A Surprising Repurposing of Central Nervous System Drugs against Squamous Cell Carcinoma of the Bladder, UM-UC-5.

The potential benefits of drug repurposing have gained attention as an alternative to developing de novo drugs. The potential of using central nervous system (CNS) drugs as anticancer drugs has been explored in several types of human cancers, such as breast and colon cancer, among others. Here, we examine the effect of the CNS drugs sertraline, paroxetine, and chlorpromazine on human squamous carcinoma cells of the bladder (UM-UC-5). After exposing UM-UC-5 cells to increased concentrations of each drug for 48 h, we assessed their metabolic activity using an MTT assay. Based on those results, we calculated cell viability and the half-maximal inhibitory concentration (IC50) values. The results suggest that the CNS drugs were effective against UM-UC-5 in the order of potency of sertraline > chlorpromazine > paroxetine. Interestingly, sertraline was more potent than 5-fluorouracil (5-FU), a widely used anticancer drug. This study demonstrated, for the first time, the promising anticancer activity of CNS drugs on human bladder cancer cells in vitro and supports the repurposing of CNS drugs to improve cancer treatment. Nevertheless, further studies are necessary to understand their mechanism of action and in vivo activity.

New Perspective for Using Antimicrobial and Cell-Penetrating Peptides to Increase Efficacy of Antineoplastic 5-FU in Cancer Cells.

This study explores the effectiveness of the antineoplastic agent 5-FU in cancer cells by leveraging the unique properties of cationic antimicrobial peptides (CAMPs) and cell-penetrating peptides (CPPs). Traditional anticancer therapies face substantial limitations, including unfavorable pharmacokinetic profiles and inadequate specificity for tumor sites. These drawbacks often necessitate higher therapeutic agent doses, leading to severe toxicity in normal cells and adverse side effects. Peptides have emerged as promising carriers for targeted drug delivery, with their ability to selectively deliver therapeutics to cells expressing specific receptors. This enhances intracellular drug delivery, minimizes drug resistance, and reduces toxicity. In this research, we comprehensively evaluate the ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of various AMPs and CPPs to gain insights into their potential as anticancer agents. The peptide synthesis involved a solid-phase synthesis using a Liberty Microwave Peptide Synthesizer. The peptide purity was confirmed via LC-MS and HPLC methods. For the ADMET screening, computational tools were employed, assessing parameters like absorption, distribution, metabolism, excretion, and toxicity. The cell lines A549 and UM-UC-5 were cultured and treated with 5-FU, CAMPs, and CPPs. The cell viability was measured using the MTT assay. The physicochemical properties analysis revealed favorable drug-likeness attributes. The peptides exhibited potential inhibitory activity against CYP3A4. The ADMET predictions indicated variable absorption and distribution characteristics. Furthermore, we assessed the effectiveness of these peptides alone and in combination with 5-FU, a widely used antineoplastic agent, in two distinct cancer cell lines, UM-UC-5 and A549. Our findings indicate that CAMPs can significantly reduce the cell viability in A549 cells, while CPPs exhibit promising results in UM-UC-5 cells. Understanding these multifaceted effects could open new avenues for antiviral and anticancer research. Further, experimental validation is necessary to confirm the mechanism of action of these peptides, especially in combination with 5-FU.

Understanding the Clinical Use of Levosimendan and Perspectives on its Future in Oncology.

Drug repurposing, also known as repositioning or reprofiling, has emerged as a promising strategy to accelerate drug discovery and development. This approach involves identifying new medical indications for existing approved drugs, harnessing the extensive knowledge of their bioavailability, pharmacokinetics, safety and efficacy. Levosimendan, a calcium sensitizer initially approved for heart failure, has been repurposed for oncology due to its multifaceted pharmacodynamics, including phosphodiesterase 3 inhibition, nitric oxide production and reduction of reactive oxygen species. Studies have demonstrated that levosimendan inhibits cancer cell migration and sensitizes hypoxic cells to radiation. Moreover, it exerts organ-protective effects by activating mitochondrial potassium channels. Combining levosimendan with traditional anticancer agents such as 5-fluorouracil (5-FU) has shown a synergistic effect in bladder cancer cells, highlighting its potential as a novel therapeutic approach. This drug repurposing strategy offers a cost-effective and time-efficient solution for developing new treatments, ultimately contributing to the advancement of cancer therapeutics and improved outcomes for patients. Further investigations and clinical trials are warranted to validate the effectiveness of levosimendan in oncology and explore its potential benefits in a clinical setting.

