CLIC1-mediated autophagy confers resistance to DDP in gastric cancer.

Gastric cancer has been a constant concern to researchers as one of the most common malignant tumors worldwide. The treatment options for gastric cancer include surgery, chemotherapy and traditional Chinese medicine. Chemotherapy is an effective treatment for patients with advanced gastric cancer. Cisplatin (DDP) has been approved as a critical chemotherapy drug to treat various kinds of solid tumors. Although DDP is an effective chemotherapeutic agent, many patients develop drug resistance during treatment, which has become a severe problem in clinical chemotherapy. This study aims to investigate the mechanism of DDP resistance in gastric cancer. The results show that intracellular chloride channel 1 (CLIC1) expression was increased in AGS/DDP and MKN28/DDP, and as compared to the parental cells, autophagy was activated. In addition, the sensitivity of gastric cancer cells to DDP was decreased compared to the control group, and autophagy increased after overexpression of CLIC1. On the contrary, gastric cancer cells were more sensitive to cisplatin after transfection of CLIC1siRNA or treatment with autophagy inhibitors. These experiments suggest that CLIC1 could alter the sensitivity of gastric cancer cells to DDP by activating autophagy. Overall, the results of this study recommend a novel mechanism of DDP resistance in gastric cancer.

Tumor suppressor CLCA1 inhibits angiogenesis via TGFB1/SMAD/VEGF cascade and sensitizes hepatocellular carcinoma cells to Sorafenib.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly vascularized tumor with a poor prognosis. Novel vascular-related therapeutic targets and prognostic markers remain urgently needed. AIMS: To investigate the role and mechanism of CLCA1 in hepatocellular carcinoma. METHODS: Immunofluorescence, Co-immunoprecipitation and rescue experiment were used to determine the specific mechanisms of CLCA1. Chemosensitivity assay was used to measure the impact of CLCA1 on Sorafenib. RESULTS: CLCA1 was dramatically downregulated in hepatocellular carcinoma cell lines and tissues. Ectopic expression of CLCA1 induced cell apoptosis and G0/G1 phase arrest while suppressed cell growth, inhibited migration and invasion, reversal of epithelial mesenchymal transition in vitro and reduced xenograft tumor growth in vivo. Mechanistically, CLCA1 could co-localize and interact with TGFB1, thereby suppressing HCC angiogenesis through the TGFB1/SMAD/VEGF signaling cascade in vitro and in vivo. Moreover, CLCA1 also enhanced the sensitivity of HCC cells to the first-line targeted therapy, Sorafenib. CONCLUSION: CLCA1 sensitizes HCC cells to Sorafenib and suppresses hepatocellular carcinoma angiogenesis through downregulating TGFB1 signaling cascade. This newly identified CLCA1 signaling pathway may help guide the anti-angiogenesis therapies for hepatocellular carcinoma. We also support the possibility of CLCA1 being a prognostic biomarker for hepatocellular carcinoma.

The role of ion channels in the relationship between the immune system and cancer.

