Cholesterol Exacerbates the Pathophysiology of Non-Alcoholic Steatohepatitis by Upregulating Hypoxia-Inducible Factor 1 and Modulating Microcirculatory Dysfunction.

Cholesterol is a pivotal lipotoxic molecule that contributes to the progression of Non-Alcoholic Steatohepatitis NASH). Additionally, microcirculatory changes are critical components of Non-Alcoholic Fatty Liver Disease (NAFLD) pathogenesis. This study aimed to investigate the role of cholesterol as an insult that modulates microcirculatory damage in NAFLD and the underlying mechanisms. The experimental model was established in male C57BL/6 mice fed a high-fat high-carbohydrate (HFHC) diet for 39 weeks. Between weeks 31-39, 2% cholesterol was added to the HFHC diet in a subgroup of mice. Leukocyte recruitment and hepatic stellate cells (HSC) activation in microcirculation were assessed using intravital microscopy. The hepatic microvascular blood flow (HMBF) was measured using laser speckle flowmetry. High cholesterol levels exacerbated hepatomegaly, hepatic steatosis, inflammation, fibrosis, and leukocyte recruitment compared to the HFHC group. In addition, cholesterol decreased the HMBF-cholesterol-induced activation of HSC and increased HIF1A expression in the liver. Furthermore, cholesterol promoted a pro-inflammatory cytokine profile with a Th1-type immune response (IFN-γ/IL-4). These findings suggest cholesterol exacerbates NAFLD progression through microcirculatory dysfunction and HIF1A upregulation through hypoxia and inflammation. This study highlights the importance of cholesterol-induced lipotoxicity, which causes microcirculatory dysfunction associated with NAFLD pathology, thus reinforcing the potential of lipotoxicity and microcirculation as therapeutic targets for NAFLD.

Análise de impacto orçamentário dos inibidores da PARP no tratamento do carcinoma de ovário avançado a partir de evidências de mundo real sob a perspectiva de um hospital federal referência em oncologia / Budget impact analysis of PARP inhibitors in the treatment of advanced ovarian cancer from on real-world evidence the perspective of a federal hospital reference in oncology

Objetivo: Avaliar o impacto orçamentário do tratamento com iPARP como primeira linha de manutenção, comparado ao tratamento-padrão a partir de evidências de mundo real sob a perspectiva de um hospital público referência em oncologia no Rio de Janeiro. Métodos: Foi aplicada uma análise de impacto orçamentário para estimar a introdução das tecnologias iPARP, olaparibe e niraparibe, em comparação com o cenário referência, utilizando dados de eficácia e evidências de mundo real, e considerando os custos globais de tratamento da doença em cinco anos. Este estudo foi aprovado pelo Comitê de Ética em Pesquisa, CAAE: 95157018.9.0000.5274. Resultados: A análise demonstrou que o cenário referência apresentou um impacto orçamentário no valor de R$ 3.578.768,04 em cinco anos. No cenário alternativo, o custo incremental do olaparibe chegou a ser 23,8% maior, comparado ao niraparibe, atingindo um custo de R$ 23.736.459,20 versus R$ 18.076.951,81, respectivamente. Os parâmetros que apresentaram maior impacto nas análises para a tecnologia olaparibe foram a difusão da tecnologia e o preço do medicamento. Contudo, para o niraparibe, os parâmetros de maior impacto foram a duração do tratamento, a difusão da tecnologia e a dose utilizada, demonstrando maior suscetibilidade de variação. Conclusão: Os iPARP no tratamento de pacientes com carcinoma de ovário avançado, apesar de apresentarem custo incremental de aproximadamente R$ 23 milhões em cinco anos, apontam para uma potencial redução de custos associados à progressão da doença.

