Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 201
Filtrar
2.
Diagnosis (Berl) ; 7(1): 69-73, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31256063

RESUMO

Background Liver abscess is the most common extraintestinal manifestation of Entamoeba histolytica. Clinical manifestations could appear after returning from an endemic area or several years after the exposure. The diagnosis usually requires microbiological confirmation. Case presentation We present a case of a 55-year-old woman diagnosed with Crohn's disease treated with immunosuppressive drugs, who was admitted to the Emergency Service with liver parenchyma abscesses. Computed tomography (CT)-guided puncture showed pus, and both Gram staining and fresh parasite visualization were negative. Hepatic pus bacteriological culture was reported as negative and parasite multiplex polymerase chain reaction (PCR) was performed, being positive for E. histolytica. The same PCR was performed on blood, pleural fluid and stool samples, all of them being positive for E. histolytica. Conclusions Reviewing the clinical history of this patient, it was observed that parasite detection in three stool samples was negative 2 months before the current admission. Due to the lack of sensitivity of the microscopy techniques, we propose to routinely perform parasite detection in stools using molecular techniques, especially in immunocompromised patients.


Assuntos
Entamoeba histolytica/genética , Fezes/parasitologia , Abscesso Hepático/parasitologia , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Cefotaxima/administração & dosagem , Cefotaxima/uso terapêutico , Feminino , Humanos , Hospedeiro Imunocomprometido , Enteropatias Parasitárias/complicações , Abscesso Hepático/diagnóstico por imagem , Abscesso Hepático/terapia , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Reação em Cadeia da Polimerase/métodos , Punções/métodos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
3.
Exp Parasitol ; 206: 107768, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31539540

RESUMO

Canine leishmaniosis due to Leishmania infantum is a widespread zoonotic disease. Although aminosidine can be an effective treatment, current therapeutic recommendations do not advocate its use, mainly due to concerns regarding the potential nephrotoxicity and ototoxicity of this drug. The aim of this randomized, blinded, controlled study was to evaluate the nephrotoxicity and ototoxicity of aminosidine-allopurinol combination and compare it with that of meglumine antimonate-allopurinol combination in non-azotemic dogs with leishmaniosis. Forty dogs with leishmaniosis were randomly assigned to be treated with either aminosidine at 15 mg/kg, subcutaneously, once daily for 28 days (group A) or with meglumine antimonate at 100 mg/kg, subcutaneously, once daily for 28 days (group B). In addition to either drug, dogs in both groups were administered allopurinol at 10 mg/kg per os twice daily for 2 months. Kidney function was evaluated through measurement of serum creatinine, urea nitrogen, inorganic phosphorus, and cystatin-c concentrations and complete urinalysis, including protein-to-creatinine ratio, at baseline and after 14, 28, and 60 days from the beginning of the treatment. At the same time points, vestibular and auditory functions were evaluated through neurological examination and brainstem auditory evoked response (BAER) recordings of wave I, wave V, inter-wave I-V latencies, and minimum hearing thresholds. None of the dogs developed clinicopathological evidence of kidney disease during the study. Serum creatinine concentration increased >0.3 mg/dl over baseline in 2 dogs in group A and in 5 dogs in group B. Parameters of kidney function were not significantly different or were improved compared to baseline and the only difference between the two groups was the lower concentration of serum creatinine in group A. None of the dogs developed peripheral vestibular syndrome or hearing impairment. At the end of the study, parameters of auditory function were not significantly different or were improved compared to baseline and there were no differences between the two groups. The results of this study show that the nephrotoxicity and ototoxicity of aminosidine, when administered to non-azotemic dogs with leishmaniosis at 15 mg/kg subcutaneously once daily for 28 days along with allopurinol, is minimal and does not differ from that of meglumine antimonate.


Assuntos
Alopurinol/efeitos adversos , Doenças do Cão/tratamento farmacológico , Audição/efeitos dos fármacos , Rim/efeitos dos fármacos , Leishmaniose Visceral/veterinária , Paromomicina/efeitos adversos , Alopurinol/administração & dosagem , Alopurinol/uso terapêutico , Animais , Cóclea/efeitos dos fármacos , Creatinina/sangue , Doenças do Cão/parasitologia , Cães , Método Duplo-Cego , Combinação de Medicamentos , Potenciais Evocados Auditivos do Tronco Encefálico , Feminino , Perda Auditiva/induzido quimicamente , Perda Auditiva/veterinária , Injeções Subcutâneas/veterinária , Leishmania infantum , Leishmaniose Visceral/tratamento farmacológico , Masculino , Antimoniato de Meglumina/administração & dosagem , Antimoniato de Meglumina/efeitos adversos , Antimoniato de Meglumina/uso terapêutico , Exame Neurológico/veterinária , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Distribuição Aleatória , Vestíbulo do Labirinto/efeitos dos fármacos
5.
Acta Trop ; 197: 105045, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31158341