The immune system is capable of identifying and eliminating cancer, a complicated illness marked by unchecked cellular proliferation. The significance of ion channels in the complex interaction between the immune system and cancer has been clarified by recent studies. Ion channels, which are proteins that control ion flow across cell membranes, have variety of physiological purposes, such as regulating immune cell activity and tumor development. Immune cell surfaces contain ion channels, which have been identified to control immune cell activation, motility, and effector activities. The regulation of immune responses against cancer cells has been linked to a number of ion channels, including potassium, calcium, and chloride channels. As an example, potassium channels are essential for regulating T cell activation and proliferation, which are vital for anti-tumor immunity. Calcium channels play a crucial role when immune cells produce cytotoxic chemicals in order to eliminate cancer cells. Chloride channels also affect immune cell infiltration and invasion into malignancies. Additionally, tumor cells' own expressed ion channels have an impact on their behavior and in the interaction with the immune system. The proliferation, resistance to apoptosis, and immune evasion of cancer cells may all be impacted by changes in ion channel expression and function. Ion channels may also affect the tumor microenvironment by controlling angiogenesis, inflammatory responses, and immune cell infiltration. Ion channel function in the interaction between the immune system and cancer has important implications for cancer treatment. A possible method to improve anti-tumor immune responses and stop tumor development is to target certain ion channels. Small compounds and antibodies are among the ion channel modulators under investigation as possible immunotherapeutics. The complex interaction between ion channels, the immune system, and cancer highlights the significance of these channels for tumor immunity. The development of novel therapeutic strategies for the treatment of cancer will be made possible by unraveling the processes by which ion channels control immune responses and tumor activity. Hence, the main driving idea of the present chapter is trying to understand the possible function of ion channels in the complex crosstalk between cancer and immunoresponse. To this aim, after giving a brief journey of ion channels throughout the history, a classification of the main ion channels involved in cancer disease will be discussed. Finally, the last paragraph will focus on more recently advancements in the use of biomaterials as therapeutic strategy for cancer treatment. The hope is that future research will take advantage of the promising combination of ion channels, immunomodulation and biomaterials filed to provide better solutions in the treatment of cancer disease.

CLIC1 regulation of cancer stem cells in glioblastoma.

Chloride intracellular channel 1 (CLIC1) has emerged as a therapeutic target in various cancers. CLIC1 promotes cell cycle progression and cancer stem cell (CSC) self-renewal. Furthermore, CLIC1 is shown to play diverse roles in proliferation, cell volume regulation, tumour invasion, migration, and angiogenesis. In glioblastoma (GB), CLIC1 facilitates the G1/S phase transition and tightly regulates glioma stem-like cells (GSCs), a rare population of self-renewing CSCs with central roles in tumour resistance to therapy and tumour recurrence. CLIC1 is found as either a monomeric soluble protein or as a non-covalent dimeric protein that can form an ion channel. The ratio of dimeric to monomeric protein is altered in GSCs and depends on the cell redox state. Elucidating the mechanisms underlying the alterations in CLIC1 expression and structural transitions will further our understanding of its role in GSC biology. This review will highlight the role of CLIC1 in GSCs and its significance in facilitating different hallmarks of cancer.

Targeting macrophagic PIM-1 alleviates osteoarthritis by inhibiting NLRP3 inflammasome activation via suppressing mitochondrial ROS/Cl- efflux signaling pathway.

BACKGROUND: Osteoarthritis (OA), in which macrophage-driven synovitis is considered closely related to cartilage destruction and could occur at any stage, is an inflammatory arthritis. However, there are no effective targets to cure the progression of OA. The NOD-, LRR-,and pyrin domain-containing protein 3 (NLRP3) inflammasome in synovial macrophages participates in the pathological inflammatory process and treatment strategies targeting it are considered to be an effective approach for OA. PIM-1 kinase, as a downstream effector of many cytokine signaling pathways, plays a pro-inflammatory role in inflammatory disease. METHODS: In this study, we evaluated the expression of the PIM-1 and the infiltration of synovial macrophages in the human OA synovium. The effects and mechanism of PIM-1 were investigated in mice and human macrophages stimulated by lipopolysaccharide (LPS) and different agonists such as nigericin, ATP, Monosodium urate (MSU), and Aluminum salt (Alum). The protective effects on chondrocytes were assessed by a modified co-culture system induced by macrophage condition medium (CM). The therapeutic effect in vivo was confirmed by the medial meniscus (DMM)-induced OA in mice. RESULTS: The expression of PIM-1 was increased in the human OA synovium which was accompanied by the infiltration of synovial macrophages. In vitro experiments, suppression of PIM-1 by SMI-4a, a specific inhibitor, rapidly inhibited the NLRP3 inflammasome activation in mice and human macrophages and gasdermin-D (GSDME)-mediated pyroptosis. Furthermore, PIM-1 inhibition specifically blocked the apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization in the assembly stage. Mechanistically, PIM-1 inhibition alleviated the mitochondrial reactive oxygen species (ROS)/chloride intracellular channel proteins (CLICs)-dependent Cl- efflux signaling pathway, which eventually resulted in the blockade of the ASC oligomerization and NLRP3 inflammasome activation. Furthermore, PIM-1 suppression showed chondroprotective effects in the modified co-culture system. Finally, SMI-4a significantly suppressed the expression of PIM-1 in the synovium and reduced the synovitis scores and the Osteoarthritis Research Society International (OARSI) score in the DMM-induced OA model. CONCLUSIONS: Therefore, PIM-1 represented a new class of promising targets as a treatment of OA to target these mechanisms in macrophages and widened the road to therapeutic strategies for OA.

