Use of topical rSm29 in combination with intravenous meglumine antimoniate in the treatment of cutaneous leishmaniasis: A randomized controlled trial.

BACKGROUND: Cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis is associated with an inflammatory response. Granzyme (GzmB) and IL-1ß play a key role in the pathology. Meglumine antimoniate (MA) is the first-choice drug for the treatment of CL, but therapy failure is observed in up to 50% of the cases. The protein, rSm29 of Schistosoma mansoni, down-modulates pro-inflammatory cytokine production. We evaluate if the combination of topical rSm29 plus MA increases the cure rate of CL. METHODS: In this randomized clinical trial, 91 CL patients were allocated in 3 groups. All cases received MA (20 mg/kg/weight) for 20 days. Group 1 used topical rSm29 (10 µg), group 2 a placebo topically applied, and group 3 received only MA. RESULTS: The cure rate on day 90 was 71% in subjects treated with rSm29 plus MA, and 43% in patients who received MA plus placebo or MA alone (P < 0.05). There was a decrease in GzmB and an increase in IFN-γ (P < 0.05) in supernatants of skin biopsies of the lesions obtained on D7 of therapy (P < 0.05) in patients who received rSm29. CONCLUSION: rSm29 associated with MA reduces GzmB levels, is more effective than MA alone, and decreases CL healing time. CLINICAL TRIALS REGISTRATION: ClinicalTrial.gov under NCT06000514.

Cost-effectiveness study of therapeutic approaches for mucosal leishmaniasis.

This study aimed to estimate the cost-effectiveness of four therapeutic approaches available for mucosal leishmaniasis in Brazil: miltefosine, meglumine antimoniate, combined with and without pentoxifylline, and liposomal amphotericin B. The perspective adopted was that of the Brazilian Unified National Health System (SUS). The outcome of interest was "cured patient", which was analyzed using a decision tree model. Estimates of direct costs and effectiveness were obtained from the scientific literature. Meglumine antimoniate alone was the base comparator strategy; liposomal amphotericin B showed an incremental cost-effectiveness ratio (ICER) of USD 7,409.13 per cured patient, and the combination of meglumine antimoniate with pentoxifylline presented an ICER of USD 85.13. Miltefosine was absolutely dominated, with higher cost and similar effectiveness when compared to meglumine antimoniate. Sensitivity analyses, varying the cost by ±25%, did not change the results. However, when the cost of miltefosine was estimated at less than USD 171.23, this strategy was dominant over meglumine antimoniate alone. The results confirm that treatment with liposomal amphotericin B remains the option with the highest ICER among the approaches analyzed. Miltefosine may be cost-effective based on the variation in the acquisition price, which deserves attention because it is the only available oral option. The non-accounting of other aspects prevent the use of these results immediately to support decision-making, but they point out the need to negotiate the prices of drugs available for mucosal leishmaniasis and indicates the need of encouraging technology transfer or other actions aimed at expanding the performance of the Brazilian national industrial complex.

Natural resistance to meglumine antimoniate is associated with treatment failure in cutaneous leishmaniasis caused by Leishmania (Viannia) panamensis.

The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.

Topical application of ozonated sunflower oil accelerates the healing of lesions of cutaneous leishmaniasis in mice under meglumine antimoniate treatment.

Besides being scarce, the drugs available for treating cutaneous leishmaniasis have many adverse effects. Ozone is an option to enhance the standard treatment due to the wound-healing activity reported in the literature. In this study, we evaluated the efficiency of ozonated sunflower oil as an adjuvant in treating cutaneous lesions caused by Leishmania amazonensis. BALB/c mice were infected with L. amazonensis, and after the lesions appeared, they were treated in four different schedules using the drug treatment with meglumine antimoniate (Glucantime®), with or without ozonated oil. After thirty days of treatment, the lesions' thickness and their parasitic burden, blood leukocytes, production of NO and cytokines from peritoneal macrophages and lymph node cells were analyzed. The group treated with ozonated oil plus meglumine antimoniate showed the best performance, improving the lesion significantly. The parasitic burden showed that ozonated oil enhanced the leishmanicidal activity of the treatment, eliminating the parasites in the lesion. Besides, a decrease in the TNF levels from peritoneal macrophages and blood leukocytes demonstrated an immunomodulatory action of ozone in the ozonated oil-treated animals compared to the untreated group. Thus, ozonated sunflower oil therapy has been shown as an adjuvant in treating Leishmania lesions since this treatment enhanced the leishmanicidal and wound healing effects of meglumine antimoniate.

Efficacy of the treatment using a microemulsion loaded with epoxy-α-lapachone in combination with meglumine antimoniate against murine infection by Leishmania (Leishmania) amazonensis.

