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1.
Am J Trop Med Hyg ; 106(3): 857-860, 2022 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-35008061

RESUMO

Cutaneous leishmaniasis (CL) frequently entails chronic skin lesions that heal only slowly. Until now, the available therapeutic options are very limited. Here, we present a case of a 5½-year-old Syrian refugee with two progressive lower-leg skin ulcers caused by Leishmania tropica. The patient received topical treatment with LeiProtect®, a newly developed, hydroxypropylcellulose-based, filmogenic gel containing nontoxic concentrations of pharmaceutical sodium chlorite. The skin lesions completely healed within 8 weeks and did not relapse during 1 year of follow-up, underlining the efficacy of this novel local therapy of CL.


Assuntos
Leishmania tropica , Leishmaniose Cutânea , Criança , Cloretos , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Pessoa de Meia-Idade , Preparações Farmacêuticas , Síria
2.
Cell Rep Med ; 1(9): 100163, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33377134

RESUMO

Combination immunotherapy with antibodies directed against PD-1 and CTLA-4 shows improved clinical benefit across cancer indications compared to single agents, albeit with increased toxicity. Leveraging the observation that PD-1 and CTLA-4 are co-expressed by tumor-infiltrating lymphocytes, an investigational PD-1 x CTLA-4 bispecific DART molecule, MGD019, is engineered to maximize checkpoint blockade in the tumor microenvironment via enhanced CTLA-4 blockade in a PD-1-binding-dependent manner. In vitro, MGD019 mediates the combinatorial blockade of PD-1 and CTLA-4, confirming dual inhibition via a single molecule. MGD019 is well tolerated in non-human primates, with evidence of both PD-1 and CTLA-4 blockade, including increases in Ki67+CD8 and ICOS+CD4 T cells, respectively. In the ongoing MGD019 first-in-human study enrolling patients with advanced solid tumors (NCT03761017), an analysis undertaken following the dose escalation phase revealed acceptable safety, pharmacodynamic evidence of combinatorial blockade, and objective responses in multiple tumor types typically unresponsive to checkpoint inhibitor therapy.


Assuntos
Anticorpos/uso terapêutico , Antígeno CTLA-4/imunologia , Imunoterapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/efeitos dos fármacos , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Receptor de Morte Celular Programada 1/imunologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
3.
BMC Infect Dis ; 19(1): 1005, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779597

RESUMO

BACKGROUND: Lupoid cutaneous leishmaniasis (LCL) is known as a rare but serious complication of anthroponotic cutaneous leishmaniasis (ACL) resistant to conventional treatments. Sodium chlorosum, a pro-oxidative preparation of pharmaceutical sodium chlorite (NaClO2), has been successfully used for the treatment of Old World cutaneous leishmaniasis lesions (OWCL) and of some LCL cases in Afghanistan. This clinical trial study aimed to evaluate the effect of a last resort therapy with topical 0.09% sodium chlorosum on LCL in Iran. METHODS: Twenty Iranian patients (12 women and 8 men) with LCL refractory to treatment were included in this salvage study. A magistral preparation of sodium chlorosum (10 mM NaClO2 in amphiphilic basic cream) was applied twice daily to the lesions for 6 weeks and continued up to 12 weeks in patients who showed a clinical response within the first 6 weeks. Responders were followed up for a maximum of 1 year. Lesions were photographed during weekly visits. Disappearance of erythema and indurated lesions were rated as complete clinical response. RESULTS: Patients with a mean age of 28.6 (±24.3) and with an ACL proven lesion history of 3.8 (±1.4) years were treated for an average of 7.9 (±1.8) weeks. At the end of the treatment period (12th week), a complete response was observed in 9 of 20 patients (45%). During the one-year follow-up period, LCL lesions recurred in 4 of these 9 patients (with one patient showing only a tiny lesion) and one case lost to follow up whereas the other four remained completely lesion-free. Mild temporary side-effects such as erythema and itching were seen in 4 of 20 patients (20%). CONCLUSIONS: Topical sodium chlorosum showed promising therapeutic results and can be considered as safe, painless, and relatively effective treatment for LCL, an ethical prerequisite for a two-armed controlled trial. TRIAL REGISTRATION: This study was registered in Iranian registry of clinical trials on 2019-02-02 with registration number IRCT20190114042356N1.