RESUMO

Cutaneous leishmaniasis is the most common form of leishmaniasis caused by different species of Leishmania parasites. The emergence of resistance, toxicity, long term treatment, high cost of the current drugs, and intracellular nature of the parasite are the major difficulties for the treatment of leishmaniasis. Although the therapeutic effect of paromomycin (PM) on leishmaniasisLeishmania parasite). PM-loaded into mannosylated CS (MCS) nanoparticles using dextran (PM-MCS-dex-NPs) was prepared by ionic gelation and then characterized. The particle size and Zeta potential of PM-MCS-dex-NPs were obtained as 246 nm and + 31 mV, respectively. Mannosylation of CS was qualitatively evaluated by Fourier-transform infrared spectroscopy and quantitatively measured by CHNO elemental analysis; also, a mannosylation level of 17% (w) was attained. Encapsulation efficiency (EE), drug release profile, and THP-1 cell uptake potential were determined. A value of 83.5% for EE and a higher release rate in acidic media were achieved. THP-1 cell uptake level of PM-MCS-dex-NPs after 6 h was ˜2.8 and ˜3.9 times of non-mannosylated CS nanoparticles (PM-CS-dexIn vitroGlucantim, PM-CS-dex-NPs, and PM-MCS-dex-NPs after 48 h were obtained as 1846 ±â€¯158, 1234 ±â€¯93, 784 ±â€¯52 and 2714 ±â€¯126 µg mL-1Glucantim, PM-CS-dex-NPs, and PM-MCS-dex-NPs after 48 h were obtained as 105.0 ±â€¯14.0, 169.5 ±â€¯9.8, 65.8 ±â€¯7.3 and 17.8 ±â€¯1.0 µg mL-1Glucantim, PM-CS-dex-NPs and PM-MCS-dexGlucantim, PM-CS-dex-NPs, and PM-MCS-dex-NPs at a typical concentration of 20 µg mL-1 were 71.78, 69.94, 83.14 and 33.41%, respectively. While the effect of PM-CS-dex-NPs was more salient on amastigotes, PM-MCS-dex-NPs effectively affected both stages of the parasite, especially the amastigote one. This indicated that the mannosylated formulation acts as a targeted delivery system. The findings of this study revealed that this novel targeted formulation represented a strong anti-leishmanial activity.


Assuntos
Quitosana , Sistemas de Liberação de Medicamentos , Leishmaniose/tratamento farmacológico , Nanopartículas , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Animais , Quitosana/síntese química , Quitosana/química , Nanopartículas/química , Espectroscopia de Infravermelho com Transformada de Fourier
6.
PLoS Negl Trop Dis ; 13(5): e0007253, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31048871

RESUMO

BACKGROUND: Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. METHODS: We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. RESULTS: The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. CONCLUSIONS: Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.


Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Paromomicina/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Gentamicinas/administração & dosagem , Humanos , Leishmania major/efeitos dos fármacos , Leishmania major/fisiologia , Leishmaniose Cutânea/parasitologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tunísia , Adulto Jovem
7.
Nanomedicine (Lond) ; 14(4): 387-406, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30688557

RESUMO

AIM: The present study evaluates the efficacy of paromomycin (PM)-loaded mannosylated thiomeric nanoparticles for the targeted delivery to pathological organs for the oral therapy of visceral leishmaniasis. MATERIALS & METHODS: Mannosylated thiolated chitosan (MTC)-coated PM-loaded PLGA nanoparticles (MTC-PLGA-PM) were synthesized and evaluated for morphology, drug release, permeation enhancing and antileishmanial potential. RESULTS: MTC-PLGA-PM were spherical in shape with a size of 391.24 ± 6.91 nm and an encapsulation efficiency of 67.16 ± 14%. Ex vivo permeation indicated 12.73-fold higher permeation of PM with MTC-PLGA-PM against the free PM. Flow cytometry indicated enhanced macrophage uptake and parasite killing in Leishmania donovani infected macrophage model. In vitro antileishmanial activity indicated 36-fold lower IC50 for MTC-PLGA-PM as compared with PM. The in vivo studies indicated 3.6-fold reduced parasitic burden in the L. donovani infected BALB/c mice model. CONCLUSION: The results encouraged the concept of MTC-PLGA-PM nanoparticles as promising strategy for visceral leishmaniasis.