Leishmaniasis is a disease caused by Leishmania spp., affecting millions of people around the world. For decades, its treatment has been based on pentavalent antimonials, which notoriously cause toxic side effects in patients. In this study, epoxy-α-lapachone incorporated into an oil-in-water-type microemulsion (ELAP-ME) and meglumine antimoniate (MA) were assayed in monotherapy and in combination (ELAP-ME/MA) in BALB/c mice infected with Leishmania (Leishmania) amazonensis. In general, there was a reduction in paw lesion size (up to 37% reduction) and decreases of parasite loads in the footpad (∼40%) and lymph nodes (∼31%) of animals treated with ELAP-ME/MA, when compared to the non-treated control groups. Analyses of serum biochemical parameters revealed that the ELAP-ME/MA showed lower renal and hepatic toxicity when compared to MA 2-doses/week monotherapy. These findings indicate that the ELAP-ME/MA combination may be a promising approach for the treatment of cutaneous leishmaniasis.

Self-reporting of hearing loss and tinnitus in the diagnosis of ototoxicity by meglumine antimoniate in patients treated for American tegumentary Leishmaniasis.

INTRODUCTION: American Tegumentary Leishmaniasis (ATL) treatment is based on pentavalent antimonials (Sb5+), but these drugs have been associated to several adverse effects. Hearing loss and tinnitus during treatment with meglumine antimoniate (MA) have already been reported. This study aimed to describe the usefulness of self-reporting of hearing loss and tinnitus in diagnosing MA-induced ototoxicity. METHODS: A prospective longitudinal study was conducted with 102 patients with parasitological diagnosis of ATL, treated with different MA schemes. The presence of clinical auditory toxicity was defined as the emergence or worsening of self-reporting hearing loss and/or tinnitus during monitoring. Measures of sensitivity, specificity, and the positive and negative predictive value of the patient's self-reporting of hearing loss and tinnitus in relation to the result of the audiometric test (considered the gold standard) were calculated. RESULTS: The age of the evaluated patients ranged from 15 to 81 years, with a median of 41 years, and most were male (73.5%). Seventy-five patients (73.5%) had cutaneous leishmaniasis and 27 (26.5%) mucosal leishmaniasis. Eighty-six patients (84.3%) received intramuscular (IM) treatment and 16 (15.7%) were treated with intralesional MA. During treatment, 18 (17,6%) had tinnitus and 7 (6,9%) had complaint of hearing loss. 53 (52%) patients had cochlear toxicity confirmed by tone threshold audiometry and high frequency audiometry, from which 60% received a dose of 20 mg Sb5+/kg/day (p = 0.015) and 96.2% were treated with IM MA (p = 0.001). Tinnitus has greater specificity and positive predictive value than hearing loss, with a low number of false positives, but with a high false negative value. CONCLUSION: Although the large number of false negatives suggests that self-report of hearing loss or tinnitus cannot be considered a good screening test for referring the patient to an audiometry, the low number of false positives suggests the need to value the patient's complaint for referral. Otherwise, this study reinforces the importance of audiological monitoring during treatment with MA, especially in those patients with self-reporting of hearing loss or tinnitus when treated with 20 mg Sb5+/kg/day via IM.

THE WATER-SOLUBLE CONTRAST FOR ADHESIVE SMALL BOWEL OBSTRUCTION: ARE THERE ADVANTAGES?

BACKGROUND: Adhesive small bowel obstruction is one of the most common causes of surgical emergencies, representing about 15% of hospital admissions. Defining the need and timing of surgical intervention still remains a challenge. AIMS: To report the experience of using meglumine-based water-soluble contrast in a tertiary hospital in southern Brazil, comparing with the world literature. METHODS: Patients suspected of having adhesive small bowel obstruction, according to their clinical conditions, underwent an established protocol, consisting of the administration of water-soluble contrast, followed by plain abdominal radiograph within 12 hours and by a new clinical evaluation. The protocol was initiated after starting conservative management, including fasting and placement of a nasogastric tube, as well as intravenous fluid reposition. RESULTS: A total of 126 patients were submitted to the protocol. The water-soluble contrast test sensitivity and specificity after the first radiograph were 94.6 and 91.0%, respectively; after the second radiograph, these values were 92.3 and 100%. The general test values for sensitivity and specificity were 91.9 and 100%, respectively. CONCLUSIONS: The measure parameters evaluated in this study were similar to those found in the literature, contributing to endorse the importance of this test in the evaluation of patients with adhesive small bowel obstruction. The particular relevance of this study was the similar results that were found using a different type of meglumine-based contrast, which is available in Brazil.

A Randomized, Controlled, Noninferiority, Multicenter Trial of Systemic vs Intralesional Treatment With Meglumine Antimoniate for Cutaneous Leishmaniasis in Brazil.

BACKGROUND: Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). METHODS: Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10-20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. RESULTS: We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5-91.4) and 67.8% (53.3-78.3) per protocol (PP) and 70.6% (58.3-81.0) and 59.7% (47.0-71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6-88 + 8) and 71.2% (57.9-82.2) PP and 69.1% (55.2-78.5) and 64.2% (50.0-74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. CONCLUSIONS: IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. CLINICAL TRIALS REGISTRATION: REBEC: RBR-6mk5n4.