Assuntos
Cloretos/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Administração Tópica , Adolescente , Adulto , Criança , Pré-Escolar , Cloretos/efeitos adversos , Resistência a Medicamentos , Eritema/etiologia , Feminino , Humanos , Irã (Geográfico) , Leishmaniose Cutânea/terapia , Masculino , Pessoa de Meia-Idade , Terapia de Salvação , Creme para a Pele/efeitos adversos , Creme para a Pele/química , Creme para a Pele/uso terapêutico , Resultado do Tratamento , Adulto Jovem
4.
Infect Dis Poverty ; 7(1): 12, 2018 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-29444705

RESUMO

BACKGROUND: The present health economic evaluation in Afghanistan aims to support public health decision makers and health care managers to allocate resources efficiently to appropriate treatments for cutaneous leishmaniasis (CL) elicited by Leishmania tropica or Leishmania major. METHODS: A decision tree was used to analyse the cost and the effectiveness of two wound care regimens versus intra-lesional antimony in CL patients in Afghanistan. Costs were collected from a societal perspective. Effectiveness was measured in wound free days. The incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (NMB) were calculated. The model was parameterized with baseline parameters, sensitivity ranges, and parameter distributions. Finally, the model was simulated and results were evaluated with deterministic and probability sensitivity analyses. Final outcomes were the efficiency of the regimens and a budget impact analysis in the context of Afghanistan. RESULTS: Average costs per patients were US$ 11 (SE = 0.016) (Group I: Intra-dermal Sodium Stibogluconate [IL SSG]), US$ 16 (SE = 7.58) (Group II: Electro-thermo-debridement [ETD] + Moist wound treatment [MWT]) and US$ 25 (SE = 0.48) (Group III: MWT) in patients with a single chronic CL ulcer. From a societal perspective the budget impact analysis shows that the regimens' drug costs are lower than indirect disease cost. Average effectiveness in wound free days are 177 (SE = 0.36) in Group II, 147 (SE = 0.33) in Group III, and 129 (SE = 0.27) in Group I. The ICER of Group II versus Group I was US$ 0.09 and Group III versus Group I US$ 0.77, which is very cost-effective with a willingness-to-pay threshold of US$ 2 per wound free day. Within a Monte-Carlo probabilistic sensitivity analysis Group II was cost-effective in 80% of the cases starting at a willingness-to-pay of 80 cent per wound free day. CONCLUSIONS: Group II provided the most cost-effective treatment. The non-treatment alternative is not an option in the management of chronic CL ulcers. MWT of Group III should at least be practiced. The cost-effectiveness of Group III depends on the number of dressings necessary until complete wound closure.


Assuntos
Análise Custo-Benefício , Leishmaniose Cutânea , Modelos Estatísticos , Cicatrização , Afeganistão/epidemiologia , Gluconato de Antimônio e Sódio/economia , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/economia , Antiprotozoários/uso terapêutico , Desbridamento/economia , Árvores de Decisões , Humanos , Leishmaniose Cutânea/economia , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/terapia , Método de Monte Carlo , Ensaios Clínicos Controlados Aleatórios como Assunto , Úlcera/economia , Úlcera/epidemiologia , Úlcera/terapia
5.
BMC Infect Dis ; 14: 619, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25420793