Tezacaftor-ivacaftor para o tratamento de pacientes com fibrose cística com 12 anos de idade ou mais com mutação F508del do gene CFTR em homozigose ou com mutação F508del e uma das seguintes mutações: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, e 3849+10kbC→T: [maio de 2022] / Tezacaftor-ivacaftor for the treatment of cystic fibrosis patients 12 years of age and older with F508del mutation of the CFTR gene in homozygous or F508del mutation and one of the following mutations: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T: [May 2022]

INTRODUÇÃO: A Fibrose Cística é uma doença grave e rara, que comete vários sistemas orgânicos com repercussão direta na qualidade de vida de pacientes e familiares, bem como reduz significativamente a sobrevida dos portadores da enfermidade. Tezacaftor-ivacaftor têm mecanismos de ação complementares. Tezacaftor facilita o processamento celular e o tráfico de formas normais e mutantes de CFTR, para aumentar a quantidade de proteína CFTR madura enviada à superfície celular. O ivacaftor é um potencializador da proteína CFTR que aumenta a probabilidade de abertura do canal na superfície da célula para melhorar o transporte de cloreto. Para a atividade adequada de ivacaftor, a proteína CFTR deve estar presente na superfície da célula. O ivacaftor pode aumentar a quantidade de proteína CFTR na superfície da célula levada pelo tezacaftor, levando a um aumento adicional do transporte de cloreto, quando comparado a qualquer substância ativa sozinha. O efeito combinado do tezacaftor e do ivacaftor é o aumento da quantidade e função da proteína CFTR na superfície celular, resultando no aumento do transporte de cloreto. PERGUNTA: Tezacaftor-ivacaftor é efica

Clinical and Genetic Features of Chinese Adult Patients With Chronic Non-Bacterial Osteomyelitis: A Single Center Report.

Objectives: Chronic non-bacterial osteomyelitis (CNO) is a rare polygenic autoinflammatory bone disease. We aimed to characterize the clinical manifestations and gene variants of Chinese adult patients with CNO. Methods: By reviewing data of all CNO patients being diagnosed and followed up at the Center for Adult Autoinflammation Diseases, Department of Rheumatology, Peking Union Medical College Hospital, clinical and genetic features of these patients were evaluated and concluded. Results: The median age of disease onset was 19 (6-64) years old, and adult-onset was observed in 6 (60%) patients. The mean time of diagnosis delay was 92 ± 78 months. The common symptoms were bone pain (10, 100%), fever (9, 90%), and arthritis (6, 60%). In total, there were 54 skeletal lesions, and each patient had no less than 2 lesions. The most frequently affected sites included lower limbs (20.5%), mandible, vertebrae and pelvis (17.5%, separately). Variants of 4 genes were detected in our study including COL1A1, PSTPIP1, LRP5 and CLCN7. In seven patients who were treated with combination therapy containing tumor necrosis factor (TNF) α inhibitors, five (55.6%) had a complete response and 2 (44.4%) had a partial response. Conclusion: This is the first and largest case series of CNO in the Chinese adult patients. Four novel genetic mutations potentially associated with CNO were identified. Notably, CNO should be considered in the differential diagnosis of adult patients with long disease course and recurrent multifocal osteomyelitis of unknown cause, and these patients might benefit from combination therapy containing TNFα inhibitors.