Inotersena para o tratamento da polineuropatia amiloidótica familiar relacionada à transtirretina em pacientes adultos em estágio 2 ou pacientes não respondedores a tafamidis meglumina / Inotersena for the treatment of transthyretin-related familial amyloidotic polyneuropathy in stage 2 adult patients or patients nonresponders to tafamidis meglumine

INTRODUÇÃO: A amiloidose por transtirretina (TTR) é um distúrbio sistêmico caracterizado pela deposição extracelular de fibrilas amiloides e compostas por TTR, que é uma proteína de transporte plasmático de tiroxina e vitamina A produzida predominantemente pelo fígado. A polineuropatia amiloidótica familiar relacionada à transtirretina (PAF-TTR) é uma doença multissistêmica rara, progressiva, hereditária e altamente incapacitante. É um distúrbio autossômico dominante e até o momento mais de 100 mutações de TTR diferentes foram identificadas em todo o mundo, essas mutações desestabilizam a proteína TRR. PAF-TTR é uma doença multissintomática que pode apresentar neuropatia periférica (sensorial e motora), neuropatia autonômica, comprometimento gastrointestinal, cardiomiopatia, nefropatia ou deposição ocular. As manifestações clínicas da amiloidose sistêmica são determinadas principalmente pela proteína precursora e pelos órgãos envolvidos. No entanto, há considerável sobreposição clínica entre todos os tipos de amiloidose. Estimativas de preva

"It's not all about the disease": do treatment and socioeconomic status affect perceived impact and satisfaction of patients treated for cutaneous leishmaniasis?

BACKGROUND: This cross-sectional study compared the general impact of cutaneous leishmaniasis (CL) and patient satisfaction with treatment and health services as perceived by those undergoing different therapeutic regimens in an endemic region in South-Eastern Brazil. We also investigated the factors associated with both outcomes (general impact and satisfaction). METHODS: We included 84 patients with CL treated between 2018 and 2019 with intravenous meglumine antimoniate, liposomal amphotericin B, or intralesional meglumine antimoniate therapy. Data were collected through interviews that assessed sociodemographic characteristics, comorbidity status, access and use of health services for CL diagnosis and treatment, and the items of the Cutaneous Leishmaniasis Impact Questionnaire (CLIQ). The CLIQ is a psychometric questionnaire previously validated to assess the general impact of CL on patient satisfaction with treatment and health services. Multivariate logistic regression analysis was used to identify the factors associated with high CL impact and low patient satisfaction. RESULTS: The general impact of CL and patient satisfaction with treatment and health services were not significantly associated with the therapeutic regimen. High CL impact was associated with low family income (odds ratio [OR]:3.3; 95% confidence interval [CI]:1.0-10.3), occurrence of complications/adverse effects during treatment (OR:7.7; 95%CI:2.4-25.6), and additional costs during diagnosis and/or treatment (OR:12.1; 95% CI:2.8-52.4). Low satisfaction was associated with high disease impact (OR: 9.5; 95% CI:2.7-33.9), occurrence of complications/adverse effects (OR:4.2; 95% CI:1.3-13.0), and high family income (OR:7.1; 95%CI:1.7-28.2). CONCLUSIONS: Our data support public health policies aimed at reducing the impact of CL and its treatment as well as the use of therapy with fewer adverse effects.

Efficacy of intralesional meglumine antimoniate in the treatment of canine tegumentary leishmaniasis: A Randomized controlled trial.

Dogs living in areas of Leishmania (Viannia) braziliensis transmission may present canine tegumentary leishmaniasis (CTL) characterized by cutaneous or muzzle ulcers as well as asymptomatic L. braziliensis infection. It is not clear if dogs participate in the transmission chain of L. braziliensis to humans. However, dogs may remain with chronic ulcers for a long time, and as there are no public policies about CTL, these animals die or are sacrificed. Here we compare the efficacy of intralesional meglumine antimoniate with intralesional 0.9% NaCl solution in CTL treatment. This randomized control study included 32 dogs with cutaneous or muzzle lesions who had L. braziliensis DNA detected by PCR in tissue biopsied. Group one received 5ml of intralesional Glucantime, and group two received 5ml 0.9% NaCl solution, both applied in the four cardinal points on days 0, 15, and 30. Cure was defined as complete healing of the ulcers in the absence of raised borders on day 90. There was no difference in animals' demographic and clinical features in the two groups (p >.05). While at the endpoint, the cure rate was 87.5% in the group test, and in those who received 0.9 NaCl the cure rate was only 12.5%. As important as the high cure rate, the healing time was faster in dogs treated with antimony than in those treated with saline (p < .001). Intralesional meglumine antimoniate is effective in the treatment of dogs with L. braziliensis infection and accelerates the healing time of CTL.