Assuntos
Leishmaniose Visceral/tratamento farmacológico , Nanopartículas/química , Paromomicina/química , Paromomicina/uso terapêutico , Animais , Antiprotozoários/administração & dosagem , Antiprotozoários/química , Antiprotozoários/uso terapêutico , Células Cultivadas , Citometria de Fluxo , Lectinas Tipo C/metabolismo , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/patogenicidade , Leishmaniose Visceral/metabolismo , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Paromomicina/administração & dosagem , Receptores de Superfície Celular/metabolismo
8.
Clin Infect Dis ; 68(5): 844-849, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30260376

RESUMO

BACKGROUND: Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% paromomycin topical formulations have been in clinical experimentation. Recently, 15% paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. METHODS: We performed a randomized trial of 15% paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia. RESULTS: Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5-88%) for paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3-30%) for Aquaphilic vehicle (P < .0001 vs paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48-85.5%) for intralesional pentamidine. Both paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5-10% of patients. CONCLUSIONS: Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% paromomycin-Aquaphilic from one form of Old World CL to CL more generally. CLINICAL TRIALS REGISTRATION: NCT03096457.


Assuntos
Antiprotozoários/uso terapêutico , Leishmania braziliensis , Leishmaniose Cutânea/tratamento farmacológico , Paromomicina/uso terapêutico , Administração Tópica , Adulto , Antiprotozoários/administração & dosagem , Humanos , Paromomicina/administração & dosagem , Pentamidina/administração & dosagem , Pentamidina/uso terapêutico , Adulto Jovem
9.
Pharm Dev Technol ; 24(3): 390-393, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29873575

RESUMO

Ex vivo evaluation of drug release and skin permeation from topical formulations of antileishmanial drug paromomycin sulphate was carried out using intact full thickness human skin. Potency-based microbiological assay was used for the analysis of paromomycin concentrations. A total percentage drug recovery of 86 ± 26% was obtained. Incubation periods of 1 and 3 h resulted in percentage drug permeation into deep skin layers ranging from 1.3 ± 0.04% to 5.3 ± 2.0% with paraffin-based ointment and from 1.6 ± 0.8% to 3.9 ± 1% with microemulsion-based emulgel. Although a small percentage, this is still significantly higher than those previously reported using animal skin models.


Assuntos
Antiprotozoários/administração & dosagem , Paromomicina/administração & dosagem , Absorção Cutânea , Pele/metabolismo , Administração Cutânea , Animais , Antiprotozoários/farmacocinética , Liberação Controlada de Fármacos , Emulsões , Feminino , Humanos , Pomadas , Paromomicina/farmacocinética , Permeabilidade , Especificidade da Espécie , Fatores de Tempo
10.
PLoS Negl Trop Dis ; 12(10): e0006830, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30346949

RESUMO

BACKGROUND: In 2010, WHO recommended the use of new short-course treatment regimens in kala-azar elimination efforts for the Indian subcontinent. Although phase 3 studies have shown excellent results, there remains a lack of evidence on a wider treatment population and the safety and effectiveness of these regimens under field conditions. METHODS: This was an open label, prospective, non-randomized, non-comparative, multi-centric trial conducted within public health facilities in two highly endemic districts and a specialist referral centre in Bihar, India. Three treatment regimens were tested: single dose AmBisome (SDA), concomitant miltefosine and paromomycin (Milt+PM), and concomitant AmBisome and miltefosine (AmB+Milt). Patients with complicated disease or significant co-morbidities were treated in the SDA arm. Sample sizes were set at a minimum of 300 per arm, taking into account inter-site variation and an estimated failure risk of 5% with 5% precision. Outcomes of drug effectiveness and safety were measured at 6 months. The trial was prospectively registered with the Clinical Trials Registry India: CTRI/2012/08/002891. RESULTS: Out of 1,761 patients recruited, 50.6% (n = 891) received SDA, 20.3% (n = 358) AmB+Milt and 29.1% (n = 512) Milt+PM. In the ITT analysis, the final cure rates were SDA 91.4% (95% CI 89.3-93.1), AmB+Milt 88.8% (95% CI 85.1-91.9) and Milt+PM 96.9% (95% CI 95.0-98.2). In the complete case analysis, cure rates were SDA 95.5% (95% CI 93.9-96.8), AmB+Milt 95.5% (95% CI 92.7-97.5) and Milt+PM 99.6% (95% CI 98.6-99.9). All three regimens were safe, with 5 severe adverse events in the SDA arm, two of which were considered to be drug related. CONCLUSION: All regimens showed acceptable outcomes and safety profiles in a range of patients under field conditions. Phase IV field-based studies, although extremely rare for neglected tropical diseases, are good practice and an important step in validating the results of more restrictive hospital-based studies before widespread implementation, and in this case contributed to national level policy change in India. TRIAL REGISTRATION: Clinical trial is registered at Clinical trial registry of India (CTRI/2012/08/002891, Registered on 16/08/2012, Trial Registered Prospectively).