Tezacaftor-ivacaftor para o tratamento de pacientes com fibrose cística com 12 anos de idade ou mais com mutação F508del do gene CFTR em homozigose ou com mutação F508del e uma das seguintes mutações: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, e 3849+10kbC→T: [fev. 2022] / Tezacaftor-ivacaftor for the treatment of cystic fibrosis patients 12 years of age and older with a homozygous F508del mutation of the CFTR gene or with an F508del mutation and one of the following mutations: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, and 3849+10kbC→T: [Feb. 2022]

INTRODUÇÃO: A Fibrose Cística é uma doença grave e rara, que acomete vários sistemas orgânicos com repercussão direta na qualidade de vida de pacientes e familiares, bem como reduz significativamente a sobrevida dos portadores da enfermidade. Tezacaftor-ivacaftor têm mecanismos de ação complementares. Tezacaftor facilita o processamento celular e o tráfico de formas normais e mutantes de CFTR, para aumentar a quantidade de proteína CFTR madura enviada à superfície celular. O ivacaftor é um potencializador da proteína CFTR que aumenta a probabilidade de abertura do canal na superfície da célula para melhorar o transporte de cloreto. Para a atividade adequada de ivacaftor, a proteína CFTR deve estar presente na superfície da célula. O ivacaftor pode aumentar a quantidade de proteína CFTR na superfície da célula levada pelo tezacaftor, levando a um aumento adicional do transporte de cloreto, quando comparado a qualquer substância ativa sozinha. O efeito combinado do tezacaftor e do ivacaftor é o aumento da quantidade e função da proteína CFTR na superfície celular, resultando no aumento do transporte de cloreto. TECNOLOGIA: Tezacaftor-ivacaftor (Symdeko®). PERGUNTA: Tezacaftor-ivacaftor é eficaz,seguro e custo-efetivo no tratamento de FC homozigótica para a mutação F508del ou heterozigótica para essa mutação e com uma outra mutação no gene CFTR responsivo ao tezacaftor-ivacaftor em pacientes com 12 anos de idade ou mais, quando comparado à terapia de suporte atualmente disponível no SUS? EVIDÊNCIAS CLÍNICAS: Dois ECR duplo cegos (EVOLVE e EXPAND) forneceram evidências sobre a eficácia e segurança do tezacaftor-ivacaftor em pacientes com FC com idade ≥ 12 anos que tenham duas cópias da mutação F508del, ou que tenham uma cópia da mutação F508del e pelo menos uma das seguintes mutações no gene da FC: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, e 3849+10kbC→T. Tezacaftor-ivacaftor proporcionou melhora no escore do domínio respiratório do CFQ-R até a semana 24 de 5,1 pontos (IC95%: 3,2-7,0) e a alteração média da linha de base do estudo para a média da semana 4 e semana 8 foi de 11,1 (IC95%: 8,7-13,6; p<0,001) pontos. Houve melhora na função respiratória no estudo EVOLVE comparado ao placebo (diferença média de quadrados mínimos ao longo de 24 semanas de 4,0 pontos percentuais; IC 95%, 3,1-4,8; p<0,001) e no estudo EXPAND, a diferença média dos mínimos quadrados desde o início do estudo até a semana 4 e semana 8 foi de 6,8 (IC95%: 5,7-7,8) pontos percentuais (p<0,001) versus ivacaftor. Tezacaftor-ivacaftor também proporcionou 35% menos risco de ocorrência de exacerbações pulmonares no estudo EVOLVE com RR = 0,65 (IC 95%: 0,48-0,88; p=0,005) e de 46% menos risco no estudo EXPAND com RR = 0,54 (IC 95%: 0,26-1,13; p=0,10). Em relação ao estado nutricional avaliado por meio do IMC, não foram observadas diferenças estatisticamente significativas. A concentração de cloreto no suor foi reduzida em 10,1 mmol/L no estudo EVOLVE (IC95%; -11,4 a -8,8) e em comparação com aqueles que receberam placebo: tezacaftor-ivacaftor, -9,5 mmol/L (IC95%: -11,7, -7,3; p<0,001) e versus ivacaftor foi de -5,1 mmol (IC95%: -7,0 a -3,1; p<0,001) no estudo EXPAND. Não foram identificados óbitos nos estudos e a frequência de eventos adversos foi menor nos pacientes do grupo tezacaftorivacaftor comparado a ivacaftor isolado ou placebo. A qualidade da evidência foi considerada moderada para todos os desfechos avaliados de acordo com a ferramenta GRADE. AVALIAÇÃO ECONÔMICA: O demandante apresentou um modelo de microssimulação para avaliar a razão de custoefetividade incremental (RCEI) com o uso, durante toda a vida, de tezacaftor-ivacaftor em combinação ao tratamento padrão para pacientes com FC com idade ≥12 anos homozigotos para a mutação F508del do gene CFTR (F/F) ou heterozigotos para a mutação F508del e uma segunda mutação associada à atividade residual de CFTR (F/RF), em comparação com o tratamento padrão isolado no SUS. Observou-se que tezacaftor-ivacaftor resultou em 