Repurposing of the Drug Tezosentan for Cancer Therapy.

Tezosentan is a vasodilator drug that was originally developed to treat pulmonary arterial hypertension. It acts by inhibiting endothelin (ET) receptors, which are overexpressed in many types of cancer cells. Endothelin-1 (ET1) is a substance produced by the body that causes blood vessels to narrow. Tezosentan has affinity for both ETA and ETB receptors. By blocking the effects of ET1, tezosentan can help to dilate blood vessels, improve the blood flow, and reduce the workload on the heart. Tezosentan has been found to have anticancer properties due to its ability to target the ET receptors, which are involved in promoting cellular processes such as proliferation, survival, neovascularization, immune cell response, and drug resistance. This review intends to demonstrate the potential of this drug in the field of oncology. Drug repurposing can be an excellent way to improve the known profiles of first-line drugs and to solve several resistance problems of these same antineoplastic drugs.

Improvement of the In Vitro Cytotoxic Effect on HT-29 Colon Cancer Cells by Combining 5-Fluorouacil and Fluphenazine with Green, Red or Brown Propolis.

Cancer is regard as one of the key factors of mortality and morbidity in the world. Treatment is mainly based on chemotherapeutic drugs that, when used in targeted therapies, have serious side effects. 5-fluorouracil (5-FU) is a drug commonly used against colorectal cancer (CRC), despite its side effects. Combination of this compound with natural products is a promising source in cancer treatment research. In recent years, propolis has become the subject of intense pharmacological and chemical studies linked to its diverse biological properties. With a complex composition rich in phenolic compounds, propolis is described as showing positive or synergistic interactions with several chemotherapeutic drugs. The present work evaluated the in vitro cytotoxic activity of the most representative propolis types, such as green, red and brown propolis, in combination with chemotherapeutic or CNS drugs on HT-29 colon cancer cell lines. The phenolic composition of the propolis samples was evaluated by LC-DAD-ESI/MSn analysis. According to the type of propolis, the composition varied; green propolis was rich in terpenic phenolic acids and red propolis in polyprenylated benzophenones and isoflavonoids, while brown propolis was composed mainly of flavonoids and phenylpropanoids. Generally, for all propolis types, the results demonstrated that combing propolis with 5-FU and fluphenazine successfully enhances the in vitro cytotoxic activity. For green propolis, the combination demonstrated an enhancement of the in vitro cytotoxic effect compared to green propolis alone, at all concentrations, while for brown propolis, the combination in the concentration of 100 µg/mL gave a lower number of viable cells, even when compared with 5-FU or fluphenazine alone. The same was observed for the red propolis combination, but with a higher reduction in cell viability. The combination index, calculated based on the Chou-Talalay method, suggested that the combination of 5-FU and propolis extracts had a synergic growth inhibitory effect in HT-29 cells, while with fluphenazine, only green and red propolis, at a concentration of 100 µg/mL, presented synergism.

Repurposing Benztropine, Natamycin, and Nitazoxanide Using Drug Combination and Characterization of Gastric Cancer Cell Lines.

Gastric cancer (GC) ranked as the fifth most incident cancer in 2020 and the third leading cause of cancer mortality. Surgical prevention and radio/chemotherapy are the main approaches used in GC treatment, and there is an urgent need to explore and discover innovative and effective drugs to better treat this disease. A new strategy arises with the use of repurposed drugs. Drug repurposing coupled with drug combination schemes has been gaining interest in the scientific community. The main objective of this project was to evaluate the therapeutic effects of alternative drugs in GC. For that, three GC cell lines (AGS, MKN28, and MKN45) were used and characterized. Cell viability assays were performed with the reference drug 5-fluororacil (5-FU) and three repurposed drugs: natamycin, nitazoxanide, and benztropine. Nitazoxanide displayed the best results, being active in all GC cells. Further, 5-FU and nitazoxanide in combination were tested in MKN28 GC cells, and the results obtained showed that nitazoxanide alone was the most promising drug for GC therapy. This work demonstrated that the repurposing of drugs as single agents has the ability to decrease GC cell viability in a concentration-dependent manner.

