RESUMO
The abnormal accumulation of fibrillar α-synuclein in the substantia nigra contributes to Parkinson's disease (PD). Chemical chaperones like 4-phenyl butyric acid (4PBA) show neuroprotective potential, but high doses are required. A derivative, 5-phenyl valeric acid (5PVA), has reported therapeutic potential for PD by reducing Pael-R expression. This study assessed 5PVA's efficacy in PD animals and its molecular mechanism. In vitro studies revealed 5PVA's anti-aggregation ability against alpha-synuclein and neuroprotective effects on SHSY5Y neuroblastoma cells exposed to rotenone. PD-like symptoms were induced in SD rats with rotenone, followed by 5PVA treatment at 100 mg/kg and 130 mg/kg. Behavioral analysis showed significant improvement in memory and motor activity with 5PVA administration. Histopathological studies demonstrated normal neuronal histoarchitecture in mid-brain tissue sections of 5PVA-treated animals compared to the PD group. mRNA studies revealed significant suppression in the expression of various protein folding and heat-shock protein markers in the 5PVA-treated group. In conclusion, 5PVA, with its anti-aggregation ability against alpha-synuclein, acts as a chemical chaperone, showing potential as a therapeutic candidate for PD treatment.
Assuntos
Estresse do Retículo Endoplasmático , Ratos Sprague-Dawley , Rotenona , alfa-Sinucleína , Animais , alfa-Sinucleína/metabolismo , Rotenona/toxicidade , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ratos , Masculino , Linhagem Celular Tumoral , Humanos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Ácidos Pentanoicos/farmacologia , Ácidos Pentanoicos/uso terapêutico , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/patologia , Agregados Proteicos/efeitos dos fármacosRESUMO
Immoderate caspase-mediated apoptosis in chronic liver injury is a crucial driver of sustained HSC activation and worsening hepatic inflammation as well as fibrosis, with the ultimate outcome of liver cirrhosis and its consequences. Therefore, the inhibition of hepatocyte apoptosis by caspase cascade blockage may be a promising therapeutic strategy to achieve fibrosis regression in chronic liver diseases. Emricasan is a broad-spectrum, liver-targeted caspase inhibitor with a favorable pharmacokinetic profile, characterized by prolonged retention in the liver and low systemic exposure after oral administration. In animal models, emricasan had a clear intrahepatic anti-apoptotic effect with consequent elimination of circulating pro-inflammatory cytokines and favorable impact in liver fibrogenesis and portal pressure. Even though, this intrahepatic drug effect confirmed in human clinical trials, no clear linkage was emerged with portal hypertension, liver function or liver histology in both non-cirrhotic and cirrhotic patients except from a subgroup of patients with high MELD score (> 15) or severe HVPG (> 16 mmHg). As emricasan treatment appeared safe and well-tolerated, irrespective the severity of liver disease, more studies are required to clarify better these subgroups of patients who may benefit most from this drug.
Assuntos
Hipertensão Portal , Ácidos Pentanoicos , Animais , Humanos , Hipertensão Portal/tratamento farmacológico , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Ácidos Pentanoicos/farmacologia , Ácidos Pentanoicos/uso terapêuticoRESUMO
BACKGROUND: Gastroesophageal reflux and Barrett's esophagus are significant risk factors for the development of esophageal adenocarcinoma. Group IIa secretory phospholipase A2 (sPLA2) catalyzes the production of various proinflammatory metabolites and plays a critical role in promoting reflux-induced inflammatory changes within the distal esophagus. We hypothesized that inhibition of sPLA2 in human Barrett's cells would attenuate adhesion molecule expression via decreased activation of nuclear factor kappa B (NF-κB) and decrease cell proliferation, possibly mitigating the invasive potential of Barrett's esophagus. MATERIALS AND METHODS: Normal human esophageal epithelial cells (HET1A) and Barrett's cells (CPB) were assayed for baseline sPLA2 expression. CPB cells were treated with a specific inhibitor of sPLA2 followed by tumor necrosis factor-α. Protein expression was evaluated using immunoblotting. Cell proliferation was assessed using an MTS cell proliferation assay kit. Statistical analysis was performed using the Student's t-test or analysis of variance, where appropriate. RESULTS: CPB cells demonstrated higher baseline sPLA2 expression than HET1A cells (P = 0.0005). Treatment with 30 µM sPLA2 inhibitor significantly attenuated intercellular adhesion molecule-1 (P = 0.004) and vascular cell adhesion molecule-1 (P < 0.0001) expression as well as decreased NF-κB activation (P = 0.002). sPLA2 inhibition decreased cell proliferation in a dose-dependent manner (P < 0.001 for 15, 20, and 30 µM doses). CONCLUSIONS: sPLA2 inhibition in human Barrett's cells decreases cellular adhesive properties and NF-κB activation as well as decreases cell proliferation, signifying downregulation of the inflammatory response and possible attenuation of cellular malignant potential. These findings identify sPLA2 inhibition as a potential chemopreventive target for premalignant lesions of the esophagus.