A phase II multicenter randomized study to evaluate the safety and efficacy of combining thermotherapy and a short course of miltefosine for the treatment of uncomplicated cutaneous leishmaniasis in the New World.

BACKGROUND: Systemic pentavalent antimonials, mainly meglumine antimoniate, continue to be the first-choice drugs for treatment of cutaneous leishmaniasis (CL) despite their toxicity, difficulty of administration and high cost. In the search for therapeutic alternatives, combining two treatment interventions has emerged as a potential alternative to either reduce the use of antimonials with the associated toxicities, or to increase efficacy. Here, we report the results of a recently completed trial assessing the efficacy and safety of a combination of thermotherapy (TT) plus a short course of miltefosine (MLT) for the treatment of uncomplicated CL in Colombia and Peru. METHODS: A multicenter, randomized, evaluator-blinded, phase II, controled clinical trial was conducted. Adult volunteers with a parasitologically confirmed diagnosis of uncomplicated CL were randomly allocated to receive either a single session of TT or a combination of TT plus a short course of MLT (3 weeks). Therapeutic response outcomes and safety were assessed. RESULTS: 130 subjects were included in the study, of whom 64 were randomly assigned to the TT arm and 66 to the TT + MLT arm. Cure at 3 months' follow-up was achieved in 57.8% (n = 37) and 80.3% (n = 53) in the TT and TT + MLT groups, respectively, in the intention to treat analysis. The TT + MLT regimen was better that TT alone (p = 0.0055). The presence of vesicles at the site of heat application was the most common adverse event reported associated with the use of TT; while vomiting (31.8%) and elevation of liver enzymes (28.8%) were the most frequent adverse events reported associated with the use of MLT. CONCLUSION: The combination of TT plus a short course of MLT was shown to be significantly better than TT alone for the treatment of uncomplicated CL in the New World. TRIAL REGISTRATION: Registered in clinicaltrials.gov NCT02687971.

Systemic clostridiosis due to Clostridium perfringens infection in Equus asinus - case report / Clostridiose sistêmica devido a infecção de Clostridium perfringens em Equus asinus - relato de caso

Clostridial infections, particularly clostridial myonecrosis, can be fulminant and fatal; they often arise without an obvious history of trauma. The majority of equine clostridial myonecrosis cases are associated with intramuscular injection. This paper presents the first report of clostridial myositis by C. perfringens in a donkey after an injection of flunixin meglumine on the neck, describing the clinical, necroscopic, and histopathological events. Bacterial isolation and biochemical tests confirmed the definitive diagnosis of C. perfringens.

Clostridioses, particularmente a mionecrose clostridial, podem ser fulminantes e fatais; elas geralmente surgem sem um histórico óbvio de trauma. A maioria dos casos de mionecrose clostridial equina está associada à injeção intramuscular. Este artigo apresenta o primeiro relato de miosite clostridial por C. perfringens em jumento após injeção de flunixina meglumina no pescoço, descrevendo os achados clínicos, necroscópicos e histopatológicos. Isolamento bacteriano e testes bioquímicos confirmaram o diagnóstico definitivo de C. perfringens.

Tafamidis en cardiomiopatía amiloide por transtirretina / Tafamidis in transthyretin amyloid cardiomyopathy