Assuntos
Antiprotozoários/administração & dosagem , Antiprotozoários/efeitos adversos , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Leishmaniose Visceral/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfotericina B/administração & dosagem , Anfotericina B/efeitos adversos , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Paromomicina/administração & dosagem , Paromomicina/efeitos adversos , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Estudos Prospectivos , Resultado do Tratamento , Adulto Jovem
11.
Infect Dis Poverty ; 7(1): 80, 2018 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-30099967

RESUMO

BACKGROUND: Adverse effects of antileishmanial drugs can affect patients' quality of life and adherence to therapy for visceral leishmaniasis (VL) and post-kala-azar dermal leishmaniasis (PKDL). In Bangladesh, there are 26 treatment centers that manage leishmaniasis cases coming from 100 endemic upazilas (subdistricts) of 26 districts (these include VL, PKDL, treatment failure, and relapse VL and cutaneous leishmaniasis cases). This study aimed to investigate the feasibility of using focused pharmacovigilance for VL (VLPV) in Bangladesh's National Kala-azar Elimination Programme for the early detection and prevention of expected and unexpected adverse drug reactions (ADRs). METHODS: This activity has been going on since December 2014. Activity area includes secondary public hospital or Upazila health complex (UHC) in hundred sub districts and Surya Kanta Kala-azar Research Center (SKKRC) in Mymensingh District, a specialized center for management of complicated VL and PKDL cases. Communicable Disease Control (CDC) of the Directorate General of Health Services (DGHS) assigned twenty five of hundred UHCs and SKKRC (total 26) as treatment centers depending on their suitable geographical location. This was implemented for better management of VL cases with Liposomal Amphotericin B (AmBisome®) to ensure patient convenience and proper utilization of this expensive donated drug. A VLPV expert committee and a UHC VLPV team were established, an operational manual and pharmacovigilance report forms were developed, training and refresher training of health personnel took place at UHCs and at the central level, collected information such as patient data including demographics, treatment history and response, adverse events were analyzed. This report includes information for the period from December 2014 to December 2016. RESULTS: From December 2014 to December 2016, 1327 leishmaniasis patients were treated and 1066 (80%) were available for VLPV. Out of these, 57, 33, 9, and 1% were new VL, PKDL, VL relapse, and other cases, respectively. Liposomal amphotericin B was mostly used (82%) for case management, followed by miltefosine (20%) and paromomycin (3%). Out of the 1066 patients, 26% experienced ADRs. The most frequent ADR was fever (17%, 176/1066), followed by vomiting (5%, 51/1066). Thirteen serious adverse events (SAEs) (eight deaths and five unexpected SAEs) were observed. The expert committee assessed that three of the deaths and all unexpected SAEs were possibly related to treatment. Out of the five unexpected SAEs, four were miltefosine-induced ophthalmic complications and the other was an AmBisome®-induced avascular necrosis of the nasal alae. The Directorate General of the Drug Administration entered the ADRs into the World Health Organization Uppsala Monitoring Centre (WHO-UMC) VigiFlow database. CONCLUSIONS: This study found that VLPV through NKEP is feasible and should be continued as a routine activity into the public health system of Bangladesh to ensure patient safety against anti-leishmanial drugs.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/epidemiologia , Leishmaniose Visceral/epidemiologia , Paromomicina/administração & dosagem , Farmacovigilância , Fosforilcolina/análogos & derivados , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/mortalidade , Lesão Renal Aguda/patologia , Adolescente , Adulto , Idoso , Anfotericina B/efeitos adversos , Antiprotozoários/efeitos adversos , Bangladesh/epidemiologia , Feminino , Humanos , Leishmania donovani/efeitos dos fármacos , Leishmania donovani/crescimento & desenvolvimento , Leishmania tropica/efeitos dos fármacos , Leishmania tropica/crescimento & desenvolvimento , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/mortalidade , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/patologia , Paromomicina/efeitos adversos , Segurança do Paciente , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Qualidade de Vida , Recidiva , Análise de Sobrevida
13.
Clin Microbiol Infect ; 24(6): 591-598, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29138100