Assuntos
Esôfago de Barrett/patologia , Esôfago/patologia , Fosfolipases A2 do Grupo II/antagonistas & inibidores , Ácidos Pentanoicos/farmacologia , Adenocarcinoma/patologia , Adenocarcinoma/prevenção & controle , Esôfago de Barrett/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/prevenção & controle , Esôfago/citologia , Fosfolipases A2 do Grupo II/metabolismo , Humanos , Ácidos Pentanoicos/uso terapêuticoRESUMO
Parkinson's disease, the second common neurodegenerative disease is clinically characterized by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) with upregulation of neuroinflammatory markers and oxidative stress. Autophagy lysosome pathway (ALP) plays a major role in degradation of damaged organelles and proteins for energy balance and intracellular homeostasis. However, dysfunction of ALP results in impairment of α-synuclein clearance which hastens dopaminergic neurons loss. In this study, we wanted to understand the neuroprotective efficacy of Val in rotenone induced PD rat model. Animals received intraperitoneal injections (2.5 mg/kg) of rotenone daily followed by Val (40 mg/kg, i.p) for four weeks. Valeric acid, a straight chain alkyl carboxylic acid found naturally in Valeriana officianilis have been used in the treatment of neurological disorders. However, their neuroprotective efficacy has not yet been studied. In our study, we found that Val prevented rotenone induced upregulation of pro-inflammatory cytokine oxidative stress, and α-synuclein expression with subsequent increase in vital antioxidant enzymes. Moreover, Val mitigated rotenone induced hyperactivation of microglia and astrocytes. These protective mechanisms prevented rotenone induced dopaminergic neuron loss in SNpc and neuronal fibers in the striatum. Additionally, Val treatment prevented rotenone blocked mTOR-mediated p70S6K pathway as well as apoptosis. Moreover, Val prevented rotenone mediated autophagic vacuole accumulation and increased lysosomal degradation. Hence, Val could be further developed as a potential therapeutic candidate for treatment of PD.
Assuntos
Antioxidantes/farmacologia , Antiparkinsonianos/farmacologia , Autofagia , Neurônios Dopaminérgicos/efeitos dos fármacos , Estresse Oxidativo , Doença de Parkinson/tratamento farmacológico , Ácidos Pentanoicos/farmacologia , Animais , Antioxidantes/uso terapêutico , Antiparkinsonianos/uso terapêutico , Apoptose , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Neurônios Dopaminérgicos/metabolismo , Masculino , Doença de Parkinson/etiologia , Ácidos Pentanoicos/uso terapêutico , Ratos , Ratos Wistar , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Rotenona/toxicidade , Serina-Treonina Quinases TOR/metabolismo , Desacopladores/toxicidade , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9-/- tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Caspase 9/metabolismo , Inibidores de Caspase/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Colorretais/terapia , Ácidos Pentanoicos/uso terapêutico , Animais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Caspase 9/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transplante de Neoplasias , Transdução de Sinais , Regulação para CimaRESUMO
Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often arises in patients with a background of chronic liver disease and it is characterised by the rapid onset of jaundice and the development of myriad complications. Medical therapy for severe alcoholic hepatitis relies on corticosteroids, which have modest effectiveness. Abstinence from alcohol is critically important in patients with alcoholic hepatitis, but recidivism is high. Because of the absence of effective medical treatments for alcoholic hepatitis and alcohol dependency, there is a pressing need to develop new and effective therapeutics. Supported by promising preliminary and preclinical studies, many ongoing clinical trials of new therapies for alcoholic hepatitis are currently underway and are discussed further in this Series paper.