CONTEXTO: transtirretina (ATTR), una enfermedad sistémica, poco frecuente, que se caracteriza por la presencia de depósitos de fibras de amiloide de transtirretina en varios tejidos y órganos. La transtirretina es una proteína sintetizada en el hígado cuya función es transportar tiroxina y retinol hacia los tejidos. Debido a una mutación génica o al envejecimiento, se ensambla de manera anómala, lo que permite que se agrupen entre sí y formen fibrillas amiloides que luego se depositaran en muchos órganos incluido el corazón. Existen dos tipos de ATTR-CM. El primero es hereditario, presenta una mutación en el gen de la transtirretina (autosómica dominante, con penetrancia incompleta), lo que resulta en el depósito de amiloide en corazón, nervios y con menor frecuencia riñones y otros órganos. Se presenta en pacientes con antecedentes familiares de ATTR o insuficiencia cardíaca y es más prevalente en hombres. Los síntomas se presentan con mayor frecuencia en mayores de 50, pero pueden iniciarse entre los 20 y los 80 años. TECNOLOGÍA: Tafamidis es una medicación oral, de administración diaria, cuya función es estabilizar la forma tetramérica nativa de la transtirretina. Se une al sitio de unión de tiroxina inhibiendo la disociación del tetrámero de TTR, el paso limitante en el proceso amiloidogénico.4 De esta forma, se impide la formación de fibrillas y fibras de amiloide que se depositarían en diferentes tejidos. OBJETIVO: El objetivo del presente informe es evaluar la evidencia disponible acerca de la eficacia, seguridad y aspectos relacionados a las políticas de cobertura del uso de tafamidis para cardiomiopatía amiloide por transtirretina en pacientes adultos. MÉTODOS: Se realizó una búsqueda en las principales bases de datos bibliográficas, en buscadores genéricos de internet, y financiadores de salud. Se priorizó la inclusión de revisiones sistemáticas (RS), ensayos clínicos controlados aleatorizados (ECAs), evaluaciones de tecnologías sanitarias (ETS), evaluaciones económicas, guías de práctica clínica (GPC) y políticas de cobertura de diferentes sistemas de salud. RESULTADOS: Se incluyeron un ECAs, una RS, cuatro GPC, una evaluación económica, y 12 informes de políticas de cobertura de tafamidis para cardiomiopatía amiloide por transtirretina. CONCLUSIONES: Evidencia de alta calidad muestra que el agregado de tafamidis al tratamiento estándar en pacientes con miocardiopatía amiloide por transtirretina produce un beneficio neto mayor dado que reduce la mortalidad por todas las causas en pacientes con clase funcional I/II de NYHA frente a placebo. Asimismo, reduce las hospitalizaciones por causa cardiovascular en este mismo grupo. Las guías de práctica clínica relevadas recomiendan el uso de tafamidis en pacientes con miocardiopatía amiloide por transtirretina. Remarcan su beneficio en estadios iniciales de la enfermedad y que la selección de pacientes debería ajustarse a los subgrupos en los que se evidencio beneficio. No se encontraron financiadores de salud latinoamericanos que presten cobertura para tafamidis en miocardiopatía amiloide por transtirretina. La mayoría de los financiadores estatales de países de altos ingresos no incluyen tafamidis entre sus coberturas de salud debido a su alto costo. Francia contempla su cobertura con un porcentaje de reembolso cercano a 60% y Canadá lo incluye entre sus coberturas, condicional a una reducción de precios. Si bien no se encontraron estudios de costo efectividad o impacto presupuestario en Argentina, su uso no resulto costo efectivo en una evaluación económica estadounidense y fue explicitamente excluido de la cobertura de otros sistemas de salud por su impacto presupuestario.

Unusual manifestation of genital cutaneous leishmaniasis in an immunocompetent patient from São Paulo, Brazil: A case report.

A 31-year-old male patient developed an ulcer on the glans penis that evolved for three months without healing. We diagnosed it as leishmaniasis using polymerase chain reaction. No immunosuppression or associated diseases were observed. The patient was treated with meglumine antimoniate that cured the lesion in a month post-treatment. Here, we report this case of cutaneous leishmaniasis lesion at the unusual location of glans penis in an immunocompetent individual. The lesion likely developed due to the bite of a vector, highlighting the need for considering cutaneous leishmaniasis among differential diagnosis of sexually transmitted diseases in areas endemic for leishmaniasis.

Tafamidis meglumina no tratamento de pacientes com cardiomiopatia amiloide associada à transtirretina (selvagem ou hereditária) acima de 60 anos de idade / Tafamidis meglumine does not treat patients with amyloid cardiomyopathy associated with transthyretin (selvagem or hereditary) over 60 years of age