RESUMO

OBJECTIVES: To evaluate the evidence for use of different formulations of amphotericin B (AmB), minimum effective dose for each formulation and its comparative efficacy against other drugs in achieving definitive cure of visceral leishmaniasis. METHODS: This systematic review and meta-analysis included following data sources: PubMed, Embase, Scopus, Web of Science and CINAHL. Controlled prospective clinical trials (randomized or nonrandomized, including dose-ranging studies) conducted between 1996 and 2017 with at least one treatment group receiving AmB were included (published data only). The primary outcome was definitive cure at 6 months. Adverse events and mortality were assessed as secondary outcomes. The PROSPERO registration number for this review is CRD42017067488. RESULTS: Thirty-one studies (26 from India) that enrolled 6903 patients into 84 study groups met the selection criteria. In India, liposomal AmB was not inferior to AmB deoxycholate (relative risk 1.00, 95% confidence interval (CI) 0.96-1.03, two randomized controlled trials (RCTs), 514 participants, high-quality evidence), and a single dose of the earlier formulation as low as 3.75 mg/kg achieved a cure rate of over 89% (95% CI 70.6-97.2). AmB deoxycholate was as effective as miltefosine (relative risk 0.99, 95% CI 0.95-1.03, two trials, 523 participants, high-quality evidence) and may be better than paromomycin (relative risk 1.04, 95% CI 1.02-1.07, one trial, 667 participants, low-quality evidence) in achieving definitive cure. CONCLUSIONS: AmB is an efficacious drug in the Indian subcontinent. Further evidence is needed from prospective clinical trials in other endemic geographical regions.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Ensaios Clínicos como Assunto , Ácido Desoxicólico/administração & dosagem , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Composição de Medicamentos , Medicina Baseada em Evidências , Feminino , Humanos , Masculino , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Fosforilcolina/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
14.
Pan Afr Med J ; 27: 287, 2017.
Artigo em Francês | MEDLINE | ID: mdl-29187956

RESUMO

Leishmaniases are parasitic diseases occurring in endemic tropical and subtropical areas and caused by protozoa of the genus leishmania, transmitted by a diptera (sand fly). We here report a case of topical cutaneous leishmaniasis discovered in a 15-year old boy with painless ulcer on his left leg, who had been staying in South Africa. Clinical examination showed painless non-itchy ulcer, occurred 1 month before, on the antero-internal part of his left leg with crusts and scars caused by insect bites, all evolving in a context of patient's general health status, without mucosal or visceral lesions. Skin biopsy allowed specific parasitologic diagnosis revealing topical zoonotic cutaneous leishmaniasis caused by L. major. The patient underwent topical treatment based on paramomycin and oral fluconazole resulting in ulcer healing at the end of 2 months.


Assuntos
Úlcera da Perna/diagnóstico , Leishmaniose Cutânea/diagnóstico , Zoonoses/diagnóstico , Administração Tópica , Adolescente , Animais , Antiparasitários/administração & dosagem , Biópsia , Fluconazol/administração & dosagem , Humanos , Úlcera da Perna/tratamento farmacológico , Úlcera da Perna/parasitologia , Leishmania major/isolamento & purificação , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/patologia , Masculino , Paromomicina/administração & dosagem , Resultado do Tratamento , Zoonoses/tratamento farmacológico , Zoonoses/parasitologia
15.
Cochrane Database Syst Rev ; 12: CD005067, 2017 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-29192424