Objective: Assess the budgetary impact of treatment with iPARP as a first line of maintenance, compared to standard treatment based on real-world evidence from the perspective of a public hospital reference in oncology at Rio de Janeiro. Methods: A budget impact analysis was applied to estimate the introduction of iPARP, olaparib and niraparib technologies, compared to the reference scenario, using efficacy data and real-world evidence, and considering the global costs of treating the disease in five years. This study was approved by the Research Ethics Committee, CAAE: 95157018.9.0000.5274. Results: The analysis showed that the reference scenario presented a budgetary impact of R$ 3,578,768.04 in five years. In the alternative scenario, the incremental cost of olaparib reached 23.8% higher compared to niraparib, reaching a cost of R$ 23,736,459.20 versus R$ 18,076,951.81, respectively. The parameters that had the greatest impact on the analyzes for the olaparib technology were technology diffusion and drug price. However, for niraparib, the parameters with the greatest impact were the duration of treatment, the diffusion of the technology and the dose used, demonstrating greater susceptibility to variation. Conclusion: iPARP in the treatment of patients with advanced ovarian carcinoma, despite having an incremental cost of approximately R$ 23 million in five years, point to a potential reduction in costs associated with disease progression.

Pharmacological profile and potential drug interactions in ovarian cancer hospitalized patients.

The aim of this study was to identify the main therapeutic classes prescribed to ovarian cancer patients and the potential drug interactions (PDI) during hospitalization. This descriptive retrospective work was carried out in a referral gynecological cancer hospital from the Brazilian public health system. The first 24 h inpatients' prescriptions were evaluated to obtain the pharmacological profile data. Clinical and epidemiological characteristics were collected through the analysis of electronic medical records. A total of 236 patients were included in the study, of which 154 (65.25%) had PDI, with a mean of 1.43 ± 1.76 interactions per patient. The main therapeutic classes prescribed were analgesics and antiemetics (35%), compatible with the oncologic supportive care. All PDI identified (n = 331) were categorized by severity, using the Micromedex database, resulting in: 1.51% contraindicated, 67.67% major, 24.77% moderate, and 6.04% minor. The more prevalent PDI were ondansetron/tramadol (22.05%) and metoclopramide/tramadol (7.25%), both major. An association between PDI and polypharmacy was observed, which did not occur between age or length of stay. Ongoing prescription review by the pharmaceutical team is necessary to identify, monitor, and manage PDI-related adverse events and carry out required interventions with patients, physicians, and nurses. Taken together the data showed that even in a specialized hospital, the complexity of the pharmacotherapy can cause harm to the ovarian cancer patient. The clinical pharmacist acting in a multidisciplinary team is important for improving patient safety in oncology services.

Simvastatin Improves Microcirculatory Function in Nonalcoholic Fatty Liver Disease and Downregulates Oxidative and ALE-RAGE Stress.

Increased reactive oxidative stress, lipid peroxidation, inflammation, and fibrosis, which contribute to tissue damage and development and progression of nonalcoholic liver disease (NAFLD), play important roles in microcirculatory disorders. We investigated the effect of the modulatory properties of simvastatin (SV) on the liver and adipose tissue microcirculation as well as metabolic and oxidative stress parameters, including the advanced lipoxidation end product-receptors of advanced glycation end products (ALE-RAGE) pathway. SV was administered to an NAFLD model constructed using a high-fat-high-carbohydrate diet (HFHC). HFHC caused metabolic changes indicative of nonalcoholic steatohepatitis; treatment with SV protected the mice from developing NAFLD. SV prevented microcirculatory dysfunction in HFHC-fed mice, as evidenced by decreased leukocyte recruitment to hepatic and fat microcirculation, decreased hepatic stellate cell activation, and improved hepatic capillary network architecture and density. SV restored basal microvascular blood flow in the liver and adipose tissue and restored the endothelium-dependent vasodilatory response of adipose tissue to acetylcholine. SV treatment restored antioxidant enzyme activity and decreased lipid peroxidation, ALE-RAGE pathway activation, steatosis, fibrosis, and inflammatory parameters. Thus, SV may improve microcirculatory function in NAFLD by downregulating oxidative and ALE-RAGE stress and improving steatosis, fibrosis, and inflammatory parameters.