Assuntos
Corticosteroides/uso terapêutico , Alcoolismo/terapia , Anti-Inflamatórios/uso terapêutico , Hepatite Alcoólica/terapia , Abstinência de Álcool , Alcoolismo/complicações , Antibacterianos/uso terapêutico , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/etiologia , Humanos , Ácidos Pentanoicos/uso terapêutico , Probióticos/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , Transdução de Sinais , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Psoriasis is a common inflammatory skin disorder that is characterized by keratinocyte hyperproliferation and abnormal differentiation, resulting in the thickening of the epidermis and stratum corneum. In this study, we investigated in vitro and in vivo pharmacological effects of tussilagonone (TGN), a sesquiterpenoid isolated from Tussilago farfara, on transcription factors relevant for the pathogenesis of psoriasis. TGN inhibited activation of NF-κB and STAT3, leading to the attenuated expression of psoriasis-related inflammatory genes and suppression of keratinocyte hyperproliferation. Mechanistically, we show that the inhibition of NF-κB and STAT3 by TGN is mediated through activation of the cytoprotective transcription factor NRF2. Evaluation of in vivo antipsoriatic effects of topical TGN in the imiquimod-induced psoriasis-like dermatitis mouse model demonstrated amelioration of imiquimod-induced phenotypical changes, lesion severity score, epidermal thickening, and reduction in dermal cellularity. The spleen index also diminished in TGN-treated mice, suggesting anti-inflammatory properties of TGN. Moreover, TGN significantly attenuated the imiquimod-induced mRNA levels of psoriasis-associated inflammatory cytokines and antimicrobial peptides and reduced epidermal hyperproliferation. Taken together, TGN, as a potent NRF2 activator, is a promising therapeutic candidate for the development of antipsoriatic agents derived from medicinal plants.
Assuntos
Anti-Inflamatórios/farmacologia , Fator 2 Relacionado a NF-E2/agonistas , Ácidos Pentanoicos/farmacologia , Psoríase/tratamento farmacológico , Sesquiterpenos/farmacologia , Administração Cutânea , Adulto , Animais , Anti-Inflamatórios/uso terapêutico , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Imiquimode/toxicidade , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Ácidos Pentanoicos/uso terapêutico , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Sesquiterpenos/uso terapêutico , Tussilago/químicaRESUMO
BACKGROUND & AIMS: Caspase-mediated apoptosis and inflammation contribute to progression of liver disease. Emricasan is a pan-caspase inhibitor that reduced serum markers of apoptosis and liver inflammation in patients with hepatitis C and non-alcoholic steatohepatitis (NASH). METHODS: We performed a multicenter study of 86 patients with cirrhosis (Child-Pugh class A or B; mean score, 6.9; 38% with alcohol-associated cirrhosis, 29% with HCV-associated cirrhosis, and 23% with NASH) and model for end-stage liver disease (MELD) scores of 11-18 (mean, 12.8). Patients were randomly assigned to groups given placebo (N = 42) or Emricasan (25 mg, N = 44), twice daily for 3 months; subjects then received open-label Emricasan (25 mg) twice-daily for 3 months. The primary endpoint was the change from baseline in serum levels of cleaved keratin 18 (CK-18) at month 3. RESULTS: Seventy-four patients completed the 3-month study period (40 given Emricasan and 34 given placebo); 69 patients received open-label Emricasan for 3 months afterward. At the 3-month timepoint, Emricasan significantly reduced mean MELD (P = .003) and Child-Pugh (P = .003) scores in subjects with high MELD scores (15 or more), compared with placebo, with significant reductions in INR (95% CI, -0.2882 to -0.0866) and total bilirubin (95% CI, -1.5069 to -0.0823) vs placebo. There were no significant differences between Emricasan and placebo groups in mean MELD (P = .466) or Child-Pugh (P = .124) scores overall at 3 months compared to placebo. Of patients with high MELD scores, 6/9 given Emricasan (67%) had a reduction of 2 points or more at month 3, compared with 2/10 given placebo (20%). Serum levels of full-length CK-18 (P = .02) and caspase 3/7 (P < .001), but not cleaved CK-18 (P = .092), decreased significantly at 3 months in the Emricasan vs placebo group. Emricasan was well tolerated, and adverse events were balanced between groups. Emricasan's effects were generally maintained or increased after 6 months of treatment. CONCLUSIONS: In a randomized trial of patients with cirrhosis, we found 3 months treatment with Emricasan to improve liver function, compared with placebo, reducing MELD and Child-Pugh scores, INR, and total bilirubin in patients with MELD scores ≥15. ClinicalTrials.gov no: NCT02230670.