Atorvastatin and Nitrofurantoin Repurposed in the Context of Breast Cancer and Neuroblastoma Cells.

Chemotherapy still plays a central role in the treatment of cancer. However, it is often accompanied by off-target effects that result in severe side-effects and development of drug resistance. The aim of this work was to study the efficacy of different repurposed drugs on the viability of MCF-7 and SH-SY5Y breast cancer and neuroblastoma cells, respectively. In addition, combinations of these repurposed drugs with a classical chemotherapeutic drug (doxorubicin) were also carried out. The cytotoxic effects of the repurposed drugs were evaluated individually and in combination in both cancer cell lines, assessed by MTT assays and morphological evaluation of the cells. The results demonstrated that atorvastatin reduced the viability of both cell lines. However, nitrofurantoin was able to induce cytotoxic effects in MCF-7 cells, but not in SH-SY5Y cells. The combinations of the repurposed drugs with doxorubicin induced a higher inhibition on cell viability than the repurposed drugs individually. The combination of the two repurposed drugs demonstrated that they potentiate each other. Synergism studies revealed that the combination of doxorubicin with the two repurposed drugs was more effective in SH-SY5Y cells, compared to MCF-7 cells. Taken together, our preliminary study highlights the potential use of atorvastatin and nitrofurantoin in the context of breast cancer and neuroblastoma.

In Vitro Drug Repurposing: Focus on Vasodilators.

Drug repurposing aims to identify new therapeutic uses for drugs that have already been approved for other conditions. This approach can save time and resources compared to traditional drug development, as the safety and efficacy of the repurposed drug have already been established. In the context of cancer, drug repurposing can lead to the discovery of new treatments that can target specific cancer cell lines and improve patient outcomes. Vasodilators are a class of drugs that have been shown to have the potential to influence various types of cancer. These medications work by relaxing the smooth muscle of blood vessels, increasing blood flow to tumors, and improving the delivery of chemotherapy drugs. Additionally, vasodilators have been found to have antiproliferative and proapoptotic effects on cancer cells, making them a promising target for drug repurposing. Research on vasodilators for cancer treatment has already shown promising results in preclinical and clinical studies. However, additionally research is needed to fully understand the mechanisms of action of vasodilators in cancer and determine the optimal dosing and combination therapy for patients. In this review, we aim to explore the molecular mechanisms of action of vasodilators in cancer cell lines and the current state of research on their repurposing as a treatment option. With the goal of minimizing the effort and resources required for traditional drug development, we hope to shed light on the potential of vasodilators as a viable therapeutic strategy for cancer patients.

Age-related tolerance to paraquat-induced parkinsonism in Drosophila melanogaster.

Paraquat (PQ) is a widely used herbicide that can cross the dopaminergic neuronal membrane, accumulate in mitochondria and damage complex I of the electron transport chain, leading to neuronal death. In Drosophila melanogaster, PQ exposure leads to the development of parkinsonism and is a classical model for studying Parkinson's Disease (PD). Muscle mitochondrial dysfunction, affecting survival and locomotion, is described in familial PD in D. melanogaster mutants. However, no study has shown the effects of PQ-induced parkinsonism in D. melanogaster regarding muscle ultrastructure and locomotor behavior at different ages. Thus, we evaluated survival, locomotion, and morphological parameters of mitochondria and myofibrils using transmission electron microscopy in 2 and 15-day-old D. melanogaster, treated with different PQ doses: control, 10, 50, 100, 150, and 200 mM. PQ100mM presented 100% lethality in 15-day-old D. melanogaster, while in 2-day-old animals PQ150mM produced 20% lethality. Bradykinesia was only observed in 15-day-old D. melanogaster treated with PQ10 mM and PQ50 mM. However, these results are unlikely to be associated with changes to morphology. Taken together, our data indicate pathophysiological differences between PQ-induced parkinsonism and familial parkinsonism in D. melanogaster (resultant from gene mutations), demonstrating for the first time a differential susceptibility to PQ in two developmental stages.

The Advances in Glioblastoma On-a-Chip for Therapy Approaches.

