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OBJECTIVE: To determine the effective dose and therapeutic potential of maropitant using through expression of mediators of oxidative stress, inflammatory and of the unfolded protein response (UPR) (bio) markers on spinal cord using a model of neuropathic pain induced through chronic constriction injury (CCI) in rats. STUDY DESIGN: Randomized, blinded, prospective experimental study. ANIMALS: 98 male Wistar rats. METHODS: Rats were anesthetized with sevoflurane and after CCI, they were randomly assigned to the following groups that received: vehicle, 3, 6, 15, 30 e 50 mg/kg/24q of maropitant. The effect on inflammatory mediators (IL10, TNFα), oxidative stress (GPx, CAT, SOD), microglial (IBA-1) and neuronal (NeuN, TACR1) markers was evaluated though immunohistochemistry and expression levels of markers of hypoxia (HIF1α, Nrf2), antioxidant enzymes (Catalse, Sod1 and GPx1), and endoplasmic reticulum stress mediators (GRP78, CHOP and PERK) through qRT-PCR. RESULTS: Intraperitoneal injection (IP) of maropitant inhibited nociception with ID50 values of 4,1 mg/kg (5,85-19,36) in a neuropathic pain model through CCI. A dose of 30 mg/kg/24q was significantly effective in reducing mechanical allodynia 1 to 4h after treatment with nociception inhibition (145,83%). A reduction in the expression of hypoxia factors (HIF1α, Nrf2) was observed, along with an increase in antioxidant activity (CAT, SOD and GPX). Additionally, there was a reduction in inflammatory markes (IL10, TNFα), microglial (IBA-1), and neuronal markers (NeuN, TACR1). CONCLUSION AND CLINICAL RELEVANCE: These findings demonstrate that the determined dose, administered daily for seven days, had an antinociceptive effect, as well as anti-inflammatory and antioxidant activity.
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Neuralgia , Traumatismos de los Nervios Periféricos , Quinuclidinas , Ratas , Masculino , Animales , Antioxidantes/metabolismo , Ratas Wistar , Enfermedades Neuroinflamatorias , Traumatismos de los Nervios Periféricos/tratamiento farmacológico , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-10/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estudios Prospectivos , Estrés Oxidativo , Hiperalgesia/tratamiento farmacológico , Estrés del Retículo Endoplásmico , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Superóxido Dismutasa/metabolismo , Hipoxia/tratamiento farmacológicoRESUMEN
PURPOSE: To investigate the protective effect of penehyclidine hydrochloride (PHC) on cardiopulmonary bypass (CPB)-related lung injury in rats. METHODS: Thirty-six rats were divided into control, CPB and PHC groups. The CPB model was established in CPB and PHC groups. In PHC group, 2-mg/kg PHC was added to the pre-filling solution for CPB modeling. At 30 min before CPB (T1), immediately after left hilar opening (T2) and end of experiment (T3), the hemodynamic indexes, blood gas indexes, serum inflammatory factors, lung wet-day ratio and water content and lung tissue oxidative stress indexes were determined. RESULTS: At T2 and T3, compared with CPB group, in PHC group the heart rate and mean arterial pressure increased significantly, the oxygenation index increased significantly, the respiratory index decreased significantly, and the lung wet-day ratio and water content decreased significantly. At T3, compared with CPB group, in PHC groups the serum tumor necrosis factor α, interleukin 6 and interleukin 1ß levels decreased significantly, the lung tissue superoxide dismutase level increased significantly, and the myeloperoxidase and malondialdehyde levels decreased significantly. CONCLUSIONS: PHC treatment can alleviate the CPB-related lung injury in rats. The mechanisms may be related to its reducing inflammatory response and resisting oxidative stress.
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Lesión Pulmonar Aguda , Puente Cardiopulmonar , Lesión Pulmonar Aguda/patología , Animales , Puente Cardiopulmonar/efectos adversos , Pulmón/patología , Estrés Oxidativo , Quinuclidinas , Ratas , Ratas Sprague-Dawley , AguaRESUMEN
BACKGROUND: Dry eye disease (DED) is a condition that compromises the ocular surface and affects millions of people around the world. In recent years, a scheme has been proposed for the treatment of DED, with the use of artificial tear being the mainstay of treatment. In this scheme, the use of secretagogues is suggested as part of the treatment for patients with moderate to severe affectation. With this systematic review, we aim to evaluate the effectiveness and safety of secretagogues for DED. METHODS: Electronic databases will be searched; we will include randomized controlled trials that compare secretagogues and artificial tears. Study inclusion will not be restricted on the basis of language or publication status. We will use Google Translate to assess studies written in languages other than English and Spanish. Identification, evaluation, data extraction, and assessment of risk of bias will be conducted by two authors of the review, a third review author will resolve any disagreement. The outcomes will be the ocular surface disease index score, tear film break-up time, Schirmer test score, VRQoL Score, and tear film osmolarity. We will use the Cochrane Collaboration Risk of Bias 2 (RoB 2) tool for assessing the risk of bias of the included studies. Based on the heterogeneity of the included studies, we will combine the findings in a meta-analysis using a fixed effect model if heterogeneity ≤ 50% or a random effect model if heterogeneity > 50%. If we deem meta-analysis as inappropriate, we will document the reasons and report findings from the individual studies narratively. DISCUSSION: Based on the evidence obtained, we will evaluate the effect of pilocarpine, cevimeline, and diquafosol and compare it to artificial tears on multiple outcome measures. This systematic review aims to determine the efficacy and safety of the secretagogues pilocarpine, cevimeline, and diquafosol to help clinicians in the decision-making process. TRIAL REGISTRATION: PROSPERO CRD42020218407 .