Assuntos
Inibidores de Caspase/uso terapêutico , Doença Hepática Terminal/tratamento farmacológico , Doença Hepática Terminal/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Ácidos Pentanoicos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Método Duplo-Cego , Feminino , Humanos , Queratina-18/sangue , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Soro/química , Resultado do TratamentoRESUMO
Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect.
Assuntos
Hipertensão Portal/tratamento farmacológico , Ácidos Pentanoicos/uso terapêutico , Pressão na Veia Porta/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Caspase 3/sangue , Feminino , Humanos , Hipertensão Portal/sangue , Hipertensão Portal/etiologia , Queratina-18/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Ácidos Pentanoicos/farmacologiaRESUMO
Development of portal hypertension (PHT) is a central prognostic factor in patients with cirrhosis. Circulating microparticles (MPs) are released by hepatocytes in a caspase-dependent manner, are increased in circulation of patients with cirrhosis, and contribute to PHT via induction of impaired vasoconstrictor responses. Here, we tested the hypothesis that emricasan, a pan-caspase inhibitor, ameliorates PHT and reduction in release of MPs. We used a short-term and long-term protocol following common bile-duct ligation (BDL) in C57BL/6 mice (10 and 20 days, respectively). Mice were treated daily via intraperitoneal injection with 10 mg/kg/day of emricasan or placebo. Circulating MP levels were analyzed using flow cytometry and function via ex vivo angiogenesis assays. In contrast to BDL-placebo group, nearly all BDL-emricasan-treated mice survived after long-term BDL. Assessment of portal pressure showed a significant increase in BDL-placebo mice compared to sham-placebo mice. In contrast, BDL-emricasan mice had significantly lower levels of portal pressure compared to BDL-placebo mice. Although emricasan treatment resulted in a decrease in fibrosis, the changes did not reach statistical significance, suggesting that the effects on PHT are at least in part independent of the anti-fibrotic effects of the drug. Following short-term BDL, hepatocellular cell death as well as liver fibrosis had improved and circulating MPs were significantly reduced in BDL-emricasan mice compared to BDL-placebo. Circulating MPs from BDL-placebo mice induced endothelial cell activation, and this was significantly reduced in MPs from BDL-emricasan mice. Our results indicate that emricasan treatment improves survival and PHT in a murine model of long-term BDL. Emricasan is a promising agent for the treatment of PHT. KEY MESSAGE: Emricasan, a pan-caspase inhibitor, improves survival and portal hypertension induced by long-term bile-duct ligation (BDL) in mice Emricasan reduces liver damage, hepatocyte death, and fibrosis, following short-term BDL in mice, and these changes are associated with a decrease in circulating microparticle (MPs) Circulating MPs from BDL-placebo but not from BDL-emiricasan-treated mice activate endothelial cells ex vivo.
Assuntos
Inibidores de Caspase/uso terapêutico , Hipertensão Portal/tratamento farmacológico , Ácidos Pentanoicos/uso terapêutico , Animais , Ductos Biliares/cirurgia , Modelos Animais de Doenças , Ligadura , Camundongos Endogâmicos C57BLRESUMO
Apoptosis and receptor-interacting protein kinase 1/3(RIPK1/3)-mediated necroptosis contribute to the cerebral ischemia/reperfusion (I/R) injury. Emricasan is an inhibitor of caspases in clinical trials for liver diseases while ponatinib could be a potential inhibitor for RIPK1/3. This study aims to investigate the effect of emricasan and/or ponatinib on cerebral I/R injury and the underlying mechanisms. Firstly, we evaluated the status of apoptosis and necroposis in a rat model of cerebral I/R under different conditions, which showed noticeable apoptosis and necroptosis under condition of 2-h ischemia and 24-h reperfusion; next, the preventive or therapeutic effect of emricasan or ponatinib on cerebral I/R injury was tested. Administration of emricasan or ponatinib either before or after ischemia could decrease the neurological deficit score and infarct volume; finally, the combined therapeutic effect of emricasan with ponatinib on I/R injury was examined. Combined application of emricasan and ponatinib could further decrease the I/R injury compared to single application. Emricasan decreased the activities of capase-8/-3 in the I/R-treated brain but not the protein levels of necroptosis-relevant proteins: RIPK1, RIPK3, and mixed lineage kinase domain-like (MLKL), whereas ponatinib suppressed the expressions of these proteins but not the activities of capase-8/-3. Combination of emricasan with ponatinib could suppress both capase-8/-3 and necroptosis-relevant proteins. Based on these observations, we conclude that combination of emricasan with ponatinib could synergistically reduce I/R injury in rat brain through simultaneous prevention of apoptosis and necroptosis. Our findings might lay a basis on extension of the clinical indications for emricasan and ponatinib in treating ischemic stroke.