This systematic review aimed to verify the use of microfluidic devices in the process of implementing and evaluating the effectiveness of therapeutic approaches in glioblastoma on-a-chip, providing a broad view of advances to date in the use of this technology and their perspectives. We searched studies with the variations of the keywords "Glioblastoma", "microfluidic devices", "organ-on-a-chip" and "therapy" of the last ten years in PubMed and Scopus databases. Of 446 articles identified, only 22 articles were selected for analysis according to the inclusion and exclusion criteria. The microfluidic devices were mainly produced by soft lithography technology, using the PDMS material (72%). In the microenvironment, the main extracellular matrix used was collagen type I. Most studies used U87-MG glioblastoma cells from humans and 31.8% were co-cultivated with HUVEC, hCMEC/D3, and astrocytes. Chemotherapy was the majority of therapeutic approaches, assessing mainly the cellular viability and proliferation. Furthermore, some alternative therapies were reported in a few studies (22.6%). This study identified a diversity of glioblastoma on-a-chip to assess therapeutic approaches, often using intermediate levels of complexity. The most advanced level implemented the intersection between different biological systems (liver-brain or intestine-liver-brain), BBB model, allowing in vitro studies with greater human genetic similarity, reproducibility, and low cost, in a highly customizable platform.

Repurposed Drugs in Gastric Cancer.

Gastric cancer (GC) is one of the major causes of death worldwide, ranking as the fifth most incident cancer in 2020 and the fourth leading cause of cancer mortality. The majority of GC patients are in an advanced stage at the time of diagnosis, presenting a poor prognosis and outcome. Current GC treatment approaches involve endoscopic detection, gastrectomy and chemotherapy or chemoradiotherapy in an adjuvant or neoadjuvant setting. Drug development approaches demand extreme effort to identify molecular mechanisms of action of new drug candidates. Drug repurposing is based on the research of new therapeutic indications of drugs approved for other pathologies. In this review, we explore GC and the different drugs repurposed for this disease.

Síndrome de Silver-Russell: Características clínicas, de neurodesenvolvimento e comunicação: Estudo de casos clínicos / Silver-Russell syndrome: clinical, neurodevelopmental and communication characteristics: clinical case studies

RESUMO A Síndrome de Silver Russel (SSR) é uma condição geneticamente heterogênea com fenótipo clínico que inclui restrição do crescimento intrauterino e pós-natal, alterações craniofaciais, assimetrias corporais, baixo índice de massa corporal e dificuldades alimentares. Há expectativa de alterações do desenvolvimento motor, da coordenação global e de fala. O presente estudo tem como objetivo apresentar características da síndrome, do neurodesenvolvimento e comunicação de três crianças do sexo masculino, com diagnóstico da síndrome, na faixa etária de 16, 18 e 44 meses, respectivamente. Cumpriram-se os critérios éticos. Foi realizada análise de prontuário, com objetivo de coletar informações da anamnese realizada com os responsáveis, e da avaliação realizada com as crianças. A avaliação foi realizada por meio da aplicação dos seguintes instrumentos: Observação do Comportamento Comunicativo (OCC), Teste de Screening de Desenvolvimento Denver-II (TSDD-II) e o Early Language Milestone Scale (ELMS). O levantamento de características confirmou a hipótese da SSR; na OCC verificou-se atraso nos comportamentos comunicativos para todos os participantes; no TSDD-II verificou-se atraso nas habilidades motora grossa, motora fina-adaptativa, linguagem e pessoal social. Na ELM verificou-se escores aquém do esperado para as funções auditiva receptiva e auditiva expressiva com habilidades receptivas mais desenvolvidas do que as habilidades expressivas. A SSR merece ser reconhecida pela comunidade científica, uma vez que as características fenotípicas e os dados de vida pregressa, possibilitam que seja levantada a hipótese da síndrome, visando o diagnóstico correto precocemente e um planejamento terapêutico que minimize os efeitos deletérios desta condição.