RESUMO

BACKGROUND: Cutaneous leishmaniasis, caused by a parasitic infection, is considered one of the most serious skin diseases in many low- and middle-income countries. Old World cutaneous leishmaniasis (OWCL) is caused by species found in Africa, Asia, the Middle East, the Mediterranean, and India. The most commonly prescribed treatments are antimonials, but other drugs have been used with varying success. As OWCL tends to heal spontaneously, it is necessary to justify the use of systemic and topical treatments. This is an update of a Cochrane Review first published in 2008. OBJECTIVES: To assess the effects of therapeutic interventions for the localised form of Old World cutaneous leishmaniasis. SEARCH METHODS: We updated our searches of the following databases to November 2016: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers and checked the reference lists of included studies for further references to relevant randomised controlled trials (RCTs). We wrote to national programme managers, general co-ordinators, directors, clinicians, WHO-EMRO regional officers of endemic countries, pharmaceutical companies, tropical medicine centres, and authors of relevant papers for further information about relevant unpublished and ongoing trials. We undertook a separate search for adverse effects of interventions for Old World cutaneous leishmaniasis in September 2015 using MEDLINE. SELECTION CRITERIA: Randomised controlled trials of either single or combination treatments in immunocompetent people with OWCL confirmed by smear, histology, culture, or polymerase chain reaction. The comparators were either no treatment, placebo/vehicle, and/or another active compound. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias and extracted data. We only synthesised data when we were able to identify at least two studies investigating similar treatments and reporting data amenable to pooling. We also recorded data about adverse effects from the corresponding search. MAIN RESULTS: We included 89 studies (of which 40 were new to this update) in 10,583 people with OWCL. The studies included were conducted mainly in the Far or Middle East at regional hospitals, local healthcare clinics, and skin disease research centres. Women accounted for 41.5% of the participants (range: 23% to 80%). The overall mean age of participants was 25 years (range 12 to 56). Most studies lasted between two to six months, with the longest lasting two years; average duration was four months. Most studies were at unclear or high risk for most bias domains. A lack of blinding and reporting bias were present in almost 40% of studies. Two trials were at low risk of bias for all domains. Trials reported the causative species poorly.Here we provide results for the two main comparisons identified: itraconazole (200 mg for six to eight weeks) versus placebo; and paromomycin ointment (15% plus 10% urea, twice daily for 14 days) versus vehicle.In the comparison of oral itraconazole versus placebo, at 2.5 months' follow up, 85/125 participants in the itraconazole group achieved complete cure compared to 54/119 in the placebo group (RR 3.70, 95% CI 0.35 to 38.99; 3 studies; 244 participants). In one study, microbiological or histopathological cure of skin lesions only occurred in the itraconazole group after a mean follow-up of 2.5 months (RR 17.00, 95% CI 0.47 to 612.21; 20 participants). However, although the analyses favour oral itraconazole for these outcomes, we cannot be confident in the results due to the very low certainty evidence. More side effects of mild abdominal pain and nausea (RR 2.36, 95% CI 0.74 to 7.47; 3 studies; 204 participants) and mild abnormal liver function (RR 3.08, 95% CI 0.53 to 17.98; 3 studies; 84 participants) occurred in the itraconazole group (as well as reports of headaches and dizziness), compared with the placebo group, but again we rated the certainty of evidence as very low so are unsure of the results.When comparing paromomycin with vehicle, there was no difference in the number of participants who achieved complete cure (RR of 1.00, 95% CI 0.86, 1.17; 383 participants, 2 studies) and microbiological or histopathological cure of skin lesions after a mean follow-up of 2.5 months (RR 1.03, CI 0.88 to 1.20; 383 participants, 2 studies), but the paromomycin group had more skin/local reactions (such as inflammation, vesiculation, pain, redness, or itch) (RR 1.42, 95% CI 0.67 to 3.01; 4 studies; 713 participants). For all of these outcomes, the certainty of evidence was very low, meaning we are unsure about these results.Trial authors did not report the percentage of lesions cured after the end of treatment or speed of healing for either of these key comparisons. AUTHORS' CONCLUSIONS: There was very low-certainty evidence to support the effectiveness of itraconazole and paromomycin ointment for OWCL in terms of cure (i.e. microbiological or histopathological cure and percentage of participants completely cured). Both of these interventions incited more adverse effects, which were mild in nature, than their comparisons, but we could draw no conclusions regarding safety due to the very low certainty of the evidence for this outcome.We downgraded the key outcomes in these two comparisons due to high risk of bias, inconsistency between the results, and imprecision. There is a need for large, well-designed international studies that evaluate long-term effects of current therapies and enable a reliable conclusion about treatments. Future trials should specify the species of leishmaniasis; trials on types caused by Leishmania infantum, L aethiopica, andL donovani are lacking. Research into the effects of treating women of childbearing age, children, people with comorbid conditions, and those who are immunocompromised would also be helpful.It was difficult to evaluate the overall efficacy of any of the numerous treatments due to the variable treatment regimens examined and because RCTs evaluated different Leishmania species and took place in different geographical areas. Some outcomes we looked for but did not find were degree of functional and aesthetic impairment, change in ability to detect Leishmania, quality of life, and emergence of resistance. There were only limited data on prevention of scarring.