Assuntos
Apoptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Imidazóis/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Ácidos Pentanoicos/uso terapêutico , Piridazinas/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Caspases/metabolismo , Modelos Animais de Doenças , Sinergismo Farmacológico , Quimioterapia Combinada , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Necrose/prevenção & controle , Exame Neurológico , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Estatísticas não ParamétricasRESUMO
INTRODUCTION: Irritable bowel syndrome (IBS) is a multifactorial functional gut disorder, where sensory/motor disturbances seem to play a major role, with no satisfactory treatment for a majority of patients. Cholecystokinin (CCK) is a hormone with several effects on gastrointestinal function, and IBS patients have been shown to produce altered sensory/motor responses to CCK. AREAS COVERED: Dexloxiglumide is a selective antagonist of the type 1 receptor of CCK, which has demonstrated to revert the CCK mediated effects on gastrointestinal motility and sensitivity. In humans, Dexloxiglumide has been shown to accelerate gastric emptying, slow down transit in the proximal colon, and increase the tolerance to intestinal gas. In phase 2 clinical trials Dexloxiglumide 200 mg tid has demonstrated to be superior to placebo in symptom relief in constipation predominant IBS (IBS-C). In a phase 3 withdrawal study Dexloxiglumide obtained a more sustained effect than placebo. However, these promising effects in IBS-C have not been confirmed in large phase 3 studies so far. EXPERT OPINION: Dexloxiglumide has demonstrated positive effects on important aspects of gastrointestinal function, like gastric emptying and gas tolerance, that deserves consideration in future studies. However, the available data is insufficient to recommend dexloxiglumide for treatment of IBS-C today.
Assuntos
Constipação Intestinal/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Ácidos Pentanoicos/uso terapêutico , Esvaziamento Gástrico/efeitos dos fármacos , Motilidade Gastrointestinal/efeitos dos fármacos , HumanosRESUMO
BACKGROUND: Participants with functional gut disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. To determine the role of cholecystokinin (CCK1 ) receptors on gas transit and tolerance in women with functional gut disorders. METHODS: In 12 healthy women, and 24 women with functional gut disorders (12 dyspepsia and 12 constipation-predominant irritable bowel syndrome) gas was infused into the jejunum at 12 mL/min for 3 h with simultaneous duodenal lipid infusion (intralipid 1 kcal/min), while measuring anal gas evacuation and abdominal symptoms on a 0-6 score scale. Triple-blind paired studies during iv infusion of dexloxiglumide (2.5 mg/kg bolus plus 5 mg/kg h continuous infusion), a selective CCK1 inhibitor, or saline (control) were performed in random order. RESULTS: During saline infusion participants with functional gut disorders developed significantly greater gas retention and abdominal symptoms than healthy subjects (394 ± 40 mL vs 265 ± 35 mL and 2.8 ± 0.3 vs 1.9 ± 0.4 highest abdominal symptom score, respectively; P < 0.05 for both). Dexloxiglumide increased gas retention in both groups (514 ± 35 mL and 439 ± 60 mL, respectively; P = 0.033 vs saline for both); however, despite the larger retention, dexloxiglumide reduced abdominal symptoms (2.3 ± 0.2 score and 0.8 ± 0.3 score, respectively; P = 0.05 vs saline for both). Post-hoc analysis showed that, the decrease in abdominal symptoms was more pronounced in those participants with functional gut disorders with higher basal abdominal symptoms than in the rest (P = 0.037). CONCLUSION: Inhibition of CCK1 receptors by dexloxiglumide increases intestinal gas retention and reduces abdominal symptoms in response to by intestinal gas loads. European Clinical Trials Database (EudraCT 2005-003338-16).