ABSTRACT Silver Russell Syndrome (SRS) is a genetically heterogeneous condition with a clinical phenotype that includes intrauterine and postnatal growth restriction, craniofacial alterations, body asymmetries, low body mass index, and feeding difficulties. Alterations in motor development, global coordination, and speech are expected. The current study aims to present the syndrome, neurodevelopment, and communication characteristics of three male children diagnosed with the syndrome, aged 16, 18, and 44 months, respectively. Ethical principles were followed. An analysis of the medical records, aiming to collect information of the anamnesis, conducted with the guardians, and of the assessment carried out with the children was performed. The assessment was performed by applying the following instruments: Communicative Behavior Observation (CBO), Development Screening Test Denver-II (TSDD-II), and the Early Language Milestone Scale (ELMS). The survey of characteristics confirmed the SRS hypothesis; it was verified a delay in communicative behavior for all participants in CBO; in TSDD-II there was a delay in gross motor, fine motor-adaptive, language, and social personal skills. Scores below expectations were found for receptive auditory and expressive auditory functions, with receptive abilities more developed than expressive abilities, in ELM. The SRS deserves to be recognized by the scientific community, since the phenotypic characteristics and the data from the previous life allow the hypothesis of the syndrome to be raised, aiming at an early correct diagnosis and therapeutic planning that minimizes the harmful effects of this condition.

Silver-Russell syndrome: clinical, neurodevelopmental and communication characteristics: clinical case studies. / Síndrome de Silver-Russell: Características clínicas, de neurodesenvolvimento e comunicação: Estudo de casos clínicos.

Silver Russell Syndrome (SRS) is a genetically heterogeneous condition with a clinical phenotype that includes intrauterine and postnatal growth restriction, craniofacial alterations, body asymmetries, low body mass index, and feeding difficulties. Alterations in motor development, global coordination, and speech are expected. The current study aims to present the syndrome, neurodevelopment, and communication characteristics of three male children diagnosed with the syndrome, aged 16, 18, and 44 months, respectively. Ethical principles were followed. An analysis of the medical records, aiming to collect information of the anamnesis, conducted with the guardians, and of the assessment carried out with the children was performed. The assessment was performed by applying the following instruments: Communicative Behavior Observation (CBO), Development Screening Test Denver-II (TSDD-II), and the Early Language Milestone Scale (ELMS). The survey of characteristics confirmed the SRS hypothesis; it was verified a delay in communicative behavior for all participants in CBO; in TSDD-II there was a delay in gross motor, fine motor-adaptive, language, and social personal skills. Scores below expectations were found for receptive auditory and expressive auditory functions, with receptive abilities more developed than expressive abilities, in ELM. The SRS deserves to be recognized by the scientific community, since the phenotypic characteristics and the data from the previous life allow the hypothesis of the syndrome to be raised, aiming at an early correct diagnosis and therapeutic planning that minimizes the harmful effects of this condition.

A Síndrome de Silver Russel (SSR) é uma condição geneticamente heterogênea com fenótipo clínico que inclui restrição do crescimento intrauterino e pós-natal, alterações craniofaciais, assimetrias corporais, baixo índice de massa corporal e dificuldades alimentares. Há expectativa de alterações do desenvolvimento motor, da coordenação global e de fala. O presente estudo tem como objetivo apresentar características da síndrome, do neurodesenvolvimento e comunicação de três crianças do sexo masculino, com diagnóstico da síndrome, na faixa etária de 16, 18 e 44 meses, respectivamente. Cumpriram-se os critérios éticos. Foi realizada análise de prontuário, com objetivo de coletar informações da anamnese realizada com os responsáveis, e da avaliação realizada com as crianças. A avaliação foi realizada por meio da aplicação dos seguintes instrumentos: Observação do Comportamento Comunicativo (OCC), Teste de Screening de Desenvolvimento Denver-II (TSDD-II) e o Early Language Milestone Scale (ELMS). O levantamento de características confirmou a hipótese da SSR; na OCC verificou-se atraso nos comportamentos comunicativos para todos os participantes; no TSDD-II verificou-se atraso nas habilidades motora grossa, motora fina-adaptativa, linguagem e pessoal social. Na ELM verificou-se escores aquém do esperado para as funções auditiva receptiva e auditiva expressiva com habilidades receptivas mais desenvolvidas do que as habilidades expressivas. A SSR merece ser reconhecida pela comunidade científica, uma vez que as características fenotípicas e os dados de vida pregressa, possibilitam que seja levantada a hipótese da síndrome, visando o diagnóstico correto precocemente e um planejamento terapêutico que minimize os efeitos deletérios desta condição.

Candida albicans Adaptation on Simulated Human Body Fluids under Different pH.

