cure was defined as complete clinical reepithelialization of all lesions at 3 months and no relapse during 12 months of follow-up.
                Of 182 patients whose data could be analyzed, 157 (86%) were evaluated. In the allopurinol group, 18 of 55 (33% [95% CI, 21% to 47%]) patients were cured; in the placebo group, 17 of 46 patients (37% [CI, 23% to 52%]) were cured (difference, 4% [CI, -14% to 22%]; P = 0.68); and in the Glucantime group, 52 of 56 patients (93% [CI, 83% to 98%]) were cured (P < 0.001 compared with the allopurinol and placebo groups combined). In most cases, therapy was considered to have failed because the lesion did not reepithelialize by 1.5 months after the end of therapy. Three cases of relapse (two in the allopurinol group and one in the placebo group) at the nasal mucosa (mucosal leishmaniasis) had occurred by the end of 12 months of follow-up.
                Allopurinol monotherapy has no effect on Colombian cutaneous disease primarily caused by L. panamensis and therefore is unlikely to be effective against cutaneous leishmaniasis in other endemic regions. nan Twenty-three patients from Rio de Janeiro, Brazil-an area of Leishmania (Viannia) braziliensis transmission-were randomly assigned to receive either a high dose (20 mg/kg/day) of antimony or a lower one (5 mg/kg/day) in a 30 days series. The two treatment regimens showed similar responses. In 10 out of 12 patients receiving a dose of 5 mg/kg/day and 9 out of 11 patients with a dosage of 20 mg/kg/day a complete epithelization was noted by the end of treatment. In addition patients were followed for up to 7 years. No reactivation or development of mucosal lesions were observed in both groups during the extensive follow-up. We think that a low dosage of antimony could be equally effective than a higher one, at least in the presence of the clinical picture usually seen in Rio de Janeiro. Controlled heat delivered as radio waves has been used successfully in the treatment of cutaneous leishmaniasis (CL). Here we investigated whether local heat therapy has systemic effects, as measured by the modulation of cytokine production following heat therapy of CL lesions compared with antimonial (Glucantime) treatment. Patients with CL were randomly assigned into this study. Heat (50 degrees C for 30s) was applied once. The control group received Glucantime therapy for 20 d. Cytokine production by peripheral blood mononuclear cells was assayed on days 0, 14 and 28 after onset of treatment. At the end of 28 d, 75% of lesions were healing or healed in the heat therapy group and 90% in the control group (P=0.1261). There was a decrease in IFN-gamma, IL-5 and TNF-alpha levels comparing day 0 with day 28 in both groups, but no difference between the two therapy groups. In patients with only one of several lesions treated with heat therapy, the untreated lesions also healed. Local heat therapy in CL lesions leads to systemic cytokine responses similar to that induced by systemic Glucantime therapy. Leishmaniasis is endemic in 88 countries in the world, and 350 million individuals are at risk of acquiring the disease. Treatment for American cutaneous leishmaniasis (ACL) is long, expensive, and associated with important side-effects.
                In this double-blind, placebo-controlled study, we treated 102 patients with ACL using either a combination of a single-strain Leishmania amazonensis killed promastigote vaccine plus a half dose of meglumine antimoniate, or placebo plus the same half dose regimen of meglumine antimoniate, in 10-day series followed by 10-day intervals.
                Of the 47 patients in the experimental arm, 47 (100%) were cured after four series of treatment, compared to four of 49 (8.2%) in the control group (P < 0.0001). Six patients were lost to follow-up.