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Síndromes de Ojo Seco , Gotas Lubricantes para Ojos , Síndromes de Ojo Seco/tratamiento farmacológico , Humanos , Gotas Lubricantes para Ojos/uso terapéutico , Metaanálisis como Asunto , Pilocarpina , Polifosfatos , Quinuclidinas , Secretagogos , Revisiones Sistemáticas como Asunto , Tiofenos , Nucleótidos de UraciloRESUMEN
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease characterized by long-term breathing problems and airflow limitations. International guidelines recommend using bronchodilators like long-acting beta- and muscarinic antagonists, and inhalational corticosteroids. OBJECTIVES: The cost-effectiveness of single-inhaler triple therapy containing fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) was compared to the treatments Fluticasone Furoate/Vilanterol (FF/VI), Umeclidinio/Vilanterol (UMEC/VI) and Fluticasone Propionate 250 mcg/Salmeterol 25mcg + Tiotropio 18 mcg (FP/SAL/TIO) for patients with COPD from the Chilean public health system perspective. METHODS: A cost-effectiveness analysis was performed, including a deterministic and probabilistic sensitivity analysis over a 25-year time horizon. Two scenarios were assessed to study the effect of a 3%-discount for costs and outcomes on FF/UMEC/VI. RESULTS: The incremental cost-effectiveness (ICER) of FF/UMEC/VI versus FF/VI was $10,076/QALY, being a cost-effective alternative to a threshold of one Gross Domestic Product per capita (GDPpc), while versus FP/SAL/TIO the ICER increased to $50,288/QALY, showing to be a non-cost effective alternative to 1 GDPpc, but at a threshold of 3 GDPpc. CONCLUSION: FF/UMEC/VI appears to be a cost-effective intervention for treating COPD compared to FF/VI. However, FF/UMEC/VI compared to FP/SAL/TIO showed an ICER above the threshold of 1 GDPpc, but, in comparison with lower price, the ICER was below 3 GDPpc.
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Salud Pública , Enfermedad Pulmonar Obstructiva Crónica , Androstadienos/farmacología , Androstadienos/uso terapéutico , Alcoholes Bencílicos , Broncodilatadores/uso terapéutico , Chile , Clorobencenos , Análisis Costo-Beneficio , Método Doble Ciego , Combinación de Medicamentos , Fluticasona/farmacología , Fluticasona/uso terapéutico , Volumen Espiratorio Forzado , Humanos , Quinuclidinas , Resultado del TratamientoRESUMEN
BACKGROUND: Multimodal analgesia consists of the combination of analgesic drugs at low doses to act in different places along the path of pain. Studies with continuous infusion of analgesic drugs in cats are not common. This study aimed to evaluate the analgesic effect of maropitant, lidocaine and ketamine alone or in combination (intravenous bolus + subsequent continuous intravenous infusion) in the management of acute postoperative pain in cats undergoing ovariohysterectomy. Seventy healthy cats undergoing an ovariohysterectomy received a standard anesthetic protocol consisting of acepromazine and morphine, propofol (anesthesia induction), and isoflurane (anesthesia maintenance). The animals were stratified into seven groups (n = 10 in each group): control (CG), maropitant (MG), lidocaine (LG), ketamine (KG), maropitant + lidocaine (LMG), maropitant + ketamine (KMG), and maropitant + lidocaine + ketamine (LKMG). All drugs were injected first as an intravenous bolus and then by continuous intravenous infusion. During surgery, esophageal temperature, respiratory rate, heart rate, oxygen saturation, expired isoflurane concentration, and partial pressure of carbon dioxide at the end of expiration were evaluated at 7 time points. Postoperative pain was evaluated for 6 h after extubation using the visual analogue scale and the UNESP-Botucatu multidimensional composite pain scale for assessing postoperative pain in cats. RESULTS: Adverse effects related to maropitant, lidocaine and ketamine infusion were not observed. Pain scores were lower in the MG, KG and LG groups when compared to the CG group using both scales. Although pain scores were also lower in all combination groups than CG, more animals in these groups required rescue analgesia compared to MG. This indicates that the postoperative analgesic effect of all drugs, either alone or in combination, confers analgesia, although the combinations did not promote greater analgesia. CONCLUSIONS: Continuous intravenous infusion of maropitant, lidocaine, and ketamine alone induces postoperative analgesic effect in cats undergoing ovariohysterectomy, but combinations of these drugs did not increase the analgesic effect. No adverse effect was observed with any drug or their combination.
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Enfermedades de los Gatos , Ketamina , Analgésicos/uso terapéutico , Animales , Gatos , Femenino , Infusiones Intravenosas/veterinaria , Ketamina/uso terapéutico , Lidocaína , Ovariectomía/veterinaria , Dolor Postoperatorio/tratamiento farmacológico , Dolor Postoperatorio/prevención & control , Dolor Postoperatorio/veterinaria , QuinuclidinasRESUMEN
OBJECTIVE: To perform a literature review addressing the therapeutic strategies for salivary hypofunction. BACKGROUND: Qualitative and quantitative salivary dysfunctions predispose to changes in the oral mucosa and teeth, cause impairment to oral functions and negative impact on quality of life. MATERIALS AND METHODS: A MEDLINE/PubMed search was conducted using the terms "Xerostomia" AND, "Saliva Artificial" OR, "Citric Acid," "Malic Acid," "Chewing Gum," "Acupuncture" OR, "Pilocarpine" OR, "Bethanechol" OR, "Cevimeline" OR, "Hyperbaric Oxygen Therapy" OR, "Stem Cell Therapy" OR "Genetic Therapy" and their Mesh Terms. RESULTS: We selected 25 clinical trials investigating the effects of salivary substitutes, chewing gum, malic and citric acids, pilocarpine, cevimeline, bethanechol, acupuncture, hyperbaric oxygen therapy and regenerative therapies on salivary hypofunction. In most studies, the number of participants was low and the follow-up times short. The therapeutic modalities were classified according to the level of evidence on salivary dysfunction. CONCLUSIONS: Pilocarpine and cevimeline had the strongest evidence of beneficial effect on salivary hypofunction. Citric and malic acids increase salivary flow but also increase the risk of erosion and dental caries. There are no controlled clinical trials supporting the efficacy of acupuncture, stem cell therapy and gene therapy on salivary dysfunction, although clinical observations suggest a promising effect. There is no evidence supporting salivary substitutes, chewing gum, bethanechol or hyperbaric oxygen on the treatment of salivary hypofunction.
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Agonistas Muscarínicos/uso terapéutico , Pilocarpina/uso terapéutico , Quinuclidinas/uso terapéutico , Tiofenos/uso terapéutico , Xerostomía/terapia , Terapia por Acupuntura , Betanecol/uso terapéutico , Goma de Mascar , Humanos , Oxigenoterapia Hiperbárica , Xerostomía/tratamiento farmacológicoRESUMEN
INTRODUCTION: Patients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination. This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol (VI) in patients with moderate COPD who remained symptomatic on tiotropium (TIO). METHODS: In this randomized, blinded, double-dummy, parallel-group study (NCT01899742), patients (N=494) who were prescribed TIO for ≥3 months at screening (forced expiratory volume in 1 s [FEV1]: 50%-70% of predicted; modified Medical Research Council [mMRC] score ≥1) and completed a 4-week run-in with TIO were randomized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks. Efficacy assessments included trough FEV1 at Day 85 (primary end point), 0-3 h serial FEV1, rescue medication use, Transition Dyspnea Index (TDI), St George's Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT). Safety evaluations included adverse events (AEs). RESULTS: Compared with TIO, UMEC/VI produced greater improvements in trough FEV1 (least squares [LS] mean difference: 88 mL at Day 85 [95% confidence interval {CI}: 45-131]; P<0.001) and FEV1 after 5 min on Day 1 (50 mL [95% CI: 27-72]; P<0.001). Reductions in rescue medication use over 12 weeks were greater with UMEC/VI versus TIO (LS mean change: -0.1 puffs/d [95% CI: -0.2-0.0]; P≤0.05). More patients achieved clinically meaningful improvements in TDI score (≥1 unit) with UMEC/VI (63%) versus TIO (49%; odds ratio at Day 84=1.78 [95% CI: 1.21-2.64]; P≤0.01). Improvements in SGRQ and CAT scores were similar between treatments. The incidence of AEs was similar with UMEC/VI (30%) and TIO (31%). CONCLUSION: UMEC/VI step-up therapy provides clinical benefit over TIO monotherapy in patients with moderate COPD who are symptomatic on TIO alone.
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Alcoholes Bencílicos/administración & dosificación , Broncodilatadores/administración & dosificación , Clorobencenos/administración & dosificación , Pulmón/efectos de los fármacos , Antagonistas Muscarínicos/administración & dosificación , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Quinuclidinas/administración & dosificación , Bromuro de Tiotropio/administración & dosificación , Anciano , Argentina , Alcoholes Bencílicos/efectos adversos , Broncodilatadores/efectos adversos , Clorobencenos/efectos adversos , Sustitución de Medicamentos , Europa (Continente) , Femenino , Volumen Espiratorio Forzado , Humanos , Análisis de Intención de Tratar , Análisis de los Mínimos Cuadrados , Modelos Logísticos , Pulmón/fisiopatología , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Quinuclidinas/efectos adversos , Recuperación de la Función , Sudáfrica , Encuestas y Cuestionarios , Factores de Tiempo , Bromuro de Tiotropio/efectos adversos , Resultado del Tratamiento , Estados Unidos , Capacidad VitalRESUMEN
BACKGROUND: Although TRPA1, SP, histamine and 5-hydroxytryptamine (5-HT) have recognized contribution to nociceptive mechanisms, little is known about how they interact with each other to mediate inflammatory pain in vivo. In this study we evaluated whether TRPA1, SP, histamine and 5-HT interact, in an interdependent way, to induce nociception in vivo. METHODS AND RESULTS: The subcutaneous injection of the TRPA1 agonist allyl isothiocyanate (AITC) into the rat's hind paw induced a dose-dependent and short lasting behavioral nociceptive response that was blocked by the co-administration of the TRPA1 antagonist, HC030031, or by the pretreatment with antisense ODN against TRPA1. AITC-induced nociception was significantly decreased by the co-administration of selective antagonists for the NK1 receptor for substance P, the H1 receptor for histamine and the 5-HT1A or 3 receptors for 5-HT. Histamine- or 5-HT-induced nociception was decreased by the pretreatment with antisense ODN against TRPA1. These findings suggest that AITC-induced nociception depends on substance P, histamine and 5-HT, while histamine- or 5-HT-induced nociception depends on TRPA1. Most important, AITC interact in a synergistic way with histamine, 5-HT or substance P, since their combination at non-nociceptive doses induced a nociceptive response much higher than that expected by the sum of the effect of each one alone. This synergistic effect is dependent on the H1, 5-HT1A or 3 receptors. CONCLUSION: Together, these findings suggest a self-sustainable cycle around TRPA1, no matter where the cycle is initiated each step is achieved and even subeffective activation of more than one step results in a synergistic activation of the overall cycle.
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Histamina/metabolismo , Dolor/metabolismo , Serotonina/metabolismo , Sustancia P/metabolismo , Canales Catiónicos TRPC/metabolismo , Acetanilidas/farmacología , Animales , Antagonistas de los Receptores Histamínicos H1/farmacología , Isotiocianatos , Masculino , Oligonucleótidos Antisentido/farmacología , Dolor/inducido químicamente , Piperazinas/farmacología , Purinas/farmacología , Pirilamina/farmacología , Quinuclidinas/farmacología , Ratas Wistar , Receptor de Serotonina 5-HT1A/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores de Neuroquinina-1/metabolismo , Receptores de Serotonina 5-HT3/metabolismo , Antagonistas de la Serotonina/farmacología , Canal Catiónico TRPA1 , Canales Catiónicos TRPC/agonistas , Canales Catiónicos TRPC/antagonistas & inhibidores , Canales Catiónicos TRPC/genética , p-Metoxi-N-metilfenetilamina/farmacologíaRESUMEN
OBJECTIVE: To evaluate whether maropitant (1 mg kg(-1)) injected subcutaneously (SC), administered simultaneously or 30 minutes prior to intramuscular (IM) administration of morphine (0.5 mg kg(-1)) and acepromazine (0.05 mg kg(-1)), reduces the incidence of salivation, retching and emesis in dogs. STUDY DESIGN: Randomized, controlled, prospective clinical trial. ANIMALS: Sixty dogs scheduled for an ovariohysterectomy as part of a population control program. METHODS: Dogs were randomly allocated to be administered maropitant (1 mg kg(-1)) SC simultaneously (group M0) or 30 minutes prior to (group M30) administration of morphine (0.5 mg kg(-1)) and acepromazine (0.05 mg kg(-1)) IM. A control group was administered normal saline (C) at T-30 and T0. Dogs were observed for 30 minutes after morphine-acepromazine administration. The occurrence of vomiting, retching and salivation were recorded, as well as the time to first emesis and the number of emetic events per dog. RESULTS: The occurrence of salivation was not different between the groups. Retching and vomiting occurred significantly less frequently in M30 than in the other two groups (p < 0.02). The number of emetic events was also significantly less for M30 than for the other two groups (p = 0.01). When emesis occurred, the time to the first emetic event was similar among the groups. CONCLUSIONS AND CLINICAL RELEVANCE: Maropitant (1 mg kg(-1)) SC reduced the frequency of morphine-induced emesis by as much as 70% when administered 30 minutes in advance. Simultaneous administration of maropitant and morphine-acepromazine produced no measurable effect on the frequency of retching or vomiting.
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Acepromazina/administración & dosificación , Analgésicos Opioides/efectos adversos , Antieméticos/uso terapéutico , Perros , Morfina/efectos adversos , Quinuclidinas/uso terapéutico , Vómitos/veterinaria , Analgésicos Opioides/administración & dosificación , Animales , Antieméticos/administración & dosificación , Interacciones Farmacológicas , Femenino , Masculino , Morfina/administración & dosificación , Estudios Prospectivos , Quinuclidinas/administración & dosificación , Salivación/efectos de los fármacos , Método Simple Ciego , Vómitos/inducido químicamente , Vómitos/prevención & controlRESUMEN
PURPOSE: To evaluate the effects of PHA-543613 (α7-nAChR agonist) and galantamine (acetylcholinesterase inhibitor (AChEI)) on recognition memory and neurovascular coupling (NVC) response in beta-amyloid (Aß) 25-35-treated mice. METHODS: PHA-543613 (1 mg/kg, i.p.), and galantamine (3 mg/kg, s.c.), effects were tested in Aß25-35 mice model of AD. α7-nAChR antagonist, methyllycaconitine (MLA) (1 mg/kg, i.p.), was used for evaluation of receptor blockade effects. Recognition memory in animals was assessed by the novel object recognition (NOR) task. NVC response was analyzed by laser-doppler flow meter in barrel cortex by whisker stimulation method. RESULTS: Both, PHA-543613 and galantamine improve recognition memory in Aß-treated animals. However, the advantageous effects of PHA-543613 were significantly higher than galantamine. Also, pretreatment with MLA reversed both galantamine and PHA-543613 effects on NOR. Impaired NVC response in AD animals was improved by PHA-543613 and galantamine. However, MLA pretreatment disrupts this function. CONCLUSION: Activation of α7-nAChR improved recognition memory possible through enhancement of neurovascular response in Alzheimer's disease in animals.
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Péptidos beta-Amiloides , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de la Colinesterasa/farmacología , Galantamina/farmacología , Trastornos de la Memoria/tratamiento farmacológico , Acoplamiento Neurovascular/efectos de los fármacos , Fragmentos de Péptidos , Quinuclidinas/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Animales , Modelos Animales de Enfermedad , Flujometría por Láser-Doppler , Masculino , Trastornos de la Memoria/fisiopatología , Ratones Endogámicos BALB C , Pruebas Neuropsicológicas , Acoplamiento Neurovascular/fisiología , Reconocimiento en Psicología/efectos de los fármacos , Reproducibilidad de los Resultados , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the effects of PHA-543613 (α7-nAChR agonist) and galantamine (acetylcholinesterase inhibitor (AChEI)) on recognition memory and neurovascular coupling (NVC) response in beta-amyloid (Aβ) 25-35-treated mice. METHODS: PHA-543613 (1 mg/kg, i.p.), and galantamine (3 mg/kg, s.c.), effects were tested in Aβ25-35 mice model of AD. α7-nAChR antagonist, methyllycaconitine (MLA) (1 mg/kg, i.p.), was used for evaluation of receptor blockade effects. Recognition memory in animals was assessed by the novel object recognition (NOR) task. NVC response was analyzed by laser-doppler flow meter in barrel cortex by whisker stimulation method. RESULTS: Both, PHA-543613 and galantamine improve recognition memory in Aβ-treated animals. However, the advantageous effects of PHA-543613 were significantly higher than galantamine. Also, pretreatment with MLA reversed both galantamine and PHA-543613 effects on NOR. Impaired NVC response in AD animals was improved by PHA-543613 and galantamine. However, MLA pretreatment disrupts this function. CONCLUSION: Activation of α7-nAChR improved recognition memory possible through enhancement of neurovascular response in Alzheimer's disease in animals.
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Animales , Masculino , Péptidos beta-Amiloides , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Inhibidores de la Colinesterasa/farmacología , Galantamina/farmacología , Trastornos de la Memoria/tratamiento farmacológico , Acoplamiento Neurovascular/efectos de los fármacos , Fragmentos de Péptidos , Quinuclidinas/farmacología , /metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/fisiopatología , Modelos Animales de Enfermedad , Flujometría por Láser-Doppler , Ratones Endogámicos BALB C , Trastornos de la Memoria/fisiopatología , Pruebas Neuropsicológicas , Acoplamiento Neurovascular/fisiología , Reproducibilidad de los Resultados , Reconocimiento en Psicología/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Nicotinic acetylcholine receptors (nAChRs) are widely distributed in the brain. Particularly α7-containing nAChRs, associated with several physiological roles and pathologies, are one of the most abundant. Here, we studied 2-(4-hexyloxybenzyl)-1-methylquinuclidin-1-ium iodide (designated as 8d), on ion currents elicited by choline, ICh, (Ch, a selective agonist for α7-containing nAChRs), recorded in interneurons from the stratum radiatum of the rat hippocampal CA1 region by using the whole-cell voltage-clamp technique. The 8d-concentration/Ch-response relationship exhibited high and low inhibitory affinities for α7-containing nAChRs, with IC50 values of 0.59 and 6.80 µM, respectively. Interestingly, 8d in a range of 3-10 µM exerted opposite effects: a short early potentiation and a long late inhibition of the ICh; and 8d alone elicited a non-decaying inward current. Furthermore, potentiation and inhibition of the ICh by 8d depended on the membrane potential, both being stronger at -20 than at -70 mV; indicating that 8d interacts with at least two sites into the ion channel/receptor complex: one for potentiating and another for inhibiting the α7-containing nAChRs. These results suggest that 8d may act as agonist, antagonist and positive modulator of α7-containing nAChRs in hippocampal interneurons.
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Región CA1 Hipocampal/metabolismo , Interneuronas/metabolismo , Quinuclidinas/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Región CA1 Hipocampal/citología , Colina/farmacología , Técnicas In Vitro , Ratas Sprague-Dawley , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Receptor Nicotínico de Acetilcolina alfa 7/antagonistas & inhibidoresRESUMEN
We aimed to observe the effect of penehyclidine hydrochloride (PHC) on lipopolysaccharide (LPS)-induced acute kidney injury in rats and expression of tight junction proteins ZO-1 and occludin. Adult male Sprague-Dawley (SD) rats were divided randomly (N = 10) into control group (C), LPS group (LPS), low-dose PHC group (L-PHC), and high-dose PHC group (H-PHC). All rats, except C group, received a vena caudalis injection of 5.0 mg/kg LPS; after 30 min, rats in L-PHC and H-PHC groups received a vena caudalis injection of 0.3 and 0.9 mg/kg PHC. After 24 h, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, serum creatinine (Scr), and blood urea nitrogen (BUN) were detected. Histopathological changes and expression of ZO-1 and occludin were observed in renal tissues. Versus levels of TNF-α (38.5 ± 9.0), IL-1ß (46.3 ± 12.7), Scr (37.2 ± 9.3), and BUN (6.5 ± 1.1) in control group, those in LPS group, TNF-α (159.0 ± 21.3), IL-1ß (130.8 ± 18.7), Scr (98.5 ± 18.2), and BUN (12.8 ± 1.8), increased obviously (P < 0.05), with significantly structural changes and decreases of ZO-1 and occludin. However, TNF-α (111.3 ± 11.6), IL-1ß (78.4 ± 14.3), Scr (51.3 ± 12.5), BUN (8.1 ± 1.2) in H-PHC group, and TNF-α (120.8 ± 14.3), IL-1ß (92.5 ± 19.0), Scr (56.7 ± 14.7), BUN (9.7 ± 1.6) in L-PHC group were obviously decreased (P < 0.05). PHC has protective effects on acute kidney injury in sepsis, including abatement of renal tissue inflammation and functional improvement, potentially by upregulating ZO-1 and occludin.
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Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Lipopolisacáridos/efectos adversos , Sustancias Protectoras/farmacología , Quinuclidinas/farmacología , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Citocinas/sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Riñón/metabolismo , Riñón/patología , Riñón/ultraestructura , Masculino , Ocludina/genética , Ocludina/metabolismo , Sustancias Protectoras/administración & dosificación , Quinuclidinas/administración & dosificación , Ratas , Proteína de la Zonula Occludens-1/genética , Proteína de la Zonula Occludens-1/metabolismoAsunto(s)
Aprobación de Drogas , Quimioterapia/enfermería , Ácidos Carbocíclicos , Benzoxazinas/uso terapéutico , Compuestos de Boro/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Cefalosporinas/uso terapéutico , Ciclopentanos/uso terapéutico , Combinación de Medicamentos , Péptidos Similares al Glucagón/análogos & derivados , Péptidos Similares al Glucagón/uso terapéutico , Guanidinas/uso terapéutico , Humanos , Imidazoles/uso terapéutico , Fragmentos Fc de Inmunoglobulinas/uso terapéutico , Interferón beta/uso terapéutico , Isoquinolinas/uso terapéutico , Ácido Penicilánico/análogos & derivados , Ácido Penicilánico/uso terapéutico , Polietilenglicoles/uso terapéutico , Piridinas/uso terapéutico , Quinuclidinas/uso terapéutico , Proteínas Recombinantes de Fusión/uso terapéutico , Tazobactam , Triazoles/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Leishmaniases comprise a spectrum of diseases caused by protozoan parasites of the Leishmania genus. Treatments available have limited safety and efficacy, high costs, and difficult administration. Thus, there is an urgent need for safer and more-effective therapies. Most trypanosomatids have an essential requirement for ergosterol and other 24-alkyl sterols, which are absent in mammalian cells. In previous studies, we showed that Leishmania amazonensis is highly susceptible to aryl-quinuclidines, such as E5700, which inhibit squalene synthase, and to the azoles itraconazole (ITZ) and posaconazole (POSA), which inhibit C-14α-demethylase. Herein, we investigated the antiproliferative, ultrastructural, and biochemical effects of combinations of E5700 with ITZ and POSA against L. amazonensis. Potent synergistic antiproliferative effects were observed against promastigotes, with fractional inhibitory concentration (FIC) ratios of 0.0525 and 0.0162 for combinations of E5700 plus ITZ and of E5700 plus POSA, respectively. Against intracellular amastigotes, FIC values were 0.175 and 0.1125 for combinations of E5700 plus ITZ and E5700 plus POSA, respectively. Marked alterations of the ultrastructure of promastigotes treated with the combinations were observed, in particular mitochondrial swelling, which was consistent with a reduction of the mitochondrial transmembrane potential, and an increase in the production of reactive oxygen species. We also observed the presence of vacuoles similar to autophagosomes in close association with mitochondria and an increase in the number of lipid bodies. Both growth arrest and ultrastructural/biochemical alterations were strictly associated with the depletion of the 14-desmethyl endogenous sterol pool. These results suggest the possibility of a novel combination therapy for the treatment of leishmaniasis.
Asunto(s)
Inhibidores de 14 alfa Desmetilasa/farmacología , Ergosterol/antagonistas & inhibidores , Itraconazol/farmacología , Leishmania mexicana/efectos de los fármacos , Piridinas/farmacología , Quinuclidinas/farmacología , Triazoles/farmacología , Tripanocidas/farmacología , Animales , Medios de Cultivo/química , Sinergismo Farmacológico , Quimioterapia Combinada , Ergosterol/biosíntesis , Farnesil Difosfato Farnesil Transferasa/antagonistas & inhibidores , Farnesil Difosfato Farnesil Transferasa/metabolismo , Humanos , Leishmania mexicana/aislamiento & purificación , Leishmania mexicana/metabolismo , Leishmania mexicana/ultraestructura , Leishmaniasis Cutánea Difusa/parasitología , Gotas Lipídicas/efectos de los fármacos , Gotas Lipídicas/ultraestructura , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/ultraestructura , Pruebas de Sensibilidad Parasitaria , Especies Reactivas de Oxígeno/agonistas , Especies Reactivas de Oxígeno/metabolismo , Esterol 14-Desmetilasa/metabolismoRESUMEN
This article reports orthodontic treatment of a case of hypodontia of five premolars in an 11-year-old female patient with a positive tooth size-arch length discrepancy in both dental arches. The patient had a straight profile with balanced facial growth. Setup manufacture revealed the possibility of achieving ideal occlusion by mesializing permanent molars up to 15 mm, in addition to keeping a primary molar in the dental arch. With the aid of absolute anchorage, the proposed mechanics was performed and the occlusion predicted in the setup was achieved, while profile and facial growth pattern were maintained. The use of miniscrews for extensive orthodontic movements was successful. Furthermore, one primary molar was extensively mesialized. The indication of gingivoplasty to correct gingival smile proved effective. This is considered a useful technique for orthodontists.
Este artigo apresenta o tratamento ortodôntico de um caso com hipodontia de cinco pré-molares, em uma paciente, de 11 anos de idade, com discrepância positiva de modelo em ambas as arcadas. A paciente apresentava perfil reto, com crescimento facial equilibrado. Por meio da confecção de set-up, verificou-se a possibilidade de se estabelecer uma oclusão ideal por meio da mesialização, de até 15mm, dos molares permanentes e manutenção de um molar decíduo no arco. Com o auxílio de ancoragem absoluta, foi realizada a mecânica proposta, alcançando-se a oclusão prevista em set-up, além da manutenção do perfil e do padrão de crescimento facial. A utilização de mini-implantes para grandes movimentos ortodônticos foi favorável, incluindo a extensa mesialização de um molar decíduo. A indicação da gengivoplastia para correção do sorriso gengival se mostrou acertada, sendo essa uma técnica de grande auxílio à Ortodontia.
Asunto(s)
Animales , Perros , Femenino , Masculino , Enfermedades de los Perros/inducido químicamente , Hidromorfona/efectos adversos , Náusea/veterinaria , Quinuclidinas/uso terapéutico , Vómitos/veterinaria , Analgésicos Opioides/efectos adversos , Antieméticos/administración & dosificación , Antieméticos/uso terapéutico , Enfermedades de los Perros/tratamiento farmacológico , Esquema de Medicación/veterinaria , Náusea/inducido químicamente , Náusea/tratamiento farmacológico , Quinuclidinas/administración & dosificación , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológicoRESUMEN
OBJECTIVE: intra-articular co-injection of kaolin with carrageenan (CGN) in rodents is widely used as an experimental model of arthritis. However, the ability of kaolin to cause arthritis and related immune responses when administered alone is unclear. We evaluated the contribution of prostanoids and sensory C-fibres (and their neuropeptide substance P) to kaolin-induced inflammation in the rat knee. METHODS: Wistar rats, 8-10 weeks old, received an intra-articular injection of kaolin (1-10 µg/joint) or saline into the knee joint. Knee inflammation, proinflammatory cytokines, pain behaviour and secondary tactile allodynia were assessed over 5 h, when synovial leukocyte counts, histopathological changes and proinflammatory cytokine levels were evaluated. RESULTS: The intra-articular injection of kaolin caused a dose- and time-dependent knee swelling and impairment of motion that were associated with secondary tactile allodynia, elevated concentrations of IL-1ß, IL-6 and TNFα, leukocyte infiltration, and histopathological changes in the ipsilateral hindpaw. The neurokinin-1 (NK1) receptor antagonist SR140333 or neonatal treatment with capsaicin markedly reduced the inflammatory parameters, cytokines and allodynia but failed to significantly inhibit the impaired motion. The cyclo-oxygenase inhibitor indomethacin partially inhibited knee oedema and allodynia but did not affect the leukocyte influx, myeloperoxidase activity or impaired motion in the kaolin-injected rat. CONCLUSIONS: We show the first evidence that intra-articular injection of kaolin without CGN produced severe acute monoarthritis. This was highly dependent on substance P (released from C-fibres) and NK1 receptor activation, which stimulated local production of proinflammatory cytokines. This model may be of critical importance for mechanistic studies and screening new anti-inflammatory/analgesic drugs.
Asunto(s)
Antidiarreicos/toxicidad , Artritis/inducido químicamente , Caolín/toxicidad , Receptores de Neuroquinina-1/metabolismo , Animales , Animales Recién Nacidos , Artritis/complicaciones , Artritis/tratamiento farmacológico , Capsaicina/toxicidad , Citocinas/metabolismo , Modelos Animales de Enfermedad , Edema/etiología , Inhibidores Enzimáticos/uso terapéutico , Hiperalgesia/etiología , Indometacina/uso terapéutico , Articulación de la Rodilla/patología , Masculino , Dimensión del Dolor , Peroxidasa/metabolismo , Piperidinas/uso terapéutico , Quinuclidinas/uso terapéutico , Ratas , Ratas Wistar , Líquido Sinovial/metabolismoRESUMEN
This study aimed to observe the clinical curative effect of penehyclidine hydrochloride (PHC) combined with hemoperfusion in treating acute severe organophosphorus pesticide poisoning. We randomly divided 61 patients with severe organophosphorus pesticide poisoning into an experimental group (N = 31) and a control group (N = 30), and we compared the coma-recovery time, mechanical ventilation time, healing time, hospital expenses, and mortality between the two groups. The coma-recovery time, mechanical ventilation time, and healing time were lower in the experimental group than in the control group (P < 0.05), while the hospitalization expenses were higher in the experimental group than in the control group (P < 0.01); moreover, no significant difference was observed in the mortality rate between the two groups. Thus, PHC combined with hemoperfusion exerts a better therapeutic effect in acute severe organophosphorus pesticide poisoning than PHC alone.
Asunto(s)
Coma/tratamiento farmacológico , Hemoperfusión , Intoxicación por Organofosfatos/tratamiento farmacológico , Quinuclidinas/administración & dosificación , Adolescente , Adulto , Anciano , Coma/mortalidad , Coma/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Intoxicación por Organofosfatos/mortalidad , Intoxicación por Organofosfatos/patología , Compuestos Organofosforados/toxicidad , Plaguicidas/envenenamiento , Respiración ArtificialAsunto(s)
Aprobación de Drogas , Compuestos de Bencidrilo/uso terapéutico , Alcoholes Bencílicos/uso terapéutico , Clorobencenos/uso terapéutico , Dibenzazepinas/uso terapéutico , Estrógenos Conjugados (USP)/uso terapéutico , Glucósidos/uso terapéutico , Humanos , Indoles/uso terapéutico , Nitrilos , Piridonas/uso terapéutico , Pirimidinas/uso terapéutico , Quinuclidinas/uso terapéutico , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Estados Unidos , United States Food and Drug AdministrationRESUMEN
Trichomonas vaginalis causes trichomoniasis in humans, a sexually transmitted disease commonly treated with metronidazole (MTZ), a drug that presents some toxicity, causing undesirable side effects. In addition, an increase in metronidazole-resistant parasites has been reported. Thus, the development of alternative treatment is recommended. To date, the search for antiparasitic drugs has been based on different approaches: identification of active natural products, identification of parasite targets, and the use of available compounds active against other pathogenic microorganisms. Here, we analyzed the in vitro antiproliferative and ultrastructural effects on T. vaginalis of BPQ-OH, a hydroxiquinuclidine derivative that inhibits squalene synthase and is active against several protozoa and fungi. We also compared the effects of BPQ-OH on T. vaginalis and mammalian cells with those of MTZ. We found that BPQ-OH inhibits in vitro proliferation of T. vaginalis, with an IC50 of 46 µM after 24 h. Although this IC50 is 16 times higher than that of MTZ (1.8 µM), BPQ-OH is less toxic for human cell lines than MTZ, with LC50 values of 2,300 and 70 µM, and selective indexes of 50 and 39, respectively. Ultrastructural analyses demonstrated that BPQ-OH induced alterations in T. vaginalis, such as rounded and wrinkled cells, membrane blebbing and intense vacuolization, leading to cell death, whereas MTZ also caused significant changes, including a decrease in hydrogenosomes size and endoflagellar forms. Our observations identify BPQ-OH as a promising leading compound for the development of novel anti-T. vaginalis drugs and highlight the need for further testing this molecule using experimentally infected animals.