Assuntos
Dispepsia/metabolismo , Dispepsia/fisiopatologia , Flatulência/metabolismo , Flatulência/fisiopatologia , Gases/metabolismo , Trânsito Gastrointestinal , Síndrome do Intestino Irritável/metabolismo , Síndrome do Intestino Irritável/fisiopatologia , Ácidos Pentanoicos/farmacologia , Receptores da Colecistocinina/antagonistas & inibidores , Receptores da Colecistocinina/fisiologia , Adulto , Feminino , Flatulência/tratamento farmacológico , Trânsito Gastrointestinal/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Ácidos Pentanoicos/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic acid. LOX enzymes are expressed in immune, epithelial, and tumor cells that display a variety of physiological functions, including inflammation, skin disorder, and tumorigenesis. In the humans and mice, six LOX isoforms have been known. 15-LOX, a prototypical enzyme originally found in reticulocytes shares the similarity of amino acid sequence as well as the biochemical property to plant LOX enzymes. 15-LOX-2, which is expressed in epithelial cells and leukocytes, has different substrate specificity in the humans and mice, therefore, the role of them in mammals has not been established. 12-LOX is an isoform expressed in epithelial cells and myeloid cells including platelets. Many mutations in this isoform are found in epithelial cancers, suggesting a potential link between 12-LOX and tumorigenesis. 12R-LOX can be found in the epithelial cells of the skin. Defects in this gene result in ichthyosis, a cutaneous disorder characterized by pathophysiologically dried skin due to abnormal loss of water from its epithelial cell layer. Similarly, eLOX-3, which is also expressed in the skin epithelial cells acting downstream 12R-LOX, is another causative factor for ichthyosis. 5-LOX is a distinct isoform playing an important role in asthma and inflammation. This isoform causes the constriction of bronchioles in response to cysteinyl leukotrienes such as LTC4, thus leading to asthma. It also induces neutrophilic inflammation by its recruitment in response to LTB4. Importantly, 5-LOX activity is strictly regulated by 5-LOX activating protein (FLAP) though the distribution of 5-LOX in the nucleus. Currently, pharmacological drugs targeting FLAP are actively developing. This review summarized these functions of LOX enzymes under pathophysiological conditions in mammals.
Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/genética , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Asma/enzimologia , Indóis/uso terapêutico , Ácidos Pentanoicos/uso terapêutico , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Animais , Araquidonato 12-Lipoxigenase/genética , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/genética , Araquidonato 15-Lipoxigenase/metabolismo , Asma/genética , Asma/patologia , Ensaios Clínicos como Assunto , Expressão Gênica , Humanos , Ictiose/tratamento farmacológico , Ictiose/enzimologia , Ictiose/genética , Ictiose/patologia , Lipoxigenase/genética , Lipoxigenase/metabolismo , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , Neoplasias/patologiaRESUMO
BACKGROUND & AIMS: Hepatocyte apoptosis, the hallmark of non-alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH. METHODS: C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan. RESULTS: Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1-ß, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quantitative reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR. CONCLUSION: In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH.
Assuntos
Apoptose/efeitos dos fármacos , Inibidores de Caspase/uso terapêutico , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Ácidos Pentanoicos/uso terapêutico , Animais , Inibidores de Caspase/farmacologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibrose , Hepatite/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Ácidos Pentanoicos/farmacologiaRESUMO
Exercise-induced bronchoconstriction (EIB) describes the condition whereby exercise causes airflow obstruction that lasts for up to 90 minutes without treatment. This double-blind, placebo-controlled, five-way crossover study investigated the dose response and duration of action of a 5-lipoxygenase-activating protein inhibitor, GSK2190915, to inhibit EIB in subjects with asthma. Forty-seven subjects with EIB were enrolled. Exercise challenge testing was scheduled at 2, 9.5, and 24 hours after receiving a single dose of GSK2190915 (10, 50, 100, and 200 mg) or placebo in randomized order. GSK2190915 at 200 and 100 mg significantly attenuated the response to exercise at 2 and 9.5 hours postdose, respectively, compared with placebo. The adjusted