Comissão Nacional de Incorporação de Tecnologias no SUS CONTEXTO: A cardiomiopatia amiloide associada à transtirretina (TTR), ou CM-TTR, integra o grupo de doenças amiloides raras sistêmicas caracterizadas pela deposição extracelular de proteína amiloide, que resulta em falência progressiva de órgãos. A CM-TTR pode se manifestar como dois genótipos: hereditária ou selvagem (adquirida ou senil) e em ambas a proteína amiloide pode infiltrar qualquer uma ou todas as estruturas cardiovasculares, incluindo o sistema de condução, o miocárdio atrial e ventricular, tecido valvar, as artérias e coronárias. Os sintomas geralmente incluem insuficiência cardíaca, dispneia ao esforço, retenção de líquidos e hipotensão. Na prática clínica, atualmente o tratamento envolve avaliação do paciente para transplante de fígado com ou sem associação de transplante cardíaco, cujo objetivo é prevenir a formação de depósitos amiloides adicionais e reduzir o ritmo de progressão da doença. TECNOLOGIA: Tafamidis meglumina (Vindaqel®). PERGUNTA: Qual a eficácia, segurança, custo-efetividade e impacto orçamentário do tafamidis meglumina no tratamento da cardiomiopatia amiloide associada à transtirretina (CM-TTR), selvagem ou hereditária, classe NYHA II e III, em pessoas acima de 60 anos de idade, na perspectiva do SUS? EVIDÊNCIAS CIENTÍFICAS: Foram incluídos dois estudos, um randomizado de fase III e um estudo aberto de fase II. O estudo clínico de fase III comparou a eficácia e segurança de tafamidis meglumina no tratamento da CM-TTR (selvagem ou hereditária) em pacientes adultos com o placebo. O grupo de pacientes tratados com o medicamento mostrou superioridade na redução da mortalidade por todas as causas e hospitalizações por causas cardiovasculares ao longo de 30 meses de acompanhamento em relação ao grupo placebo. Também foi observada redução do número de hospitalizações em pacientes com classe funcional NYHA I ou II e redução do declínio da capacidade funcional (medida por meio do teste de caminhada de 6 minutos) e da qualidade de vida no mês 30, com diferenças observadas logo no mês seis, quando comparado com placebo. O perfil de segurança do tafamidis meglumina foi semelhante ao placebo, com menor taxa de descontinuação. O estudo de fase II reportou na semana seis de tratamento, que tafamidis meglumina estabilizou efetivamente a TTR em 96,8% (30/31) dos pacientes com a forma selvagem de CM-TTR. Um único paciente que não obteve estabilização não sofreu problemas de segurança, permanecendo sem alcançar estabilização até o final do estudo. Todos os pacientes (n = 31) experimentaram um ou mais evento adverso (EA) durante o estudo, os mais frequentes foram sintomas ou episódios de insuficiência cardíaca, como dispneia, agravamento da insuficiência cardíaca e edema. AVALIAÇÃO ECONÔMICA: A análise de custo-efetividade foi apresentada na perspectiva do SUS, empregando-se um modelo de estados transicionais do tipo cadeias de Markov para acompanhar os pacientes com CM-TTR nas classes funcionas II ou III, considerando-se a transição por diferentes estados de saúde. De acordo com o resultado apresentado, tafamidis meglumina resultou em ganhos em anos de vida ajustados pela qualidade (AVAQ) e anos de vida ganhos (AVG) a partir de custo incremental de R$ 931.918,37 e R$ 760.018,87, respectivamente, por paciente, em um horizonte temporal lifetime de 25 anos. Avaliação de impacto orçamentário: A análise do impacto orçamentário (AIO) da ampliação de uso do tafamidis meglumina no SUS, foi realizada num horizonte de 5 anos. Devido à falta de dados precisos sobre prevalência da CM-TTR no mundo e no Brasil, a população elegível ao tratamento com tafamidis meglumina foi determinada pelo método epidemiológico, empregando-se dados da literatura a partir da estimativa populacional. Como resultados da análise, uma ampliação de uso do tafamidis meglumina no tratamento da CM-TTR resultou em um impacto orçamentário de R$ 31,4 milhões no primeiro ano e, em um horizonte de temporal de 5 anos, foi calculado um total acumulado de aproximadamente R$ 1,46 bilhão. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectadas quatro tecnologias potenciais para o tratamento da cardiomiopatia amiloide associada à transtirretina (selvagem ou hereditária), em pacientes acima de 60 anos. O acoramidis é um estabilizador de transtirretina para o potencial tratamento oral de cardiomiopatia amiloide e polineuropatia associadas à transtirretina. Já os medicamentos eplonterseno, patisirana e vutrisirana são silenciadores gênicos, que agem inibindo o gene TTR consequentemente inibindo a transtirretina e a deposição de proteína amiloide. CONSIDERAÇÕES: As evidências analisadas de acordo com a ferramenta GRADE foram identificadas de qualidade baixa a alta. Quanto aos desfechos, no ECR os pacientes tratados com o tafamidis mostraram superioridade na redução da mortalidade por todas as causas e hospitalizações por causas cardiovasculares ao longo de 30 meses de acompanhamento em relação ao grupo placebo, além de redução do declínio da capacidade funcional e da qualidade de vida, em comparação com o placebo. Houve ainda, no estudo aberto, estabilização efetiva da TTR em pacientes tratados com a forma selvagem de CM-TTR, no entanto, todos os pacientes experimentaram um ou mais EA como episódios de insuficiência cardíaca, como dispneia, agravamento da insuficiência cardíaca e edema. O perfil de segurança do tafamidis meglumina foi semelhante ao placebo. Na avaliação econômica, foi realizada uma análise de custo-efetividade (ACE). O tratamento com tafamidis resultou em ganhos em AVAQ e AVG a partir de custo incremental de, respectivamente, R$ 931.918,37 e R$ 760.018,87, por paciente por benefício ganho, em um horizonte temporal lifetime de 25 anos. Já a AIO foi estimada em um cenário base e dois alternativos, em um horizonte temporal de 5 anos. O cenário base representou um impacto orçamentário de R$ 31.449.136 no primeiro ano e um acumulado de R$ 1,46 bilhão em cinco anos. Como não existem dados epidemiológicos robustos sobre a prevalência e incidência da insuficiência cardíaca no Brasil, ou no mundo, portanto, as estimativas adotadas podem ter subestimado o impacto orçamentário. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, a Conitec, em sua 93ª reunião ordinária, realizada no dia 09 de dezembro de 2020, deliberou que a matéria fosse disponibilizada em consulta pública com recomendação preliminar desfavorável à incorporação no SUS do tafamidis meglumina para tratamento para tratamento de cardiomiopatia amiloide associada à transtirretina do tipo selvagem ou hereditária, classes NYHA II e III, em pacientes acima de 60 anos de idade. Os membros do plenário concordaram que, embora a demanda envolva proposta de tratamento para uma condição clínica rara, o preço proposto para incorporação da tecnologia apresentado pelo demandante é muito elevado e não é justificado pelas evidências científicas apresentadas, pouco robustas, pois, ainda que a evidência tenha sido avaliada de boa qualidade, baixo risco de viés e alta certeza de evidência para o desfecho primário clinicamente importante, esta possui limitação amostral e imprecisões significativas a ser consideradas para recomendar uma decisão. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: A Consulta Pública nº 70/2021 foi realizada entre os dias 05/01/2021 a 25/01/2021. Foram recebidas 361 contribuições, sendo 58 pelo formulário para contribuições técnico-científicas e 303 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. As contribuições foram majoritariamente discordantes da recomendação preliminar da Conitec, não favorável à incorporação do tafamidis meglumina pra CM-TTR. As argumentações nestas contribuições destacaram os benefícios clínicos que o medicamento oferece com base em evidências já apresentadas na discussão inicial do tema e reitera que o medicamento se trata de única opção terapêutica disponível. O fabricante do medicamento, e demandante do processo de incorporação, enviou documento técnico com contribuição acerca do Monitoramento do Horizonte Tecnológico (MHT), sobre a seção de Recomendações de outras agências de ATS e objeções acerca das evidências clínicas, avaliação econômica e impacto orçamentário. Coube à SE da Conitec retificar a seção de MHT, no que diz respeito ao registro do medicamento patisirana. No entanto, não foram adicionadas na CP referências que alterassem a análise das evidências científicas e econômicas apresentadas no relatório preliminar de recomendação. RECOMENDAÇÃO FINAL: Os membros do plenário presentes na 95ª reunião ordinária da Conitec, no dia 03 de março de 2021, deliberaram, por unanimidade, recomendar a não incorporação, no SUS, tafamidis meglumina para tratamento de cardiomiopatia amiloide associada à transtirretina do tipo selvagem ou hereditária, classes NYHA II e III, em pacientes acima de 60 anos de idade. Não foram adicionadas na CP referências que alterassem a análise da evidência apresentada no relatório preliminar. Foi assinado o Registro de Deliberação nº 595/2021. DECISÃO: Não incorporar o tafamidis meglumina no tratamento de pacientes com cardiomiopatia amiloide associada à transtirretina (selvagem ou hereditária) acima de 60 anos de idade, do Sistema Único de Saúde - SUS, conforme Portaria nº 09, publicada no Diário Oficial da União nº 53, seção 1, página 84, em 19 de março de 2021.