Assuntos
Antiprotozoários/uso terapêutico , Itraconazol/uso terapêutico , Leishmaniose Cutânea/terapia , Paromomicina/uso terapêutico , Adulto , Animais , Anti-Infecciosos/uso terapêutico , Antiprotozoários/administração & dosagem , Terapias Complementares/métodos , Crioterapia/métodos , Extremo Oriente , Feminino , Temperatura Alta/uso terapêutico , Humanos , Itraconazol/administração & dosagem , Terapia a Laser , Leishmania major , Leishmania tropica , Masculino , Pessoa de Meia-Idade , Oriente Médio , Bases para Pomadas/administração & dosagem , Paromomicina/administração & dosagem , Fotoquimioterapia , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Am J Trop Med Hyg ; 97(4): 1214-1217, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28722597

RESUMO

The most common extraintestinal complication of Entamoeba histolytica is amebic liver abscess (ALA). Hepatic vein and inferior vena cava (IVC) thrombosis are rare but well-documented complications of ALA, typically attributed to mechanical compression and inflammation associated with a large abscess. We present a case of a previously healthy 43-year-old Canadian man presenting with constitutional symptoms and right upper quadrant abdominal pain. He was found to have thrombophlebitis of the IVC, accessory right hepatic vein, and bilateral iliac veins. Extensive investigations for thrombophilia were negative. Magnetic resonance imaging of the liver demonstrated a 3.2-cm focal area of parenchymal abnormality that was reported as presumptive hepatocellular carcinoma, and a 1.9-cm lesion in the caudate lobe with diffusion restriction and peripheral rim enhancement. Despite multiple biopsy attempts, a histopathological diagnosis was not achieved. Abdominal pain and fever 4 months later prompted repeat ultrasound demonstrating a 10.4- × 12.0-cm rim-enhancing fluid attenuation lesion felt to represent a liver abscess. Thick dark "chocolate brown" drainage from the lesion and positive serology for E. histolytica confirmed the diagnosis of ALA acquired from a previous trip to Cuba. The patient was started on treatment with metronidazole and paromomycin and repeat abdominal ultrasound demonstrated resolution of the abscess. This case is the first to demonstrate extensive IVC thrombosis secondary to a relatively small occult ALA and emphasizes the thrombogenic potential of ALA. Amebic infection should be considered as a rare cause of IVC thrombosis in the correct clinical context.


Assuntos
Veias Hepáticas/patologia , Abscesso Hepático Amebiano/complicações , Abscesso Hepático Amebiano/patologia , Trombose/etiologia , Veia Cava Inferior/patologia , Adulto , Antiprotozoários/administração & dosagem , Antiprotozoários/uso terapêutico , Humanos , Masculino , Metronidazol/administração & dosagem , Metronidazol/uso terapêutico , Paromomicina/administração & dosagem , Paromomicina/uso terapêutico , Trombose/patologia
17.
PLoS Negl Trop Dis ; 11(5): e0005620, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28505185

RESUMO

BACKGROUND: Since miltefosine monotherapy against visceral leishmaniasis (VL) caused by Leishmania donovani has been discontinued in the Indian subcontinent due to an increase in the number of treatment failures, single dose liposomal amphotericin B is now advocated as a treatment option of choice. Paromomycin-miltefosine combination therapy can be used as substitute first-line treatment in regions without cold-chain potential. Previous laboratory studies in the closely related species Leishmania infantum have demonstrated that paromomycin monotherapy fairly rapidly selects for resistance producing a phenotype with increased fitness. Given the possible clinical implications of these findings for the current field situation, the present study aimed to identify the potential hazards of paromomycin-miltefosine combination therapy. PRINCIPAL FINDINGS: Drug interaction studies using the fixed-ratio isobologram method revealed an indifferent interaction between paromomycin and miltefosine. In hamsters infected with L. infantum, the combination resulted in cumulative efficacy in reducing parasite burdens in the liver, spleen and bone marrow. Selected resistant lines against the single drugs did not display cross-resistance. When the intracellular amastigote stage was repeatedly exposed to the paromomycin-miltefosine combination, either in vitro or in vivo, no significant susceptibility decrease towards either drug was noted. CONCLUSIONS: These results suggest that implementation of paromomycin-miltefosine combination therapy indeed could represent a safe and affordable treatment option for L. donovani VL as miltefosine appears to overrule the anticipated rapid development of PMM resistance.


Assuntos
Antiprotozoários/administração & dosagem , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Paromomicina/administração & dosagem , Fosforilcolina/análogos & derivados , Animais , Cricetinae , Resistência a Múltiplos Medicamentos , Quimioterapia Combinada , Feminino , Camundongos , Fosforilcolina/administração & dosagem
18.
PLoS Negl Trop Dis ; 11(5): e0005635, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28558062

RESUMO

BACKGROUND: AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh. METHODS: The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment. RESULTS: 601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0-100) for AmBisome monotherapy, 99.4% (95%CI 98.2-100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6-98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5-100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved. CONCLUSION: None of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi). TRIAL REGISTRATION: ClinicalTrials.gov NCT01122771.