                The combination of a single-strain Leishmania (Leishmania) amazonensis killed promastigote vaccine with a half dose regimen of antimonial is highly effective for the treatment of ACL. The randomized, controlled study compared the therapeutic efficacy and safety of two paromomycin-containing topical preparations with the gold treatment standard, meglumine antimoniate, and with each other in 120 Ecuadorian patients with ulcerated lesions. The two paromomycin treatment comparisons were double-blinded. Group 1 (n = 14) received 15% paromomycin plus 12% methylbenzonium chloride (PR-MBCL) dissolved in a soft white paraffin base, applied twice daily for 30 days. Group 2 (n = 40) was also treated for 30 days with 15% paromomycin plus 10% urea (PR-U) dissolved in the same paraffin base. Group 3 (n = 40) received 20mg/kg/day of IM meglumine antimoniate (MA) for 10 days as per Ecuadorian Ministry of Public Health recommendations at the time of the study. The 10-day treatment was completed by 90% of the MA group compared to 72.5% of the PR-MBCL (X2 = 4.0, P = 0.045) and 75% of the PM-U (X2 = 3.1, P > 0.05) groups whose treatment regime lasted 20 days longer than the MA treatment. Post-treatment lesion burning, redness, inflammation, and soreness were more common in the two paromomycin groups compared to MA group (P < 0.05). The frequency of treatment-related side effects in the two paromomycin groups was similar. Six weeks after the start of treatment, 80.6% of MA subjects were clinically cured compared to 48.3% in the PR-MBCL (X2 = 6.1, P = 0.014) and 40% in the PM-U groups (X2 = 12.6, P = 0.002). By 12 weeks, the proportion of clinically cured subjects in the MA (91.7%) compared to PM-MBCL (79.3%) or PM-U (70%) groups was not significantly different (P > 0.05). MA-treated subjects clinically cured by 12 weeks had a faster mean healing time (29.5 +/- 12.2 days) compared to those in the PM-MBCL (versus 43.1 +/- 14.4 days, t = -3.7, P = 0.001) or PR-U groups (43.5 +/- 17 days; t = -3.2, P = 0.002). During the 48-week post-treatment follow-up period, infection reactivation was observed in 15.2% of the MA subjects compared to 17.4% in the PM-MBCL and 10.5% PM-U of subjects diagnosed as clinically healed by 12 weeks (P > 0.05). The results suggest that although the time required for the clinical healing of ulcerated lesions takes longer, topical paromomycin may be an acceptable therapeutic alternative in endemic areas where meglumine antimoniate is not available, is too costly or medically contraindicated. The efficacy and toxicity of two regimens of antimony, 28 and 40 days of 20 mg of antimony/kg/day, were compared in the treatment of culture-positive mucosal leishmaniasis involving more than one anatomic site. Forty consecutive eligible Peruvians with infiltrative or ulcerative mucosal disease of the lips, nose, palate-uvula-pharynx, or larynx-epiglottis were randomized to receive either 28 days (P28) or 40 days (P40) of sodium stibogluconate (Pentostam). Treatment was prematurely terminated due to thrombocytopenia in three patients and two patients did not complete six months of follow-up. At one month post-treatment, 13% (2 of 16) of the P28 patients and 16% (3 of 19) of the P40 patients no longer had infiltrates or ulcers and were initially considered cured. During a further 11 months of follow-up, infiltrated lesions healed in eight more P28 patients and in 10 more P40 patients. The cure rate after 12 months of follow-up was therefore 63% for both groups (10 of 16 in the P28 group and 12 of 19 in the P40 group). The total of 13 patients who had infiltrates or ulcers at the 9-12-month follow-up were considered failures. All seven patients (three in the P28 group and four in the P40 group) whose lesions were culture-positive for Leishmania at some point in the 12 months after treatment, and who were thereby parasitologic failures, were also clinical failures.