Unusual manifestation of genital cutaneous leishmaniasis in an immunocompetent patient from São Paulo, Brazil: A case report

Abstract A 31-year-old male patient developed an ulcer on the glans penis that evolved for three months without healing. We diagnosed it as leishmaniasis using polymerase chain reaction. No immunosuppression or associated diseases were observed. The patient was treated with meglumine antimoniate that cured the lesion in a month post-treatment. Here, we report this case of cutaneous leishmaniasis lesion at the unusual location of glans penis in an immunocompetent individual. The lesion likely developed due to the bite of a vector, highlighting the need for considering cutaneous leishmaniasis among differential diagnosis of sexually transmitted diseases in areas endemic for leishmaniasis.

Pregnancy rates and luteal phase characteristics of bovine embryo recipients treated with flunixin meglumine / Taxas de prenhez e características da fase lútea de receptoras de embriões tratadas com flunixina meglumina em bovinos

The aim of this study was to evaluate the effects of flunixin meglumine administration on pregnancy rates and luteal phase characteristics in bovine embryo recipients at the moment of embryo transfer. In experiment 1, in vitro produced embryos were transferred to 184 females divided as control and treated group (recipients treated with 1.1mg/kg flunixin meglumine). In experiment 2, 22 females were divided as control group; group 2 (animals submitted to a reproductive tract manipulation similar to an embryo transfer on the 7th day after estrous); and group 3 (females submitted to a manipulation and treatment with 1.1mg/kg flunixin meglumine). In experiment 1 no difference was observed between control and treated groups (40.2% and 44.6%, respectively) for pregnancy rates. In experiment 2 no difference was observed on the length of luteal phase between groups, however, animals in group 2 presented lower plasma progesterone concentrations than the control group and group 3. Therefore, we concluded that although the administration of flunixin meglumine at the moment of embryo transfer inhibited the reduction plasma progesterone concentrations, it was not effective in increasing pregnancy rates of bovine recipients.(AU)