mean maximum percentage change from baseline forced expiratory volume at 1 second within 60 minutes postexercise challenge (FEV1 (0-60)) treatment difference for GSK2190915 at 200 mg compared with placebo at 2 hours postdose was 6.30% (95% CI, 3.06, 9.54), corresponding to a 40% attenuation of the placebo response to exercise; the treatment difference between GSK2190915 at 100 mg and placebo at 9.5 hours postdose was 3.49% (95% CI, 1.02, 5.95), corresponding to a 41% attenuation of the placebo response to exercise. No significant effect was seen at 24 hours postdose with any dose; however, investigation of statistically significant treatment-related effects at this time point was limited because of the small fall in adjusted mean FEV1 (0-60) (-7.61%; 95% CI, -10.23, -4.99) after placebo. GSK2190915 may be of benefit in EIB prevention. GSK Clinical Study LPA112025; ClinicalTrials.gov identifier number: NCT00812929.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/uso terapêutico , Broncopatias/tratamento farmacológico , Broncopatias/etiologia , Exercício Físico , Indóis/uso terapêutico , Ácidos Pentanoicos/uso terapêutico , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Adulto , Asma , Constrição Patológica , Estudos Cross-Over , Teste de Esforço , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Indóis/farmacologia , Masculino , Ácidos Pentanoicos/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Patients with refractory asthma frequently have neutrophilic airway inflammation and respond poorly to inhaled corticosteroids. This study evaluated the effects of an oral 5-lipoxygenase-activating protein (FLAP) inhibitor, GSK2190915, in patients with asthma and elevated sputum neutrophils. Patients received 14 (range 13-16) days treatment with GSK2190915 100 mg and placebo with a minimum 14 day washout in a double-blind, cross-over, randomised design (N = 14). Sputum induction was performed twice pre-dose in each treatment period to confirm sputum neutrophilia, and twice at the end of each treatment period. The primary endpoint was the percentage and absolute sputum neutrophil count, averaged for end-of-treatment visits. GSK2190915 did not significantly reduce mean percentage sputum neutrophils (GSK2190915-placebo difference [95% CI]: -0.9 [-12.0, 10.3]), or mean sputum neutrophil counts (GSK2190915/placebo ratio [95% CI]: 1.06 [0.43, 2.61]). GSK2190915 resulted in a marked suppression (>90%) of sputum LTB4 and urine LTE4, but did not alter clinical endpoints. There were no safety issues. Despite suppressing the target mediator LTB4, FLAP inhibitor GSK2190915 had no short-term effect on sputum cell counts or clinical endpoints in patients with asthma and sputum neutrophilia.
Assuntos
Inibidores da Proteína Ativadora de 5-Lipoxigenase/uso terapêutico , Asma/tratamento farmacológico , Indóis/uso terapêutico , Neutrófilos/metabolismo , Ácidos Pentanoicos/uso terapêutico , Inibidores da Proteína Ativadora de 5-Lipoxigenase/farmacologia , Adulto , Idoso , Asma/fisiopatologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Indóis/farmacologia , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Ácidos Pentanoicos/farmacologia , Escarro/metabolismo , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Transient receptor potential vanilloid 1 (TRPV1) is a Ca(2+)-permeable non-selective cation channel that transmits pain signals. TRPV1 is activated by multiple stimuli such as capsaicin, acid, and heat. During inflammation, TRPV1 is reported to be sensitized by protein kinase C (PKC) in dorsal root ganglia (DRG) neurons, which leads to reduction in the threshold of the temperature for TRPV1 activation to body temperature. This sensitization is considered to contribute to chronic inflammatory pain. In a previous study, we discovered orally active 5,5-diarylpentadienamide TRPV1 antagonists. To examine the effects of our TRPV1 antagonists on PKC-sensitized TRPV1, we developed an in vitro assay system to monitor the TRPV1 sensitization by PKC. In this assay system, our TRPV1 antagonists, such as (2E,4Z)-N-[(3R)-3-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quinolyl]-5-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)-2,4-pentadienamide (K-685), inhibited the activation of TRPV1 sensitized by PKC. The potentiation of heat-induced inward currents by PKC was seen in rat DRG neurons, and K-685 attenuated these currents. Furthermore, K-685 reversed the thermal hyperalgesia and mechanical allodynia in a rat complete Freund's adjuvant-induced inflammatory pain model. These results therefore suggest that K-685 has a strong potential as a new analgesic drug for the treatment of inflammatory pain.