RESUMO

BACKGROUND: A previously published proof of principle phase IIa trial with 113 patients from Kabul showed that bipolar high-frequency (HF) electro-cauterization (EC) of cutaneous leishmaniasis (CL) ulcers and subsequent moist wound treatment (MWT) closed 85% of all Leishmania (L.) tropica lesions within 60 days. METHODS: A three-armed phase IIb, randomized and controlled clinical trial was performed in Mazar-e-Sharif. L. tropica- or L. major-infected CL patients received intradermal sodium stibogluconate (SSG) (Group I); HF-EC followed by MWT with 0.045% DAC N-055 (Group II); or MWT with 0.045% DAC N-055 in basic crème alone (Group III). The primary outcome was complete epithelialisation before day 75 after treatment start. RESULTS: 87 patients enrolled in the trial were randomized into group I (n = 24), II (n = 32) and III (n = 31). The per-protocol analysis of 69 (79%) patients revealed complete epithelialisation before day 75 in 15 (of 23; 65%) patients of Group I, in 23 (of 23; 100%) patients of Group II, and in 20 (of 23; 87%) patients of Group III (p = 0.004, Fisher's Exact Test). In the per-protocol analysis, wound closure times were significantly different between all regimens in a pair-wise comparison (p = 0.000039, Log-Rank (Mantel-Cox) test). In the intention-to-treat analysis wound survival times in Group II were significantly different from those in Group I (p = 0.000040, Log-Rank (Mantel-Cox) test). Re-ulcerations occurred in four (17%), three (13%) and seven (30%) patients of Group I, II or III, respectively (p = 0.312, Pearson Chi-Square Test). CONCLUSIONS: Treatment of CL ulcers with bipolar HF-EC followed by MWT with 0.045% DAC N-055 or with DAC N-055 alone showed shorter wound closure times than with the standard SSG therapy. The results merit further exploration in larger trials in the light of our current knowledge of in vitro and in vivo activities of chlorite. Clinicaltrials.gov ID: NCT00996463. Registered: 15th October 2009.


Assuntos
Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/uso terapêutico , Cloretos/uso terapêutico , Eletrocoagulação/métodos , Leishmaniose Cutânea/terapia , Úlcera Cutânea/terapia , Adulto , Afeganistão , Bandagens , Feminino , Humanos , Injeções Intralesionais , Leishmaniose Cutânea/complicações , Masculino , Úlcera Cutânea/etiologia , Fatores de Tempo , Resultado do Tratamento , Cicatrização , Adulto Jovem
6.
PLoS Negl Trop Dis ; 8(2): e2694, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24551257

RESUMO

BACKGROUND: Anthroponotic cutaneous leishmaniasis (CL) due to Leishmania (L.) tropica infection is a chronic, frequently disfiguring skin disease with limited therapeutic options. In endemic countries healing of ulcerative lesions is often delayed by bacterial and/or fungal infections. Here, we studied a novel therapeutic concept to prevent superinfections, accelerate wound closure, and improve the cosmetic outcome of ACL. METHODOLOGY/PRINCIPAL FINDINGS: From 2004 to 2008 we performed a two-armed, randomized, double-blinded, phase IIa trial in Kabul, Afghanistan, with patients suffering from L. tropica CL. The skin lesions were treated with bipolar high-frequency electrocauterization (EC) followed by daily moist-wound-treatment (MWT) with polyacrylate hydrogel with (group I) or without (group II) pharmaceutical sodium chlorite (DAC N-055). Patients below age 5, with facial lesions, pregnancy, or serious comorbidities were excluded. The primary, photodocumented outcome was the time needed for complete lesion epithelialization. Biopsies for parasitological and (immuno)histopathological analyses were taken prior to EC (1(st)), after wound closure (2(nd)) and after 6 months (3(rd)). The mean duration for complete wound closure was short and indifferent in group I (59 patients, 43.1 d) and II (54 patients, 42 d; p = 0.83). In patients with Leishmania-positive 2(nd) biopsies DAC N-055 caused a more rapid wound epithelialization (37.2 d vs. 58.3 d; p = 0.08). Superinfections occurred in both groups at the same rate (8.8%). Except for one patient, reulcerations (10.2% in group I, 18.5% in group II; p = 0.158) were confined to cases with persistent high parasite loads after healing. In vitro, DAC N-055 showed a leishmanicidal effect on pro- and amastigotes. CONCLUSIONS/SIGNIFICANCE: Compared to previous results with intralesional antimony injections, the EC plus MWT protocol led to more rapid wound closure. The tentatively lower rate of relapses and the acceleration of wound closure in a subgroup of patients with parasite persistence warrant future studies on the activity of DAC N-055. TRIAL REGISTRATION: ClinicalTrials.gov NCT00947362.


Assuntos
Cloretos/uso terapêutico , Eletrocoagulação , Leishmaniose Cutânea/epidemiologia , Leishmaniose Cutânea/terapia , Cicatrização/efeitos dos fármacos , Adolescente , Adulto , Afeganistão/epidemiologia , Idoso , Criança , Pré-Escolar , Cloretos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carga Parasitária , Adulto Jovem
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