7,87 anos de vida (AV) adicionais não descontados e 2,055 QALY incrementais descontados, culminando em uma RCEI de R$ 1.549.120,03/AV ganho e de R$ 1.580.752,23/QALY adicional. Destaca-se que os valores empregados podem ter sido subestimados por terem considerado a isenção de impostos, portanto, a RCEI pode ser superior, variando de 18% (somente ICMS) até 32,3% (incidência de todos os tributos). Além disso, em diferentes cenários com a variação de parâmetros, como descontos e componentes de custo, a RCEI da população total (ponderada) variou de R$ 551.274,00 a R$ 1.745.304,41. Nas análises de sensibilidade determinística univariada, os parâmetros que mais afetaram a RCEI foram a redução do declínio de ppVEF1, a adesão ao tratamento após o período de acompanhamento dos ensaios clínicos e aos valores de utilidade por gravidade da doença. A partir do diagrama de custo-efetividade da análise de sensibilidade probabilística, observou-se que tezacaftor-ivacaftor é consistentemente mais eficaz e mais caro em comparação com o tratamento padrão isoladamente. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Para se estimar a população elegível ao tezacaftor-ivacaftor no modelo de impacto orçamentário, foram utilizados dados do DATASUS com os CIDs de FC e os percentuais advindos de dados epidemiológicos no Brasil, considerado a genotipagem e a prevalência das mutações com indicação para o medicamento. Assim, estimouse que a incorporação de tezacaftor-ivacaftor no SUS resultará em um impacto orçamentário incremental acumulado de R$ 592.270.679,72 em cinco anos. Entretanto, destaca-se que os valores podem estar subestimados por ter sido considerada a isenção de impostos, portanto, um acrescimento de 18% a 32,3% pode fazer com que o impacto incremental varie de R$ 698.879.402,07 a R$ 783.574.109,27, no acumulado de cinco anos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram encontrados os medicamentos elexacaftor (em combinação com tezacaftor e ivacaftor) e VX-121 (em combinação com tezacaftor e deutivacaftor), ambos moduladores de CFTR, sendo que a associação elexacaftor + tezacaftor + ivacaftor apresenta-se sem registro na ANVISA, constando registro na agência europeia (EMA) datada de 2020 e na agência norte americana (FDA) em 2019. Em setembro de 2020, esta tecnologia foi avaliada na agência canadense CADTH, recebendo recomendação favorável mediante atendimento de condições específicas. Para a associação de VX-121 + tezacaftor + deutivacaftor, não há ainda registros em nenhuma das três agências referidas e o estudo clínico ainda está em fase de recrutamento. CONSIDERAÇÕES FINAIS: As evidências selecionadas, consideradas de qualidade moderada, demonstraram respostas superiores com o uso da associação tezacaftor-ivacaftor, quando comparada a placebo ou ivacaftor isoladamente, em todos os desfechos avaliados, à exceção no ganho de IMC. A análise de custo-efetividade realizada demonstrou uma RCEI de R$ 1.549.120,03/AV ganho e de R$ 1.580.752,23/QALY adicional, variando a depender dos parâmetros considerados. Já o impacto orçamentário incremental, foi estimado em R$ 592.270.679,72, no acumulado de cinco anos, podendo variar entre R$ 698.879.402,07 e R$ 783.574.109,27 em cinco anos, quando considerada a incidência de impostos. PERSPECTIVA DO PACIENTE: A chamada pública de número 49/2021 para participar da Perspectiva do Paciente foi aberta de 13/08/2021 a 27/08/2021 e nove pessoas se inscreveram. A indicação dos representantes titular e suplente para fazer o relato da experiência foi feita a partir de definição consensual por parte do grupo de inscritos. No relato, a participante descreveu como o uso do medicamento afetou positivamente sua qualidade de vida ao promover redução significativa da dificuldade de respirar, do cansaço, da produção de secreção e de manifestações intestinais. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Diante do exposto, o Plenário da Conitec, em sua 105ª Reunião Ordinária, no dia 09 de fevereiro de 2022, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação no SUS de tezacaftor-ivacaftor no tratamento de pacientes com fibrose cística (FC) com 12 anos de idade ou mais que tenham duas cópias da mutação F508del, ou que tenham uma cópia da mutação F508del e pelo menos uma das seguintes mutações no gene da FC: P67L, D110H, R117C, L206W, R352Q, A455E, D579G, 711+3A→G, S945L, S977F, R1070W, D1152H, 2789+5G→A, 3272-26A→G, e 3849+10kbC→T, foi considerada que há fragilidade na evidência científica apresentada e elevado impacto orçamentário. A matéria foi disponibilizada em consulta pública.