Assuntos
Analgésicos , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Adjuvante de Freund/efeitos adversos , Inflamação/complicações , Ácidos Pentanoicos/farmacologia , Ácidos Pentanoicos/uso terapêutico , Proteína Quinase C/fisiologia , Quinolonas/farmacologia , Quinolonas/uso terapêutico , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo , Animais , Dor Crônica/etiologia , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Caspases, or cysteinyl-aspartate specific proteases, are major contributing enzymes in inflammation. Caspases are highly specific cysteine proteases closely involved in inflammatory responses that are associated with programmed cell death, or apoptosis. Inappropriate regulation of cell death, therefore, substantially results in a wide array of diseases including, but not limiting to, neurodegenerative disorders, ischemic disorders, and cancer. The key molecular genes that control cell death are those cell death effectors (pro-apoptosis) of the caspase family, on one hand, and the cell death inhibitors (anti-apoptosis) of the Bcl-2 family, on the other hand. This unequivocal and unprecedented equilibrium between caspases and Bcl-2-related molecules essentially controls cells' final demise. Caspases and related proteases are potential therapeutic targets in a variety of acute and chronic diseases. Current design of biologically active molecules in recent technology is dependent on DNA-based scanning of the genome to engineer a variety of molecules such as apoptosis inhibitors, caspase regulators and caspase activators, and cytokines involved in caspase signaling. This synopsis aims to review relevant patents and to unravel the discovery of small-molecule caspase protease inhibitors and their clinical ramifications, and further sheds light on recent experimental and clinical trials, emphasizing a small molecule dubbed 3-[2-[(2- tert-butyl-phenylaminooxalyl)-amino]-propionylamino]-4-oxo-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid (IDN- 6556/PF-03491390). Current opinion on investigational drugs targeting caspases and caspase-like proteases bears the significance of understanding the mechanisms of alleviating inflammatory-related acute and chronic conditions and their biomedical applications and repercussions.
Assuntos
Caspases/metabolismo , Hepatopatias/tratamento farmacológico , Ácidos Pentanoicos/farmacologia , Inibidores de Proteases/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Patentes como Assunto , Ácidos Pentanoicos/uso terapêutico , Inibidores de Proteases/uso terapêuticoRESUMO
BACKGROUND: GSK2190915 is a high affinity 5-lipoxygenase-activating protein inhibitor being developed for the treatment of asthma. The objective of this study was to evaluate GSK2190915 efficacy, dose-response and safety in subjects with persistent asthma treated with short-acting beta2-agonists (SABAs) only. METHODS: Eight-week multicentre, randomised, double-blind, double-dummy, stratified (by age and smoking status), parallel-group, placebo-controlled study in subjects aged ≥12 years with a forced expiratory volume in 1 second (FEV1) of 50-85% predicted. Subjects (n = 700) were randomised to receive once-daily (QD) oral GSK2190915 (10-300 mg), twice-daily inhaled fluticasone propionate 100 µg, oral montelukast 10 mg QD or placebo. The primary endpoint was mean change from baseline (randomisation) in trough (morning pre-dose and pre-rescue bronchodilator) FEV1 at the end of the 8-week treatment period. Secondary endpoints included morning and evening peak expiratory flow, symptom-free days and nights, rescue-free days and nights, day and night-time symptom scores, day and night-time rescue medication use, withdrawals due to lack of efficacy, Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores. RESULTS: For the primary endpoint, there was no statistically significant difference between any dose of GSK2190915 QD and placebo. However, repeated measures sensitivity analysis demonstrated nominal statistical significance for GSK2190915 30 mg QD compared with placebo (mean difference: 0.115 L [95% confidence interval: 0.00, 0.23], p = 0.044); no nominally statistically significant differences were observed with any of the other doses. For the secondary endpoints, decreases were observed in day-time symptom scores and day-time SABA use for GSK2190915 30 mg QD versus placebo (p ≤ 0.05). No dose-response relationship was observed for the primary and secondary endpoints across the GSK2190915 dose range studied; the 10 mg dose appeared to be sub-optimal. GSK2190915 was associated with a dose-dependent reduction in urinary leukotriene E4. The profile and incidence of adverse events were similar between treatment groups. CONCLUSION: Efficacy was demonstrated for GSK2190915 30 mg compared with placebo in day-time symptom scores and day-time SABA use. No additional improvement on efficacy endpoints was gained by administration of GSK2190915 doses greater than 30 mg. GSK2190915 was well-tolerated. These results may support further studies with GSK2190915 30 mg. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01147744.