Candida albicans remains the most problematic of all Candida species, causing severe infections. Adaptation to different human body niches, such oral and urinary tracts, has been shown to be essential for survival and critical for virulence of C. albicans. Thus, the present work aimed to study the behaviour of C. albicans on simulated human body fluids (artificial saliva and urine) at different values of pH (pH 5.8 and 7) by determining its ability to develop two of the most important virulence factors: biofilms and filamentous forms. Under this study, it was demonstrated that C. albicans was able to grow as free cells and to develop biofilm communities composed of multiple cell types (yeast and elongated hyphal cells) on both simulated human body fluids and under different pH. It was interesting to note that the pH had little impact on C. albicans planktonic and biofilm growth, despite influencing the development of filamentous shapes in artificial saliva and urine. So, it was possible to infer that C. albicans presents a high plasticity and adaptability to different human body fluids, namely saliva and urine. These can be the justification for the high number of oral and urinary candidiasis in the whole world.

A study of some hepatic immunological markers, iron load and virus genotype in chronic hepatitis C.

BACKGROUND/AIMS: Host factors that may influence progression of hepatitis C infection to chronic hepatitis include T-cell responses and iron accumulation. We evaluated the hepatic expression of immunological markers relevant for a cytotoxic response in relation to viral and HFE genotype. METHODS: Frozen liver biopsies were obtained at diagnosis from 28 HFE genotyped patients. Sections stained for CD8, MHC-I, beta(2)m, HFE and CD68 were analyzed blind by morphometry. Response to therapy was available in 12 cases. RESULTS: A negative correlation was found between the number of CD8(+) cells and fibrosis. CD8(+) cells localized as clusters in portal tracts and sinusoids and were seen interacting with MHC-I positive lining cells. MHC-I and beta(2)m were expressed mainly in the endothelial and Kupffer cells. HFE was expressed in most, but not all, round and dendritic CD68(+) cells. Patients with virus genotype 3a had higher hepatic MHC-I and HFE expression, and a better-sustained response to IFN therapy than other patients. CONCLUSIONS: In chronic hepatitis C virus infection MHC-I expression in the liver seems to relate to viral-genotype. In addition, the expression of MHC-I molecules by Kupffer cells places them as probable important players in the host response to HCV.

Increased hepatic iron in mice lacking classical MHC class I molecules.

Iron accumulation in the liver in hereditary hemochromatosis (HH) has been shown to be highly variable. Some studies point to the importance of major histocompatibility complex (MHC) class I (MHC-I) and CD8(+) cells as modifiers of iron overload. In this report, using mice knockout for H2K(b-/-) and H2D(b-/-) genes, it is demonstrated that lack of classical MHC-I molecules results in a spontaneous increase of nonheme iron content in the liver (mainly located in the hepatocytes) when compared to wild-type mice. In CD8(-/-) and Rag2(-/-) mice, no spontaneous hepatic iron accumulation was observed. These results demonstrate for the first time that classical MHC-I molecules could be involved in the regulation of iron metabolism and contribute to the established genotype/phenotype discrepancies seen in HH.

Exercício de planificação operacional e financeira descentralizada e integrada - 1993/1994 / Decentralized and integrated operational and financial planning exercise - 1993/1994

1- Constatações Gerais | RAF - Como já tinha sido constatado na visita anterior a RAF esta bem organizada e Mostra ser capaz de fazer face ao aumento de volume de trabalho e de ter um controle satisfatório dos fundos alocados a Província (OGE e FE). NEP - A qualidade dos dados baixou em relação a ultima visita apresentando graves problemas organizacionais. O arquivo do NEP esta bastante desorganizado e o registo tem muitas incorrecções, sobretudo consultas externas e internamento. O fluxo de informação (consultas) dos distritos para a Província (NEP e Farmácia), parece estar bastante desorganizado. Como resultado, ambos os sectores têm informação incompleta. Aprovisionamento - Sector muito desorganizado, com registos que não permitem obter informação sobre o consumo anual dos bens materiais entrados na Província. 2. Actividades Volume de actividades - O volume de actividades realizado na província é bastante alto. A maior parte da actividade (61%) é realizada na capital c/ HP, nos 2 distritos -c/ HR, e em Massinga, que servem cerca de 35% da população. O que significa que o consumo/utilização em geral dos serviços de saúde é maior nestes distritos. Em parte, isto reflecte a discrepância que existe na distribuição dos recursos, criando uma acessibilidade e disponibilidade desiguais dos cuidados de saúde....