Assuntos
Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Paromomicina/administração & dosagem , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Anfotericina B/efeitos adversos , Antiprotozoários/efeitos adversos , Bangladesh , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paromomicina/efeitos adversos , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Recidiva , Resultado do Tratamento , Adulto Jovem
19.
Clin Drug Investig ; 37(3): 259-272, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28066878

RESUMO

INTRODUCTION: In 2010, WHO recommended a new first-line treatment for visceral leishmaniasis (VL) in Eastern Africa. The new treatment, a combination of intravenous (IV) or intramuscular (IM) sodium stibogluconate (SSG) and IM paromomycin (PM) was an improvement over SSG monotherapy, the previous first-line VL treatment in the region. To monitor the new treatment's safety and effectiveness in routine clinical practice a pharmacovigilance (PV) programme was developed. METHODS: A prospective PV cohort was developed. Regulatory approval was obtained in Sudan, Kenya, Uganda and Ethiopia. Twelve sentinel sites sponsored by the Ministries of Health, Médecins Sans Frontières (MSF) and Drugs for Neglected Diseases initiative (DNDi) participated. VL patients treated using the new treatment were consented and included in a common registry that collected demographics, baseline clinical characteristics, adverse events, serious adverse events and treatment outcomes. Six-monthly periodic safety update reports (PSUR) were prepared and reviewed by a PV steering committee. RESULTS: Overall 3126 patients were enrolled: 1962 (62.7%) from Sudan, 652 (20.9%) from Kenya, 322 (10.3%) from Ethiopia and 190 (6.1%) from Uganda. Patients were mostly male children (68.1%, median age 11 years) with primary VL (97.8%). SSG-PM initial cure rate was 95.1%; no geographical differences were noted. HIV/VL co-infected patients and patients older than 50 years had initial cure rates of 56 and 81.4%, respectively, while 1063 (34%) patients had at least one adverse event (AE) during treatment and 1.92% (n = 60) had a serious adverse event (SAE) with a mortality of 1.0% (n = 32). There were no serious unexpected adverse drug reactions. CONCLUSIONS: This first regional PV programme in VL supports SSG-PM combination as first-line treatment for primary VL in Eastern Africa. SSG-PM was effective and safe except in HIV/VL co-infected or older patients. Active PV surveillance of targeted safety, effectiveness and key VL outcomes such us VL relapse, PKDL and HIV/VL co-infection should continue and PV data integrated to national and WHO PV databases.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Paromomicina/administração & dosagem , Administração Intravenosa , Adolescente , Adulto , África Oriental , Criança , Pré-Escolar , Coinfecção , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Estudos Prospectivos , Recidiva , Resultado do Tratamento , Adulto Jovem
20.
Indian J Pharmacol ; 49(4): 297-303, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29326490

RESUMO

OBJECTIVE: The objective of this study is to investigate in vitro Caco2 permeability, metabolism and in vivo pharmacokinetic (PK) properties of paromomycin to develop an efficient dosage form with improved oral bioavailability. MATERIALS AND METHODS: For the purpose, Caco2 permeability assay, mouse microsomal stability assay and in vivo PKs in male BALB/c mice were performed. RESULTS: In Caco-2 permeability assay, paromomycin showed negligible permeability in the apical to basolateral (A-to-B) direction and vice versa (B-to-A). Marginal increase in permeability with the use of P-glycoprotein (P-gp) inhibitor, namely, verapamil suggesting paromomycin could be a P-gp substrate. Paromomycin was unstable in liver microsomes of mouse. Paromomycin showed good PK properties after intravenous dose in male BALB/c mice which included low plasma clearance, i.e., <10% of hepatic blood flow in mice, high volume of distribution (Vd), and half-life (T½) of 2.6 h. Following per oral dose, it exhibits low oral bioavailability (0.3%) with carboxymethyl cellulose formulation. Oral plasma exposure increased in mice by 10% and 15% after pretreatment with P-gp inhibitor verapamil and CYP inhibitor 1-Aminobenztriazole, respectively. CONCLUSION: Comparatively significant increase in oral plasma exposure of paromomycin was observed with an alternative oral formulation approach, use of P-gp and CYP inhibitors resulting in improved oral bioavailability up to 16%.


Assuntos
Absorção Gastrointestinal/fisiologia , Microssomos Hepáticos/metabolismo , Paromomicina/administração & dosagem , Paromomicina/metabolismo , Administração Oral , Animais , Disponibilidade Biológica , Células CACO-2 , Absorção Gastrointestinal/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Microssomos Hepáticos/efeitos dos fármacos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA