RESUMEN
Estrogen receptor (ER) activation by 17-ß estradiol (E2) can attenuate neuronal injury and behavioral impairments following global cerebral ischemia (GCI) in rodents. This study sought to further examine the discrete roles of ERs through characterization of the effects of selective ER activation on post-ischemic pro-inflammatory microglial activation, hippocampal neuronal injury, and anxiety-like behaviors. Forty-six ovariectomized (OVX) adult female Wistar rats received daily s.c injections (100⯵g/kg/day) of propylpyrazole triol (PPT; ERα agonist), diarylpropionitrile (DPN; ERß agonist), G-1 (G-protein coupled ER agonist; GPER), E2 (activating all receptors), or vehicle solution (VEH) for 21 days. After final injection, rats underwent GCI via 4-vessel occlusion (n=8 per group) or sham surgery (n=6, vehicle injections). The Open Field Test (OFT), Elevated Plus Maze (EPM), and Hole Board Test (HBT) assessed anxiety-like behaviors. Microglial activation (Iba1, CD68, CD86) in the basolateral amygdala (BLA), CA1 of the hippocampus, and paraventricular nucleus of the hypothalamus (PVN) was determined 8 days post-ischemia. Compared to sham rats, Iba1 activation and CA1 neuronal injury were increased in all ischemic groups except DPN-treated rats, with PPT-treated ischemic rats also showing increased PVN Iba1-ir expression. Behaviorally, VEH ischemic rats showed slightly elevated anxiety in the EPM compared to sham counterparts, with no significant effects of agonists. While no changes were observed in the OFT, emotion regulation via grooming in the HBT was increased in G-1 rats compared to E2 rats. Our findings support selective ER activation to regulate post-ischemic microglial activation and coping strategies in the HBT, despite minimal impact on hippocampal injury.
Asunto(s)
Ansiedad , Isquemia Encefálica , Región CA1 Hipocampal , Microglía , Fenoles , Pirazoles , Ratas Wistar , Animales , Femenino , Microglía/metabolismo , Microglía/efectos de los fármacos , Ratas , Ansiedad/metabolismo , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Isquemia Encefálica/metabolismo , Pirazoles/farmacología , Fenoles/farmacología , Ovariectomía , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Propionatos/farmacología , Propionatos/administración & dosificación , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Estradiol/farmacología , Modelos Animales de Enfermedad , Receptores de Estrógenos/metabolismo , Nitrilos/farmacologíaRESUMEN
Angus-crossbred steers (nâ =â 400; 369.7â ±â 7.6 kg) were used to determine the influence of trace mineral (TM) source and chromium propionate (Cr Prop) supplementation on performance, carcass characteristics, and ruminal and plasma variables in finishing steers. Steers were blocked by body weight (BW) and randomly assigned within block to treatments in a 2â ×â 2 factorial arrangement, with factors being: 1) TM source (STM or HTM) and 2) Cr supplementation (0 or 0.25 mg Cr/kg DM, -Cr orâ +â Cr, respectively). Treatments consisted of the addition of: 1) sulfate TM (STM; 90, 40, and 18 mg/kg DM of Zn, Mn, and Cu, respectively), 2) STM and 0.25 mg Cr/kg DM from Cr Prop, 3) hydroxychloride TM (HTM; 90, 40, and 18 mg/kg DM of Zn, Mn, and Cu, respectively), and 4) HTM and 0.25 mg Cr/kg DM from Cr Prop. Each treatment consisted of 10 replicate pens with 10 steers per pen. Body weights were obtained on consecutive days at the initiation and termination of the 154-d study. Steers were fed a steam-flaked corn-based finishing diet. Ractopamine hydrochloride was fed for the last 31 d of the study. Ruminal fluid and blood samples were obtained from one steer per pen on days 28 and 84 for ruminal volatile fatty acids (VFA) and plasma TM and glucose analysis. Steers were slaughtered at the end of the study and individual carcass data were collected. No Crâ ×â TM source interactions (P = 0.48) were detected. Steers supplemented with HTM had greater (P = 0.04) hot carcass weight (HCW), dressing percentage (DP), longissimus muscle (LM) area, and USDA yield grade (YG), and tended (P = 0.12) to have greater average daily gain (ADG) than those receiving STM. Average daily gain, gain:feed, dressing percentage, and longissimus muscle area were greater (P = 0.04) forâ +â Cr steers compared to-Cr steers. Hot carcass weight tended (P = 0.06) to be greater forâ +â Cr steers. Ruminal acetate concentrations at 28 d were lesser (P = 0.01) for HTM vs. STM steers, and greater (P = 0.04) forâ +â Cr steers compared to-Cr steers. Plasma concentrations of Zn, Cu, and Mn were not affected by TM source or Cr supplementation. Steers supplemented with Cr had greater (P = 0.05) plasma glucose concentrations than-Cr steers at 28 but not at 84 d. Results of this study indicate replacing STM with HTM improved carcass characteristics in finishing steers, and Cr Prop supplementation improved steer performance and carcass characteristics.
Trace minerals (TM) are supplemented to finishing cattle diets to prevent TM deficiencies. Sources of TM differ in their bioavailability and effect on rumen fermentation. Chromium is a TM required in low concentrations to enhance insulin activity. We tested the effect of TM source (hydroxychloride; HTM vs. sulfate; STM) and supplemental Cr propionate (Cr Prop) on performance and carcass characteristics of finishing steers. Providing 0.25 mg of supplemental Cr/kg DM, from Cr Prop, improved gain, feed efficiency, and carcass characteristics in steers. Steers supplemented with HTM tended to gain faster and had improved carcass characteristics of economic importance compared to those supplemented with STM.
Asunto(s)
Alimentación Animal , Dieta , Suplementos Dietéticos , Propionatos , Oligoelementos , Animales , Bovinos/fisiología , Bovinos/crecimiento & desarrollo , Masculino , Suplementos Dietéticos/análisis , Alimentación Animal/análisis , Dieta/veterinaria , Oligoelementos/farmacología , Oligoelementos/administración & dosificación , Propionatos/farmacología , Propionatos/administración & dosificación , Rumen/efectos de los fármacos , Rumen/metabolismo , Composición Corporal/efectos de los fármacos , Cromo/farmacología , Cromo/administración & dosificación , Fenómenos Fisiológicos Nutricionales de los Animales , Distribución Aleatoria , Carne/análisisRESUMEN
BACKGROUND: Primary biliary cholangitis is a rare, chronic cholestatic liver disease characterized by the destruction of interlobular bile ducts, leading to cholestasis and liver fibrosis. Whether elafibranor, an oral, dual peroxisome proliferator-activated receptor (PPAR) α and δ agonist, may have benefit as a treatment for primary biliary cholangitis is unknown. METHODS: In this multinational, phase 3, double-blind, placebo-controlled trial, we randomly assigned (in a 2:1 ratio) patients with primary biliary cholangitis who had had an inadequate response to or unacceptable side effects with ursodeoxycholic acid to receive once-daily elafibranor, at a dose of 80 mg, or placebo. The primary end point was a biochemical response (defined as an alkaline phosphatase level of <1.67 times the upper limit of the normal range, with a reduction of ≥15% from baseline, and normal total bilirubin levels) at week 52. Key secondary end points were normalization of the alkaline phosphatase level at week 52 and a change in pruritus intensity from baseline through week 52 and through week 24, as measured on the Worst Itch Numeric Rating Scale (WI-NRS; scores range from 0 [no itch] to 10 [worst itch imaginable]). RESULTS: A total of 161 patients underwent randomization. A biochemical response (the primary end point) was observed in 51% of the patients (55 of 108) who received elafibranor and in 4% (2 of 53) who received placebo, for a difference of 47 percentage points (95% confidence interval [CI], 32 to 57; P<0.001). The alkaline phosphatase level normalized in 15% of the patients in the elafibranor group and in none of the patients in the placebo group at week 52 (difference, 15 percentage points; 95% CI, 6 to 23; P = 0.002). Among patients who had moderate-to-severe pruritus (44 patients in the elafibranor group and 22 in the placebo group), the least-squares mean change from baseline through week 52 on the WI-NRS did not differ significantly between the groups (-1.93 vs. -1.15; difference, -0.78; 95% CI, -1.99 to 0.42; P = 0.20). Adverse events that occurred more frequently with elafibranor than with placebo included abdominal pain, diarrhea, nausea, and vomiting. CONCLUSIONS: Treatment with elafibranor resulted in significantly greater improvements in relevant biochemical indicators of cholestasis than placebo. (Funded by GENFIT and Ipsen; ELATIVE ClinicalTrials.gov number, NCT04526665.).
Asunto(s)
Chalconas , Fármacos Gastrointestinales , Cirrosis Hepática Biliar , Receptores Activados del Proliferador del Peroxisoma , Propionatos , Humanos , Administración Oral , Fosfatasa Alcalina/sangre , Bilirrubina/sangre , Chalconas/administración & dosificación , Chalconas/efectos adversos , Chalconas/uso terapéutico , Colestasis/sangre , Colestasis/tratamiento farmacológico , Colestasis/etiología , Método Doble Ciego , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/efectos adversos , Fármacos Gastrointestinales/uso terapéutico , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/complicaciones , Cirrosis Hepática Biliar/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/agonistas , PPAR alfa/agonistas , PPAR delta/agonistas , Propionatos/administración & dosificación , Propionatos/efectos adversos , Propionatos/uso terapéutico , Prurito/tratamiento farmacológico , Prurito/etiología , Resultado del Tratamiento , Ácido Ursodesoxicólico/efectos adversos , Ácido Ursodesoxicólico/uso terapéutico , Colagogos y Coleréticos/administración & dosificación , Colagogos y Coleréticos/efectos adversos , Colagogos y Coleréticos/uso terapéuticoRESUMEN
This study probed the neuroprotective influence of indole-3-propionic acid (IPA) in rats exposed to chlorpyrifos (CPF) alone at 5 mg/kg body weight or co-administered with IPA at 12.5 and 25 mg/kg for 14 days. Behavioral data indicated that IPA significantly (p < 0.05) abated CPF-mediated anxiogenic-like behaviors with concomitant improvement in the locomotor and exploratory behaviors as substantiated by track plots and heat maps data. Also, IPA mitigated CPF-mediated diminution in cholinergic and antioxidant defense systems whereas it markedly improved thioredoxin level and thioredoxin reductase activity in cerebral and cerebellar tissues of the animals. Co-administration of IPA significantly enhanced anti-inflammatory cytokine, interleukin-10 but suppressed oxidative and inflammatory stress, caspase-9 and caspase-3 activation with concomitant reduction in 8-hydroxy-2'-deoxyguanosine (8-OHdG) level and histological damage. Collectively, IPA-mediated neuroprotection involves modulation of cholinergic and redox-regulatory systems, inflammatory stress, apoptotic responses and DNA damage in cerebrum and cerebellum of rats.
Asunto(s)
Cloropirifos/toxicidad , Indoles/farmacología , Fármacos Neuroprotectores/farmacología , Propionatos/farmacología , Animales , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Cloropirifos/administración & dosificación , Daño del ADN/efectos de los fármacos , Indoles/administración & dosificación , Inflamación/tratamiento farmacológico , Insecticidas/toxicidad , Masculino , Oxidación-Reducción/efectos de los fármacos , Propionatos/administración & dosificación , Ratas WistarRESUMEN
Background: Piperine (PIP) is a powerful anti-oxidant and anti-inflammatory alkaloid which has been widely used in the treatment of various pathological conditions. However, few studies have clearly discussed the protective effects and potential mechanism of PIP in different neurological diseases. The aim of this study was to investigate the neuroprotective effect of PIP against 3-nitropropioninc acid (3-NP) induced neurobehavioral, biochemical and histopathological alterations in animals.Methods: Adult male Wistar rats were randomly divided into three groups. Group 1, the vehicle administered control group, received normal saline (p.o.). Group 2 received 3-NP (20 mg/kg.b.wt., i.p.) for 4 consecutive days. Group 3 received PIP (10 mg/kg.b.wt., p.o.) twice daily for a period of 4 days, 30 min before and 6 h after the 3-NP injection. Upon termination of treatment schedule, behavioral experiments were performed to access the behavioral outcomes. The brain striatal tissue was used for the estimation of monoamine oxidase activity and serotonin level. In addition, astrocytes activation was observed by GFAP immunostaining.Results: Our results showed that 3-NP induced behavioral impairments are attenuated by PIP co-treatment. Next, the extent of neuronal loss and astrocytes activation was reduced in the striatal brain region in PIP treated rats. Finally, it was observed that PIP alleviated the behavioral, biochemical, immunohistochemical and histological alterations.Conclusion: The results of the current study reveal the neuroprotective competency of PIP against Huntington disease like symptoms in rats.
Asunto(s)
Alcaloides/uso terapéutico , Benzodioxoles/uso terapéutico , Enfermedad de Huntington/tratamiento farmacológico , Trastornos Mentales/prevención & control , Fármacos Neuroprotectores , Nitrocompuestos/administración & dosificación , Piperidinas/uso terapéutico , Alcamidas Poliinsaturadas/uso terapéutico , Propionatos/administración & dosificación , Animales , Astrocitos/efectos de los fármacos , Astrocitos/fisiología , Conducta Animal/efectos de los fármacos , Cuerpo Estriado/química , Cuerpo Estriado/patología , Modelos Animales de Enfermedad , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/fisiopatología , Masculino , Monoaminooxidasa/análisis , Neuronas/efectos de los fármacos , Ratas , Ratas Wistar , Serotonina/análisisAsunto(s)
Mordeduras y Picaduras de Insectos/prevención & control , Repelentes de Insectos/administración & dosificación , Administración Tópica , Animales , DEET/administración & dosificación , DEET/farmacocinética , Humanos , Mordeduras y Picaduras de Insectos/metabolismo , Repelentes de Insectos/farmacocinética , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Aceites de Plantas/administración & dosificación , Propionatos/administración & dosificación , Propionatos/farmacocinéticaRESUMEN
Morbidity and mortality risks are enhanced in preeclamptic (PE) mothers and their offspring. Here, we asked if sexual dimorphism exists in (i) cardiovascular and renal damage evolved in offspring of PE mothers, and (ii) offspring responsiveness to antenatal therapies. PE was induced by administering NG-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg/day, oral gavage) to pregnant rats for 7 days starting from gestational day 14. Three therapies were co-administered orally with L-NAME, atrasentan (endothelin ETA receptor antagonist), terutroban (thromboxane A2 receptor antagonist, TXA2), or α-methyldopa (α-MD, central sympatholytic drug). Cardiovascular and renal profiles were assessed in 3-month-old offspring. Compared with offspring of non-PE rats, PE offspring exhibited elevated systolic blood pressure and proteinuria and reduced heart rate and creatinine clearance (CrCl). Apart from a greater bradycardia in male offspring, similar PE effects were noted in male and female offspring. While terutroban, atrasentan, or α-MD partially and similarly blunted the PE-evoked changes in CrCl and proteinuria, terutroban was the only drug that virtually abolished PE hypertension. Rises in cardiorenal inflammatory (tumor necrosis factor alpha, TNFα) and oxidative (isoprostane) markers were mostly and equally eliminated by all therapies in the two sexes, except for a greater dampening action of atrasentan, compared with α-MD, on tissue TNFα in female offspring only. Histopathologically, antenatal terutroban or atrasentan was more effective than α-MD in rectifying cardiac structural damage, myofiber separation, and cytoplasmic alterations, in PE offspring. The repair by antenatal terutroban or atrasentan of cardiovascular and renal anomalies in PE offspring is mostly sex-independent and surpasses the protection offered by α-MD, the conventional PE therapy.
Asunto(s)
Atrasentán/farmacología , Metildopa/farmacología , Naftalenos/farmacología , Preeclampsia/tratamiento farmacológico , Propionatos/farmacología , Animales , Atrasentán/administración & dosificación , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Modelos Animales de Enfermedad , Antagonistas de los Receptores de la Endotelina A/administración & dosificación , Antagonistas de los Receptores de la Endotelina A/farmacología , Femenino , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Masculino , Metildopa/administración & dosificación , NG-Nitroarginina Metil Éster , Naftalenos/administración & dosificación , Preeclampsia/fisiopatología , Embarazo , Atención Prenatal/métodos , Propionatos/administración & dosificación , Ratas , Receptores de Tromboxano A2 y Prostaglandina H2/antagonistas & inhibidores , Factores Sexuales , Simpaticolíticos/administración & dosificación , Simpaticolíticos/farmacologíaRESUMEN
Over the last 15 years there has been an accumulation of data supporting the concept of a gut-brain axis whereby dysbiosis of the gut microbiota can impact neurological function. Such dysbiosis has been suggested as a possible environmental exposure triggering multiple sclerosis (MS). Dysbiosis has been consistently shown to result in a reduction in short-chain fatty acid (SCFA) producing bacteria and a reduction in stool and plasma levels of propionate has been shown for MS patients independent of disease stage and in different geographies. A wealth of evidence supports the action of propionate on T-cell activity, resulting in decreased T-helper cell 1 (Th1) and T-helper cell 17 (Th17) numbers/activity and increased regulatory T cell (Treg cell) numbers/activity and an overall anti-inflammatory profile. These different T-cell populations play various roles in the pathophysiology of MS. A recent clinical study in MS patients demonstrated that supplementation of propionate reduces the annual relapse rate and slows disease progression. This review discusses this data and the relevant mechanistic background and discusses whether taming of the overactive immune system in MS is likely to allow easier bacterial and viral infection.
Asunto(s)
Esclerosis Múltiple/terapia , Propionatos/administración & dosificación , Animales , Suplementos Dietéticos , Modelos Animales de Enfermedad , Disbiosis , Microbioma Gastrointestinal/fisiología , Humanos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/microbiología , Propionatos/metabolismo , Linfocitos T/inmunologíaRESUMEN
The functions and mechanisms of GPR40 receptor to ameliorating the Alzheimer's disease (AD) by external treatment of encephalopathy remain unknown. In present study, the typical Aß1-42 induced mice model was applied to explore the functions and mechanisms of GPR40 receptor by external treatment of encephalopathy in AD. GPR40 agonist GW9508 and antagonist GW1100 were given by i.g injection to activate/inhibit the GPR40 receptor respectively in the gut of AD mouse which illustrated the function and mechanism of GPR40 receptor in ameliorating AD symptoms by external treatment of encephalopathy. A series of behavioral experiments were used to investigate the cognitive function and memory ability of mice, while molecular biology experiments such as Western blot, ELISA, flow cytometry were used to detect the corresponding changes of signaling pathways. The results revealed that intragastric administrated GW9508 could significantly ameliorate cognitive deficits of AD mouse, up-regulate the expression levels of gut-brain peptides both in blood circulation and hypothalamus thus up-regulate the expression levels of α-MSH in hypothalamus, while the negative autophagy-related proteins and inflammation-related proteins were down-regulated correspondingly. Meanwhile, GW9508 could also inhibit the pathological process of neuroinflammation in microglia. GW1100 reversed the effects of GW9508 significantly. These results suggested that GPR40 was an underlying therapeutic target for the external treatment of encephalopathy related to AD and GPR40 agonist could be explored as the emerging AD therapeutic drug.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Metilaminas/administración & dosificación , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Propionatos/administración & dosificación , Receptores Acoplados a Proteínas G/agonistas , Administración Oral , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/administración & dosificación , Péptidos beta-Amiloides/toxicidad , Animales , Técnicas de Observación Conductual , Barrera Hematoencefálica/metabolismo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/inmunología , Disfunción Cognitiva/patología , Regulación hacia Abajo/efectos de los fármacos , Humanos , Hipotálamo/efectos de los fármacos , Hipotálamo/inmunología , Hipotálamo/patología , Masculino , Metilaminas/farmacocinética , Ratones , Microglía/efectos de los fármacos , Microglía/inmunología , Microglía/patología , Enfermedades Neuroinflamatorias/diagnóstico , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/patología , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/toxicidad , Propionatos/farmacocinética , Receptores Acoplados a Proteínas G/metabolismo , Distribución TisularRESUMEN
Huntington's disease (HD) is characterized by abnormal involuntary movements together with cognitive impairment and disrupted mood changes. 3-nitropropionic acid (3-NP) is one of the chemo-toxic models used to address the striatal neurotoxicity pattern encountered in HD. This study aims to explain the neuroprotective effect of nano-formulated ivabradine (nano IVA) in enhancing behavioral changes related to 3-NP model and to identify the involvement of ras homolog enriched striatum (Rhes)/mammalian target of rapamycin (m-Tor) mediated autophagy pathway. Rats were divided into 6 groups, the first 3 groups received saline (control), ivabradine (IVA), nano IVA respectively, the fourth received a daily dose of 3-NP (20 mg/kg, s.c) for 2 weeks, the fifth received 3-NP + IVA (1 mg/kg, into the tail vein, every other day for 1 week) and the last group received 3-NP + nano IVA (1 mg/kg, i.v, every other day for 1 week). Interestingly, nano IVA reversed motor disabilities, improved memory function and overcame the psychiatric changes. It boosted expression of autophagy markers combined with down regulation of Rhes, m-Tor and b-cell lymphoma 2 protein levels. Also, it restored the normal level of neurotransmitters and myocardial function related-proteins. Histopathological examination revealed a preserved striatal structure with decreased number of darkly-degenerated neurons. In conclusion, the outcomes of this study provide a well-recognized clue for the promising neuroprotective effect of IVA and the implication of autophagy and Rhes/m-Tor pathways in the 3-NP induced HD and highlight the fact that nano formulations of IVA would be an auspicious approach in HD therapy.
Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Enfermedad de Huntington/inducido químicamente , Ivabradina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Serina-Treonina Quinasas TOR/metabolismo , Animales , Autofagia , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Enfermedad de Huntington/metabolismo , Masculino , Sistema de Administración de Fármacos con Nanopartículas , Nitrocompuestos/administración & dosificación , Propionatos/administración & dosificación , RatasRESUMEN
Cortexolone 17α-propionate, also known as clascoterone, is a potent androgen receptor inhibitor intended for the topical treatment of skin diseases associated with androgenic pathway alterations. In nonclinical studies, cortexolone 17α-propionate was found to have a weak inhibitory effect on human Ether-à-go-go-Related Gene (hERG) potassium channels, which are vital for normal electrical activity in the heart. When used in a cream formulation, little cortexolone 17α-propionate is absorbed. However, the solution formulation developed for the treatment of androgenetic alopecia leads to a measurable systemic concentration and accumulation of the antiandrogen. This phase 1 study assessed the effect of cortexolone 17α-propionate on the QTc interval using concentration-effect analysis and the effect of a meal on QTc to confirm assay sensitivity. Thirty-two volunteers were randomly assigned to receive the active drug or a matching vehicle as placebo. Participants were dosed twice daily on days 1 to 3 (225 mg applied topically as a 7.5% solution 12 hours apart) and once on day 4. Pharmacokinetic and electrocardiogram assessments were performed after supratherapeutic doses. Assay sensitivity was successfully confirmed by using the food effect on the QTc interval. The results of this concentration-QTc analysis demonstrate that cortexolone 17α-propionate and its metabolite/degradation product had no effect on the QTc interval in the concentration range tested.
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Antagonistas de Andrógenos/administración & dosificación , Cortodoxona/análogos & derivados , Interacciones Alimento-Droga , Propionatos/administración & dosificación , Administración Cutánea , Adolescente , Adulto , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/farmacocinética , Cortodoxona/administración & dosificación , Cortodoxona/efectos adversos , Cortodoxona/farmacocinética , Método Doble Ciego , Electrocardiografía , Femenino , Humanos , Masculino , Propionatos/efectos adversos , Propionatos/farmacocinética , Adulto JovenRESUMEN
Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure-response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose-response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad.
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Hiperuricemia/tratamiento farmacológico , Naftalenos/uso terapéutico , Transportadores de Anión Orgánico/antagonistas & inhibidores , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Propionatos/uso terapéutico , Piridinas/uso terapéutico , Ácido Úrico/sangre , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Combinada , Femenino , Humanos , Hiperuricemia/sangre , Hiperuricemia/orina , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Naftalenos/administración & dosificación , Naftalenos/farmacología , Propionatos/administración & dosificación , Propionatos/farmacología , Piridinas/administración & dosificación , Piridinas/farmacología , Ácido Úrico/orina , Xantina Oxidasa/antagonistas & inhibidores , Adulto JovenRESUMEN
This paper aimed to provide an insight into the mechanism of transdermal penetration of drug molecules with respect to their physicochemical properties, such as solubility (S), the presence of enantiomer (ET) and logarithm of octanol-water partition coefficient (log P), molecular weight (MW), and melting point (MP). Propionic acid derivatives were evaluated for their flux through full-thickness skin excised from hairless mice upon being delivered from silicone-based pressure-sensitive adhesive (PSA) matrices in the presence or absence of various enhancers. The skin fluxes of model compounds were calculated based on the data obtained using the method engaged with the diffusion cell system. The statistical design of experiments (DoE) based on the factorial approach was used to find variables that have a significant impact on the outcomes. For the prediction of skin flux, a quantitative equation was derived using the data-mining approach on the relationship between skin permeation of model compounds (~125 mg/ml) and involved physicochemical variables. The most influential variables for the skin flux of propionic acid derivatives were the melting point (0.97) followed by the presence of enantiomer (0.95), molecular mass (0.93), log P values (0.86), and aqueous solubility (0.80). It was concluded that the skin flux of molecular compounds can be predicted based on the relationship between their physicochemical properties and the interaction with cofactors including additives and enhancers in the vehicles.
Asunto(s)
Minería de Datos/métodos , Propionatos/administración & dosificación , Propionatos/farmacocinética , Absorción Cutánea/efectos de los fármacos , Absorción Cutánea/fisiología , Administración Cutánea , Animales , Fenómenos Químicos , Ratones , Ratones Pelados , Técnicas de Cultivo de Órganos/métodos , Propionatos/química , Piel/efectos de los fármacos , Piel/metabolismo , SolubilidadRESUMEN
Non-alcoholic steatohepatitis (NASH) is the most rapidly growing liver disease that is nevertheless without approved pharmacological treatment. Despite great effort in developing novel NASH therapeutics, many have failed in clinical trials. This has raised questions on the adequacy of preclinical models. Elafibranor is one of the drugs currently in late stage development which had mixed results for phase 2/interim phase 3 trials. In the current study we investigated the response of elafibranor in APOE*3Leiden.CETP mice, a translational animal model that displays histopathological characteristics of NASH in the context of obesity, insulin resistance and hyperlipidemia. To induce NASH, mice were fed a high fat and cholesterol (HFC) diet for 15 weeks (HFC reference group) or 25 weeks (HFC control group) or the HFC diet supplemented with elafibranor (15 mg/kg/d) from week 15-25 (elafibranor group). The effects on plasma parameters and NASH histopathology were assessed and hepatic transcriptome analysis was used to investigate the underlying pathways affected by elafibranor. Elafibranor treatment significantly reduced steatosis and hepatic inflammation and precluded the progression of fibrosis. The underlying disease pathways of the model were compared with those of NASH patients and illustrated substantial similarity with molecular pathways involved, with 87% recapitulation of human pathways in mice. We compared the response of elafibranor in the mice to the response in human patients and discuss potential pitfalls when translating preclinical results of novel NASH therapeutics to human patients. When taking into account that due to species differences the response to some targets, like PPAR-α, may be overrepresented in animal models, we conclude that elafibranor may be particularly useful to reduce hepatic inflammation and could be a pharmacologically useful agent for human NASH, but probably in combination with other agents.
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Chalconas/administración & dosificación , Cirrosis Hepática/prevención & control , Síndrome Metabólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Obesidad/prevención & control , Propionatos/administración & dosificación , Animales , Glucemia/análisis , Proteínas de Transferencia de Ésteres de Colesterol/genética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Humanos , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/genética , Masculino , Síndrome Metabólico/genética , Ratones , Ratones Transgénicos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , PPAR alfa/antagonistas & inhibidores , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Resultado del TratamientoRESUMEN
Microbial metabolites play a critical role in mucosal homeostasis by mediating physiological communication between the host and colonic microbes, whose perturbation may lead to gut inflammation. The microbial metabolite 3-indolepropionic acid (3-IPA) is one such communication mediator with potent antioxidative and anti-inflammatory activity. To apply the metabolite for the treatment of colitis, 3-IPA was coupled with acidic amino acids to yield colon-targeted 3-IPA, 3-IPA-aspartic acid (IPA-AA) and 3-IPA-glutamic acid (IPA-GA). Both conjugates were activated to 3-IPA in the cecal contents, which occurred faster for IPA-AA. Oral gavage of IPA-AA (oral IPA-AA) delivered a millimolar concentration of IPA-AA to the cecum, liberating 3-IPA. In a 2,4-dinitrobenzene sulfonic acid (DNBS)-induced rat colitis model, oral IPA-AA ameliorated rat colitis and was less effective than sulfasalazine (SSZ), a current anti-inflammatory bowel disease drug. To enhance the anticolitic activity of 3-IPA, it was azo-linked with the GPR109 agonist 5-aminonicotinic acid (5-ANA) to yield IPA-azo-ANA, expecting a mutual anticolitic action. IPA-azo-ANA (activated to 5-ANA and 2-amino-3-IPA) exhibited colon specificity in in vitro and in vivo experiments. Oral IPA-azo-ANA mitigated colonic damage and inflammation and was more effective than SSZ. These results suggest that colon-targeted 3-IPA ameliorated rat colitis and its anticolitic activity could be enhanced by codelivery of the GPR109A agonist 5-ANA.
Asunto(s)
Antiinflamatorios/administración & dosificación , Colitis/tratamiento farmacológico , Indoles/administración & dosificación , Ácidos Nicotínicos/administración & dosificación , Profármacos/administración & dosificación , Propionatos/administración & dosificación , Administración Oral , Animales , Antiinflamatorios/química , Colitis/inducido químicamente , Colitis/inmunología , Colitis/patología , Colon/efectos de los fármacos , Colon/inmunología , Colon/patología , Dinitrofluorobenceno/administración & dosificación , Dinitrofluorobenceno/análogos & derivados , Dinitrofluorobenceno/toxicidad , Modelos Animales de Enfermedad , Composición de Medicamentos/métodos , Humanos , Indoles/química , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/inmunología , Mucosa Intestinal/patología , Masculino , Ratones , Ácidos Nicotínicos/química , Profármacos/química , Propionatos/química , Células RAW 264.7 , Ratas , Receptores Acoplados a Proteínas G/agonistas , Sulfasalazina/administración & dosificaciónRESUMEN
Propionic acid (PPA) is produced by enteric gut bacteria and is a dietary short chain fatty acid. Intracerebroventricular (ICV) infusions of PPA in rodents have been shown to produce behavioural changes, including adverse effects on cognition, similar to those seen in autism spectrum disorders (ASD). Previous research has shown that repeated ICV infusions of PPA result in impaired spatial learning in a Morris water maze (MWM) as evidenced by increased search latencies, fewer direct and circle swims, and more time spent in the periphery of the maze than control rats. In the current study rats were first given non-spatial pretraining (NSP) in the water maze in order to familiarize the animals with the general requirements of the non-spatial aspects of the task before spatial training was begun. Then the effects of ICV infusions of PPA on acquisition of spatial learning were examined. PPA treated rats failed to show the positive effects of the non-spatial pretraining procedure, relative to controls, as evidenced by increased search latencies, longer distances travelled, fewer direct and circle swims, and more time spent in the periphery of the maze than PBS controls. Thus, PPA treatment blocked the effects of the pretraining procedure, likely by impairing sensorimotor components or memory of the pretraining.
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Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/fisiopatología , Aprendizaje por Laberinto/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Propionatos/farmacología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Infusiones Intraventriculares , Masculino , Propionatos/administración & dosificación , Ratas , Ratas Long-EvansRESUMEN
Propionate has antimicrobial activity and is suggested to influence lipid metabolism. Here, we investigated the effect of propionate on lipid metabolism and the gut microbiome in fructose-fed mice as a model of diet-induced steatosis and gut dysbiosis. Therefore, 48 male wild-type mice were fed isoenergetic diets with either 0% fructose (F-) or 40% fructose (F+) that contained 0% propionate (P-) or 1% propionate (P+) for 7 weeks. Mice that received the F+ diets developed fatty livers, had fewer small intestinal proteobacteria and colonic actinobacteria and were characterised by changes in bacterial genera (e.g., Allobaculum, Lachnospiraceae, and Escherichia). Interestingly, mice fed the F+ diets had higher levels of propionate and butyrate in the circulation than mice fed the F- diets (p < 0.05). Treatment with propionate influenced neither hepatic or plasma lipids nor levels of circulating SCFAs. With the exception of Verrucomicrobia, other bacterial phyla were not affected by propionate.
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Ácidos Grasos Volátiles/sangre , Fructosa/efectos adversos , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Propionatos/administración & dosificación , Animales , Bacterias/clasificación , Disbiosis , Hígado Graso , Lípidos/sangre , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
CONTEXT: Combining a sodium-glucose cotransporter 2 inhibitor with a xanthine oxidase inhibitor (XOI) and a urate transporter 1 (URAT1) inhibitor may enhance serum uric acid (sUA) lowering. However, concerns exist regarding high urinary UA (uUA) excretion rates and subsequent crystallization in renal tubules. OBJECTIVE: To assess whether dapagliflozin added to verinurad, a selective URAT1 inhibitor, and febuxostat, an XOI, increases uUA excretion. DESIGN: Randomized, placebo-controlled, 2-way crossover study (NCT03316131). PATIENTS: Adults with asymptomatic hyperuricemia. INTERVENTIONS: Subjects (N = 36) were randomized to oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days and 7 days of oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo with an intervening 7- to 21-day washout period. MAIN OUTCOME MEASURE: Difference in peak uUA excretion between groups from baseline to day 7. Secondary outcomes included changes in sUA levels and 24-h uUA excretion. RESULTS: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% confidence interval (CI): -21.0 to -4.7], dapagliflozin; -13.2 mg/h [95% CI -21.3 to -5.0], placebo). sUA concentrations were lower with dapagliflozin (mean treatment difference -62.3 µmol/L [95% CI -82.8 to -41.8]). Dapagliflozin did not impact verinurad pharmacokinetics, its main metabolites, or febuxostat or fasting plasma glucose levels vs verinurad plus febuxostat. There were no clinically relevant changes in safety parameters. CONCLUSIONS: Dapagliflozin further reduced sUA without influencing uUA excretion, suggesting that its combination with verinurad and febuxostat at the doses tested does not adversely affect kidney function. CLINICAL TRIAL REGISTRATION NUMBER: NCT03316131.
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Compuestos de Bencidrilo/administración & dosificación , Febuxostat/administración & dosificación , Glucósidos/administración & dosificación , Hiperuricemia/tratamiento farmacológico , Naftalenos/administración & dosificación , Propionatos/administración & dosificación , Piridinas/administración & dosificación , Adulto , Compuestos de Bencidrilo/efectos adversos , Estudios Cruzados , Quimioterapia Combinada , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Febuxostat/efectos adversos , Femenino , Glucósidos/efectos adversos , Supresores de la Gota/administración & dosificación , Supresores de la Gota/efectos adversos , Humanos , Hiperuricemia/sangre , Masculino , Persona de Mediana Edad , Naftalenos/efectos adversos , Propionatos/efectos adversos , Piridinas/efectos adversos , Resultado del Tratamiento , Estados Unidos , Ácido Úrico/sangre , Uricosúricos/administración & dosificación , Uricosúricos/efectos adversos , Adulto JovenRESUMEN
Several studies have demonstrated that lysophosphatidic acid (LPA) acts through its LPA receptors in multiple biological and behavioral processes, including adult hippocampal neurogenesis, hippocampal-dependent memory, and emotional regulation. However, analyses of the effects have typically involved acute treatments, and there is no information available regarding the effect of the chronic pharmacological modulation of the LPA/LPA receptors-signaling pathway. Thus, we analyzed the effect of the chronic (21 days) and continuous intracerebroventricular (ICV) infusion of C18:1 LPA and the LPA1-3 receptor antagonist Ki16425 in behavior and adult hippocampal neurogenesis. Twenty-one days after continuous ICV infusions, mouse behaviors in the open field test, Y-maze test and forced swimming test were assessed. In addition, the hippocampus was examined for c-Fos expression and α-CaMKII and phospho-α-CaMKII levels. The current study demonstrates that chronic C18:1 LPA produced antidepressant effects, improved spatial working memory, and enhanced adult hippocampal neurogenesis. In contrast, chronic LPA1-3 receptor antagonism disrupted exploratory activity and spatial working memory, induced anxiety and depression-like behaviors and produced an impairment of hippocampal neurogenesis. While these effects were accompanied by an increase in neuronal activation in the DG of C18:1 LPA-treated mice, Ki16425-treated mice showed reduced neuronal activation in CA3 and CA1 hippocampal subfields. Treatment with the antagonist also induced an imbalance in the expression of basal/activated α-CaMKII protein forms. These outcomes indicate that the chronic central modulation of the LPA receptors-signaling pathway in the brain regulates cognition and emotion, likely comprising hippocampal-dependent mechanisms. The use of pharmacological modulation of this pathway in the brain may potentially be targeted for the treatment of several neuropsychiatric conditions.
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Cognición/fisiología , Emociones/fisiología , Hipocampo/metabolismo , Lisofosfolípidos/administración & dosificación , Neurogénesis/fisiología , Receptores del Ácido Lisofosfatídico/metabolismo , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Cognición/efectos de los fármacos , Emociones/efectos de los fármacos , Hipocampo/efectos de los fármacos , Infusiones Intraventriculares , Isoxazoles/administración & dosificación , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Neurogénesis/efectos de los fármacos , Propionatos/administración & dosificación , Receptores del Ácido Lisofosfatídico/agonistas , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
RATIONALE & OBJECTIVE: Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). STUDY DESIGN: Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. SETTING & PARTICIPANTS: Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. INTERVENTION: Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. OUTCOMES: The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. RESULTS: 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: -38.6% (90% CI, -60.9% to-3.6%), -39.4% (90% CI, -61.8% to-3.8%), and-49.3% (90% CI, -68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. LIMITATIONS: Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. CONCLUSIONS: Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. FUNDING: This study was supported by AstraZeneca. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03118739.