Potassium and Chloride Ion Channels in Cancer: A Novel Paradigm for Cancer Therapeutics.

Cancer is a collection of diseases caused by specific changes at the genomic level that support cell proliferation indefinitely. Traditionally, ion channels are known to control a variety of cellular processes including electrical signal generation and transmission, secretion, and contraction by controlling ionic gradients. However, recent studies had brought to light important facts on ion channels in cancer biology.In this review we discuss the mechanism linking potassium or chloride ion channel activity to biochemical pathways controlling proliferation in cancer cells and the potential advantages of targeting ion channels as an anticancer therapeutic option.

ClC-5 alleviates renal fibrosis in unilateral ureteral obstruction mice.

Renal fibrosis is the major feature of end-stage renal disease with high mortality. Chloride (Cl-) moving along Cl- channels has been suggested to play to an important role in renal function. This study aims to investigate the role of ClC-5 in renal fibrosis in unilateral ureteral occlusion (UUO) mice. C57BL/6 mice received UUO surgery followed by delivery of adeno-associated virus encoding ClC-5 cDNA (AAVClC-5). Western blotting, real-time PCR and histological analysis were used to investigate the effects of ClC-5 on renal fibrosis and underlying mechanisms. The expression of ClC-5 was significantly decreased in renal cortex of UUO mice and transforming growth factor-ß1 (TGF-ß1)-stimulated HK2 cells. Overexpression of ClC-5 in vivo markedly ameliorated UUO-induced renal injury and fibrosis. The increased expressions of plasminogen activator inhibitor type 1, connective tissue growth factor, collagen III and collagen IV were also inhibited by ClC-5 upregulation. Moreover, UUO-induced immune cell infiltration and inflammatory cytokines release were attenuated in mice infected with AAVClC-5. In addition, the in vivo and in vitro results showed that ClC-5 overexpression prevented epithelial-to-mesenchymal transition (EMT), concomitantly with a restoration of E-cadherin expression and a decrease of vimentin, α-SMA and S100A4 expressions. Furthermore, ClC-5 overexpression inhibited UUO- or TGF-ß1-induced increase in nuclear factor kappa B (NF-κB) acetylation and matrix metalloproteinases-9 (MMP-9) expression. However, downregulation of ClC-5 in HK2 cells further potentiated TGF-ß1-induced EMT and increase in NF-κB acetylation and MMP-9 expression. ClC-5 upregulation ameliorates renal fibrosis via inhibiting NF-κB/MMP-9 pathway signaling activation, suggesting that ClC-5 may be a novel therapeutic target for treating renal fibrosis and chronic kidney disease.