(ABSTRACT TRUNCATED AT 250 WORDS) A double-blind, randomized trial was undertaken in Guatemala to determine the therapeutic efficacy of an ointment for the treatment of cutaneous leishmaniasis that contained 15% paromomycin and 12% methylbenzethonium chloride and that was applied twice a day for 20 days. The treatment group included 35 patients, and the placebo group included 33 patients. The initial clinical response rate (13 weeks after completing the treatment) was 91.4% in the treatment group and 39.4% in the placebo group. The final clinical response rate at the 12-month follow-up examination was 85.7% (31 of 35) in the treatment group and 39.4% (13 of 33) in the placebo group (P < or = 0.001). In general, the treatment was well tolerated and was never interrupted because of adverse effects. The number of adverse effects reported in the placebo group was lower than in the treatment group (16 events versus 30 events). All adverse effects reported by patients disappeared within 1 week of completing the treatment. Our findings show that the combination of paromomycin with methylbenzethonium chloride for 20 days is a good alternative for antimonial treatments of cutaneous leishmaniasis in Guatemala. Pentavalent antimony has been considered to be the standard treatment for leishmaniasis, but more recently, the orally administrable agent allopurinol ribonucleoside has been the subject of several clinical trials. In this study, these two agents were evaluated in patients with Ecuadorian cutaneous leishmaniasis. Patients were randomly assigned to the two treatment groups. The mean reduction in lesion size for the 28 patients treated with Pentostam (20 mg Sb/kg/day intramuscularly for 20 days) was 61%, 23%, and 11% after one, two, and three weeks, respectively. There was a wide range in the individual values, and some lesions markedly enlarged in the first week of therapy. An initially healed lesion was defined as one that had greater than 80% re-epithelialized by the 1.5-month post-treatment followup. All Pentostam patients demonstrated this degree of lesion resolution (100% initial healing rate), but one patient showed evidence of relapse at the three month followup resulting in a 96% complete healing rate for the 12 month observation period. Patients in the untreated control group demonstrated a strikingly high rate of healing with 9 of 12 patients having re-epithelialized all lesions after 1.5 months observation (75% initial healing rate). The mean reduction in lesion size for the untreated patients was 56%, 29%, and 25% after one, two, and three weeks, respectively. Twenty-one patients received allopurinol ribonucleoside (1,500 mg QID) plus probenecid (500 mg QID) for 28 days. Lesions in nine of these patients were healed at the time of the 1.5 month followup (41% healing rate).(ABSTRACT TRUNCATED AT 250 WORDS) A double-'blind', placebo-controlled trial of topical therapy with 15% paromomycin (aminosidine) and 10% urea in white paraffin was carried out on 53 patients with non-ulcerating cutaneous leishmaniasis in Honduras. Although the treatment was not effective, several unexpected findings emerged from the trial. Leishmania mexicana was found to be the cause of many of the skin lesions in one of the 2 study sites. These lesions were clinically indistinguishable from those caused by L. chagasi, the aetiologic agent previously found for this form of leishmaniasis. This is the first documented report of L. mexicana in Honduras. Ninety military patients with cutaneous leishmaniasis in Colombia were randomly allocated to 3 treatment regimens of parenteral aminosidine sulphate: (i) 12 mg aminosidine base/kg/d for 7 d, (ii) 12 mg/kg/d for 14 d, and (iii) 18 mg/kg/d for 14 d. With the 89 evaluable patients, the cure rates 12 months after the end of treatment were 10%, 45%, and 50%, respectively. Fifty-eight of the 66 patients who were not cured had lesions that enlarged or were unchanged by 1.5 months after treatment follow up. The other 8 patients had lesions that relapsed between 3 and 12 months after therapy. Even in group (iii) the cure rate was inferior to that (> 90%) with antimony or pentamidine previously reported in this patient population. This study indicates that parenteral aminosidine alone is less likely to be successful in the treatment of cutaneous lesihmaniasis than visceral leishmaniasis, for which a 74% cure rate has been reported. Further trials might consider the combination of aminosidine with other antileishmanial drugs. Mucosal leishmaniasis is associated with intense tissue damage and high tumor necrosis factor-alpha production. Therapeutic failure occurs in up to 42% of cases; patients who experience treatment failure will require >1 pentavalent antimony (Sb(v)) course or alternative drugs to achieve a cure. We previously showed that an inhibitor of tumor necrosis factor-alpha (pentoxifylline) combined with Sb(v) cured 90% patients refractory to monotherapy with Sb(v).