O objetivo deste estudo foi avaliar os efeitos da administração de flunixina meglumina sobre as taxas de prenhez e características da fase lútea da receptora no momento da transferência de embriões em bovinos. No experimento 1, embriões produzidos in vitro foram transferidos para 184 fêmeas, divididas em grupos controle e tratado (tratados com 1,1mg/kg de flunixina meglumina). No experimento 2, 22 fêmeas foram divididas em grupo controle (n=7); grupo 2 (n=8; animais submetidos à manipulação do trato reprodutivo semelhante à transferência de embriões no sétimo dia pós-cio); e grupo 3 (n=7; fêmeas submetidas à manipulação e ao tratamento com 1,1mg/kg de flunixina meglumina). No experimento 1, não foi observada diferença nos grupos controle e tratado (40,2% e 44,6%, respectivamente) para as taxas de prenhez. No experimento 2, não houve diferença na extensão da fase lútea entre os grupos, entretanto os animais do grupo 2 apresentaram concentrações plasmáticas de progesterona mais baixas que o grupo controle e o grupo 3. Portanto, conclui-se que a administração de flunixina meglumina no momento da transferência de embriões inibiu a redução das concentrações plasmáticas de progesterona, no entanto não foi eficaz para aumentar as taxas de prenhez de receptoras em bovinos.(AU)

Pregnancy rates and luteal phase characteristics of bovine embryo recipients treated with flunixin meglumine / Taxas de prenhez e características da fase lútea de receptoras de embriões tratadas com flunixina meglumina em bovinos

The aim of this study was to evaluate the effects of flunixin meglumine administration on pregnancy rates and luteal phase characteristics in bovine embryo recipients at the moment of embryo transfer. In experiment 1, in vitro produced embryos were transferred to 184 females divided as control and treated group (recipients treated with 1.1mg/kg flunixin meglumine). In experiment 2, 22 females were divided as control group; group 2 (animals submitted to a reproductive tract manipulation similar to an embryo transfer on the 7th day after estrous); and group 3 (females submitted to a manipulation and treatment with 1.1mg/kg flunixin meglumine). In experiment 1 no difference was observed between control and treated groups (40.2% and 44.6%, respectively) for pregnancy rates. In experiment 2 no difference was observed on the length of luteal phase between groups, however, animals in group 2 presented lower plasma progesterone concentrations than the control group and group 3. Therefore, we concluded that although the administration of flunixin meglumine at the moment of embryo transfer inhibited the reduction plasma progesterone concentrations, it was not effective in increasing pregnancy rates of bovine recipients.(AU)

O objetivo deste estudo foi avaliar os efeitos da administração de flunixina meglumina sobre as taxas de prenhez e características da fase lútea da receptora no momento da transferência de embriões em bovinos. No experimento 1, embriões produzidos in vitro foram transferidos para 184 fêmeas, divididas em grupos controle e tratado (tratados com 1,1mg/kg de flunixina meglumina). No experimento 2, 22 fêmeas foram divididas em grupo controle (n=7); grupo 2 (n=8; animais submetidos à manipulação do trato reprodutivo semelhante à transferência de embriões no sétimo dia pós-cio); e grupo 3 (n=7; fêmeas submetidas à manipulação e ao tratamento com 1,1mg/kg de flunixina meglumina). No experimento 1, não foi observada diferença nos grupos controle e tratado (40,2% e 44,6%, respectivamente) para as taxas de prenhez. No experimento 2, não houve diferença na extensão da fase lútea entre os grupos, entretanto os animais do grupo 2 apresentaram concentrações plasmáticas de progesterona mais baixas que o grupo controle e o grupo 3. Portanto, conclui-se que a administração de flunixina meglumina no momento da transferência de embriões inibiu a redução das concentrações plasmáticas de progesterona, no entanto não foi eficaz para aumentar as taxas de prenhez de receptoras em bovinos.(AU)

Therapeutic Efficacy of a Mixed Formulation of Conventional and PEGylated Liposomes Containing Meglumine Antimoniate, Combined with Allopurinol, in Dogs Naturally Infected with Leishmania infantum.

The treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote a marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP plus Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg of body weight/dose) at 4-day intervals plus allopurinol at 30 mg/kg/12 h per os (p.o.) during 130 days (LCP+Allop); LC plus Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) plus allopurinol during 130 days (LC+Allop); Allop, treated with allopurinol only; and a nontreated control. Parasite loads were evaluated by quantitative PCR in liver, spleen, and bone marrow tissue and by immunohistochemistry in the ear skin, before treatment, just after treatment, and 4 months later. The LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen, and bone marrow 4 months after treatment compared to the pretreatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin in comparison to the control group. On the basis of clinical staging and parasitological evaluations, the LCP formulation exhibited a more favorable therapeutic profile than the LC one, being therefore promising for the treatment of canine visceral leishmaniasis.