Chronic constipation: current treatment options.

Constipation is a common functional gastrointestinal disorder that affects patients of all ages. In 2007, a consensus group of 10 Canadian gastroenterologists developed a set of recommendations pertaining to the management of chronic constipation and constipation dominant irritable bowel syndrome. Since then, tegaserod has been withdrawn from the Canadian market. A new, highly selective serotonin receptor subtype 4 agonist, prucalopride, has been examined in several large, randomized, placebo-controlled trials demonstrating its efficacy and safety in the management of patients with chronic constipation. Additional studies evaluating the use of stimulant laxatives, polyethylene glycol and probiotics in the management of chronic constipation have also been published. The present review summarizes the previous recommendations and new evidence supporting different treatment modalities - namely, diet and lifestyle, bulking agents, stool softeners, osmotic and stimulant laxatives, prucalopride and probiotics in the management of chronic constipation. A brief summary of lubiprostone and linaclotide is also presented. The quality of evidence is presented by adopting the Grading of Recommendations, Assessment, Development and Evaluation system. Finally, a management pyramid for patients with chronic constipation is proposed based on the quality of evidence, impact of each modality on constipation and on general health, and their availabilities in Canada.

New treatment options for chronic constipation: mechanisms, efficacy and safety.

The present review has several objectives, the first of which is to review the pharmacology and selectivity of serotonergic agents to contrast the older serotonergic agents (which were withdrawn because of cardiac or vascular adverse effects) with the newer generation serotonin receptor subtype 4 agonists. Second, the chloride ion secretagogues that act through the guanylate cyclase C receptor are appraised and their pharmacology is compared with the approved medication, lubiprostone. Third, the efficacy and safety of the application of bile acid modulation to treat constipation are addressed. The long-term studies of surgically induced excess bile acid delivery to the colon are reviewed to ascertain the safety of this therapeutic approach. Finally, the new drugs for opiate-induced constipation are introduced. Assuming these drugs are approved, practitioners will have a choice; however, patient responsiveness will be based on trial and error. Nevertheless, the spectrum of mechanisms and demonstrated efficacy and safety augur well for satisfactory treatment outcomes.

Metabolism of [1,3-(13)C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-(13)C]succinate) in hepatocytes from Goto-Kakizaki rats.

The metabolism of [1,3-(13)C]glycerol-1,2,3-tris(methylsuccinate) and glycerol-1,2,3-tris(methyl[2,3-(13)C] succinate) was examined in hepatocytes prepared from hereditarily diabetic Goto-Kakizaki rats. Over 120 min incubation in the presence of one of the two (13)C-labelled esters (2.5 mM), the output of (13)C-enriched glucose averaged 57.1 +/- 18.5 and 54.1 +/- 22.7 nmol per 10(6) cells, when expressed as [1,3-(13)C]glycerol and [2,3-(13)C] succinate equivalent, respectively. In the case of [1,3-(13)C]glycerol-1,2,3-tris(methyl-succinate), the molecules of glucose were symmetrically labelled. In the case of glycerol-1,2,3-tris(methyl[2,3-(13)C] succinate), however, both the single-labelled and double-labelled isotopomers of glucose contained more (13)C atoms in their C(6)-C(5)-C(4) than C(1)-C(2)-C(3) moiety. These findings indicate that glycerol-1,2,3-tris(methylsuccinate), recently proposed as a novel insulinotropic tool for the treatment of non-insulin-dependent diabetes mellitus, is efficiently metabolized in hepatocytes from diabetic rats, the high rate of gluconeogenesis coinciding with channelling of D-glyceraldehyde-3-phosphate between glyceraldehyde-3-phosphate dehydrogenase and phosphofructoaldolase.