                A double-blind, placebo-controlled trial involving 23 patients with mucosal leishmaniasis evaluated the efficacy of pentoxifylline when administered in association with Sb(v), compared with Sb(v) treatment alone. Eleven patients were randomized to receive Sb(v) plus oral pentoxifylline for 30 days, and 12 patients received Sb(v) plus oral placebo. The criterion for cure was a complete healing of lesions.
                All patients in the pentoxifylline group experienced a cure with 1 course of Sb(v), whereas 5 (41.6%) of 12 patients in the placebo group required a second course of Sb(v) (P=.037). The healing time +/- standard deviation in the pentoxifylline group was 83+/-36 days, compared with 145+/-99 days in the placebo group (P=.049). No relapses were documented in either group at the 2-year follow-up visit.
                The addition of pentoxifylline to Sb(v) in mucosal leishmaniasis reduces the healing time significantly and prevents the need for further courses of Sb(v). Cutaneous leishmaniasis (CL) requires 2-6 months to heal. In an effort to reduce this healing time, we studied topically applied granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to antimonial therapy. Ten patients received antimony plus topical GM-CSF, and 10 patients received antimony plus placebo (saline). GM-CSF was diluted for topical use and was applied 3 times weekly for 3 weeks (1-2 microg/cm2/lesion). The mean +/- SD healing time was 43 +/- 14 days in the GM-CSF group and was 104+/-79 days in the placebo group (P=.043). Ten (100%) of 10 patients in the GM-CSF group healed within 60 days, compared with 5 (50%) of 10 patients in the placebo group. Two of the patients in the placebo group required retreatment with antimony. In conclusion, topically applied GM-CSF is effective in the management of CL. We determined the efficacy of the combination of the topical formulation 15% paromomycin sulfate/12% methylbenzethonium chloride (MBCL) and a short course (7 days) of parenteral meglumine antimonate (pentavalent antimony [Sb]) as treatment of American cutaneous leishmaniasis in Colombian patients. Patients were randomly assigned in unequal allocation (2:1:1:1) to group 1 (topical paromomycin/MBCL plus injectable Sb for 7 days), group 2 (topical placebo plus injectable Sb for 7 days), group 3 (topical paromomycin/MBCL plus injectable Sb for 3 days), and group 4 (injectable Sb for 20 days). Cure was defined as complete reepithelialization of all lesions without relapse. Cure rates among groups were as follows: 58% (34 of 59), group 1; 53% (16 of 30), group 2; 20% (6 of 30), group 3; and 84% (26 of 31), group 4. Seventy-one percent of the organisms identified to the species level were Leishmania braziliensis panamensis. We conclude that 10 days of therapy with paromomycin/MBCL does not augment the response of cutaneous leishmaniasis (predominately due to L. braziliensis panamensis) to a short course of treatment with meglumine antimonate. Few therapeutic options are available for mucocutaneous leishmaniasis (MCL). We conducted a randomized open trial to evaluate the efficacy, safety, and tolerance of parenteral aminosidine sulphate (AS) 14 mg/kg/d for 21 days compared with intravenous meglumine antimonate (MA) 20 mg/kg/d for 28 days in patients with moderate MCL in Cuzco, Peru. Cure was defined as complete healing with re-epithelialization within 1 year of follow-up. The trial was stopped after 38 patients were enrolled (17 in the MA group and 21 in the AS group) because of marked differences in response. Study groups were comparable in baseline characteristics. Cure rates were 0/21 in the AS group compared with 8/17 (47%, 95% confidence interval: 23-71%) in the MA group (P < 0.001). Side effects and laboratory abnormalities were mild in both groups. We conclude that parenteral AS given on its own is not effective for MCL in Peru.
Most trials have been designed and reported so poorly that they are inconclusive. There is a need for large well conducted studies that evaluate long-term effects of current therapies to improve quality and standardization of methods.