Isobolographic analysis of antinociceptive effect of ketorolac, indomethacin, and paracetamol after simultaneous peripheral local and systemic administration.

This study was designed to characterize the type of interaction (subadditive, additive, or synergistic) after simultaneous administration by two different routes (intraperitoneal plus peripheral local) of the same nonsteroidal anti-inflammatory drugs (NSAID) ketorolac and indomethacin or paracetamol. The antinociceptive effects of locally or intraperitoneally delivery of NSAIDs or paracetamol, and the simultaneous administration by the two routes at fixed-dose ratio combination were evaluated using the formalin test. Pain-related behavior was quantified as the number of flinches of the injected paw. Isobolographic analysis was used to characterize the interaction between the two routes. ED30 values were estimated for individual drugs, and isobolograms were constructed. Ketorolac, indomethacin, or paracetamol and fixed-dose ratio combinations produced a dose-dependent antinociceptive effect in the second but not in the first phase of the formalin test. The analysis of interaction type after simultaneous administration by the two routes the same NSAID or paracetamol (on basis of their ED30), revealed that the simultaneous administration of ketorolac or paracetamol was additive and for indomethacin was synergistic. Since the mechanisms underlying the additive effect of ketorolac or paracetamol and the synergistic effect of indomethacin were not explored; it is possible that the peripheral and central mechanism is occurring at several anatomical sites. The significance of these findings for theory and pain pharmacotherapy practice indicates that the combination of one analgesic drug given simultaneously by two different administration routes could be an additive or it could lead to a synergistic interaction.

Metformin: A Prospective Alternative for the Treatment of Chronic Pain.

Metformin (biguanide) is a drug widely used for the treatment of type 2 diabetes. This drug has been used for 60 years as a highly effective antihyperglycemic agent. The search for the mechanism of action of metformin has produced an enormous amount of research to explain its effects on gluconeogenesis, protein metabolism, fatty acid oxidation, oxidative stress, glucose uptake, autophagy and pain, among others. It was only up the end of the 1990s and beginning of this century that some of its mechanisms were revealed. Metformin induces its beneficial effects in diabetes through the activation of a master switch kinase named AMP-activated protein kinase (AMPK). Two upstream kinases account for the physiological activation of AMPK: liver kinase B1 and calcium/calmodulin-dependent protein kinase kinase 2. Once activated, AMPK inhibits the mechanistic target of rapamycin complex 1 (mTORC1), which in turn avoids the phosphorylation of p70 ribosomal protein S6 kinase 1 and phosphatidylinositol 3-kinase/protein kinase B signaling pathways and reduces cap-dependent translation initiation. Since metformin is a disease-modifying drug in type 2 diabetes, which reduces the mTORC1 signaling to induce its effects on neuronal plasticity, it was proposed that these mechanisms could also explain the antinociceptive effect of this drug in several models of chronic pain. These studies have highlighted the efficacy of this drug in chronic pain, such as that from neuropathy, insulin resistance, diabetic neuropathy, and fibromyalgia-type pain. Mounting evidence indicates that chronic pain may induce anxiety, depression and cognitive impairment in rodents and humans. Interestingly, metformin is able to reverse some of these consequences of pathological pain in rodents. The purpose of this review was to analyze the current evidence about the effects of metformin in chronic pain and three of its comorbidities (anxiety, depression and cognitive impairment).

Calidad de vida en los pacientes con DM-2: Un estudio transversal en el sureste mexicano / Quality of life in patients with DM-2: A cross-sectional study in the Mexican southeast

La diabetes es una enfermedad crónica y compleja con demandas y desafíos que influyen en la calidad de vida relacionada a la salud. Objetivo: determinar la calidad de vida en los pacientes con diabetes mellitus tipo 2 que acuden a los servicios médicos de la UJAT durante el periodo junio- julio del 2017. Métodos: se realizó un estudio transversal en 80 sujetos con diagnóstico de diabetes mellitus tipo 2 que acuden a un primer nivel de atención en el sureste mexicano. Se diseñó un instrumento y se obtuvieron datos sociodemográficos, de calidad de vida, antropométrica, bioquímica y clínica. Las variables fueron analizadas a través de estadística descriptiva, además, se utilizó la prueba de Chi cuadrado para explorar asociación entre variables categóricas y para variables continuas la prueba de T, considerando los estadísticamente significativos los resultados de p<0,05. Resultados: la media de edad de los pacientes estudiados fue 57,8 años. El dominio de la calidad de vida principalmente afectado fue energía, funcionamiento sexual y movilidad, y los factores que tuvieron efecto sobre la calidad de vida fueron la escolaridad, las comorbilidades, la polifarmacia, el índice de masa corporal y la hiperglucemia. Discusión: los pacientes con diagnóstico de diabetes mellitus tipo 2 que acuden a un primer nivel institucional del sureste mexicano están principalmente afectados en 3 dominios: energía y movilidad, ansiedad y preocupación y funcionamiento sexual.

Diabetes is a chronic and complex disease with demands and challenges that influence the quality of life - related to health. Objective: To determine the quality of life in patients with type 2 diabetes in the first level of care in Tabasco, during June- July 2017. Methods: A cross-sectional study was carried out in 102 subjects with type 2 diabetes. An instrument collected sociodemographic, quality of life, anthropometric, biochemical, and clinical data. The variables analyzed through descriptive statistics, also, the Chi-square test to explore the association between categorical variables, and for continuous variables, the T-test. Finally, considering the statistically significant results of p <0,05. Results: The mean age of patients included was 57,8 years old. The domain of the quality of life principally affected were energy-mobility, anxiety-concern, and sexual function, and the factors that affected the quality of life were education, comorbidi-ties, polypharmacy, body mass index, and hyperglycemia. Discussion: Patients with type 2 diabetes in the first institutional level in the Mexican south are principally affected in three domains: energy-mobility, anxiety-concern, and sexual function.

Antihyperalgesic Effects of Indomethacin, Ketorolac, and Metamizole in Rats: Effects of Metformin.

Preclinical Research Metformin-dependent mechanisms have been implicated in the antinociceptive effect of some non-steroidal anti-inflammatory drugs (NSAIDs). In this study, the effect of local peripheral or systemic administration of metformin on the local peripheral or systemic antinociception induced by indomethacin, ketorolac and metamizole was assessed in the rat carrageenan-induced thermal hyperalgesia model. Rats were injected with carrageenan (1%, 50 µl) into the right hindpaw which reduced paw withdrawal latency, a measure of thermal hyperalgesia. Local peripheral or systemic administration of indomethacin, ketorolac or metamizole dose-dependently reduced carrageenan-induced thermal hyperalgesia. Local peripheral pre-treatment with metformin (800 µg/paw) partially inhibited the anti-hyperalgesic effect of indomethacin (200 µg/paw) and metamizole (200 µg/paw), but not that of ketorolac (200 µg/paw). In contrast, systemic pre-treatment with metformin (200 mg/kg) attenuated the antihyperalgesic effect of metamizole (10 mg/kg), but not that observed with either indomethacin (10 mg/kg) or ketorolac (10 mg/kg). These findings suggest that some but not all NSAIDs have effects mediated by metformin-dependent mechanisms. Drug Dev Res 78 : 98-104, 2017. ©2017 Wiley Periodicals, Inc.

[Factors associated with delay to reperfusion therapy in patients with ST-Segment Elevation Myocardial Infarction in a hospital in the southeast of Mexico]. / Factores asociados con retraso en la terapia de reperfusión en infarto agudo de miocardio con elevación del segmento ST (IMCEST) en un hospital del sureste mexicano.

UNLABELLED: Introduction and subject: The aim of the study was to determine the factors involved in the delayed medical care of patients with ST-Segment Elevation Myocardial Infarction. METHODS: A prospective observational study was conducted in patients admitted to the coronary care unit at Dr. Juan Graham Casasús hospital with a diagnosis of ST-Segment Elevation Acute Myocardial Infarction. In all patients, clinical data, type and time of reperfusion treatment, and factors associated with delay were identified. RESULTS: Between November 2012 and January 2015 we included 213 patients with ST-Segment Elevation Myocardial Infarction. Age, diabetes, atypical chest angina and patient arrival period (night or weekend), were more frequent in patients presenting after 12 hours of onset of symptoms of myocardial infarction. Of these, hospital admission at night or weekend was the only independent predictor for delay to the emergency room. CONCLUSIONS: This study shows that in a referral hospital in southeast of Mexico, the delay attributable to the patient was the most common factor associated with care in patients with ST-Segment Elevation Myocardial Infarction. Patient arrival period was associated with delay to medical care.

Fosinopril Prevents the Development of Tactile Allodynia in a Streptozotocin-Induced Diabetic Rat Model.

The aim of this study was to evaluate fosinopril-induced changes in hemodynamic parameters and tactile allodynia in a rat model of diabetes. Diabetes was induced by streptozotocin (STZ; 50 mg/kg, i.p.) in male Wistar rats. STZ produced hyperglycemia, weight loss, polydipsia, polyphagia, and polyuria as well as long-term arterial hypotension, bradycardia, and tactile allodynia at 10-12 weeks. Daily administration of the angiotensin converting enzyme inhibitor, fosinopril (25 mg/kg, p.o., for 11 weeks) partially reduced the loss of body weight, decreased hyperglycemia, and systolic blood pressure in diabetic rats. Likewise, systemic administration of fosinopril prevented the development and maintenance of tactile allodynia in STZ-induced diabetic rats. These data suggest that fosinopril may have a role in the pharmacotherapy of diabetic neuropathic pain.

Antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rodents.

BACKGROUND: Painful neuropathy is the most common and debilitating complication of diabetes and results in hyperalgesia and allodynia. Hyperglycemia clearly plays a key role in the development and progression of diabetic neuropathy. Current therapeutic approaches are only partially successful and they are only thought to reduce the pain associated with peripheral neuropathy. Some natural products offer combined antioxidant, anti-inflammatory and antinociceptive properties that may help to treat in a more integrative manner this condition. In this regard, the purpose of this study was to investigate the antineuropathic effect of 7-hydroxy-3,4-dihydrocadalin in streptozotocin-induced diabetic rats and mice without glucose control as well as the possible mechanism of action involved in this effect. METHODS: Rats and mice were injected with 50 or 200 mg/kg streptozotocin, respectively, to produce hyperglycemia. The formalin test and von Frey filaments were used to assess the nociceptive activity. Rota-rod was utilized to measure motor activity and malondialdehyde assay to determine anti-oxidative properties. RESULTS: After 3 weeks of diabetes induction, chemical hyperalgesia was observed in streptozotocin-injected rats. Oral acute administration of 7-hydroxy-3,4-dihydrocadalin (0.3-30 mg/kg) decreased in a dose-dependent manner formalin-evoked hyperalgesia in diabetic rats. In addition, methiothepin (non-selective 5-HT receptor antagonist, 1 mg/kg, i.p.) and ODQ (guanylyl cyclase inhibitor, 2 mg/kg, i.p.), but not naltrexone (opioid receptor antagonist, 1 mg/kg, s.c.), prevented 7-hydroxy-3,4-dihydrocadalin-induced antihyperalgesic effect. The anti-hyperalgesic effect of 7-hydroxy-3,4-dihydrocadalin was similar to that produced by pregabalin (10 mg/kg, p.o.). Furthermore, oral acute administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) reduced streptozotocin-induced changes in malondialdehyde concentration from plasma samples. Unlike pregabalin, 7-hydroxy-3,4-dihydrocadalin did not affect motor activity. Six weeks after diabetes induction, tactile allodynia was observed in the streptozotocin-injected rats. At this time, oral administration of 7-hydroxy-3,4-dihydrocadalin (30 mg/kg) or pregabalin (10 mg/kg) reduced in a similar way tactile allodynia in diabetic rats. Finally, chronic oral administration of 7-hydroxy-3,4-dihydrocadalin (30-300 mg/kg, 3 times/week, during 6 weeks), significantly prevented the development of mechanical hyperalgesia and allodynia in streptozotocin-induced diabetic mice. CONCLUSIONS: Data suggests that 7-hydroxy-3,4-dihydrocadalin has acute and chronic effects in painful diabetic neuropathy. This effect seems to involve antioxidant properties as well as activation of 5-HT receptors and inhibition of guanylyl cyclase enzyme.

Evidence for the participation of peripheral α5 subunit-containing GABAA receptors in GABAA agonists-induced nociception in rats.

The activation of GABAA receptor by γ-amino butyric acid (GABA) in primary afferent fibers produces depolarization. In normal conditions this depolarization causes a reduction in the release of neurotransmitters. Therefore, this depolarization remains inhibitory. However, previous studies have suggested that in inflammatory pain, GABA shifts its signaling from inhibition to excitation by an increased GABA-induced depolarization. The contribution of peripheral α5 subunit-containing GABAA receptors to the inflammatory pain is unknown. The purpose of this study was to investigate the possible pronociceptive role of peripheral α5 subunit-containing GABAA receptors in the formalin test. Formalin (0.5%) injection into the dorsum of the right hind paw produced flinching behavior in rats. Ipsilateral local peripheral pre-treatment (-10min) with exogenous GABA (0.003-0.03µg/paw) or common GABAA receptor agonists muscimol (0.003-0.03µg/paw), diazepam (0.017-0.056µg/paw) or phenobarbital (1-100µg/paw) significantly increased 0.5% formalin-induced nociceptive behavior. The pronociceptive effects of GABA (0.03µg/paw), muscimol (0.03µg/paw), diazepam (0.056µg/paw) and phenobarbital (100µg/paw) were prevented by either the GABAA receptor antagonist bicuculline (0.01-0.1µg/paw) or selective α5 subunit-containing GABAA receptor inverse agonist L-655,708 (0.017-0.17µg/paw). The α5 subunit-containing GABAA receptor protein was expressed in dorsal root ganglion (DRG) and dorsal spinal cord of naïve rats. The formalin injection did not modify α5 subunit-containing GABAA receptor expression. Overall, these results suggest that peripheral α5 subunit-containing GABAA receptors play a pronociceptive role in the rat formalin test.

Role of NHE1 in Nociception.

Intracellular pH is a fundamental parameter to cell function that requires tight homeostasis. In the absence of any regulation, excessive acidification of the cytosol would have the tendency to produce cellular damage. Mammalian Na(+)/H(+) exchangers (NHEs) are electroneutral Na(+)-dependent proteins that exchange extracellular Na(+) for intracellular H(+). To date, there are 9 identified NHE isoforms where NHE1 is the most ubiquitous member, known as the housekeeping exchanger. NHE1 seems to have a protective role in the ischemia-reperfusion injury and other inflammatory diseases. In nociception, NHE1 is found in neurons along nociceptive pathways, and its pharmacological inhibition increases nociceptive behavior in acute pain models at peripheral and central levels. Electrophysiological studies also show that NHE modulates electrical activity of primary nociceptive terminals. However, its role in neuropathic pain still remains controversial. In humans, NHE1 may be responsible for inflammatory bowel diseases since its expression is reduced in Crohn's disease and ulcerative colitis. The purpose of this work is to provide a review of the evidence about participation of NHE1 in the nociceptive processing.

Características y alteraciones de la oclusión en la dentición primaria en preescolares de 3 a 6 años en Tabasco, México / Characteristics and alterations of the occlusion in primary dentition in 3-6 year old pre-school children from Tabasco, Mexico

Objetivo: Conocer las características de la oclusión primaria más frecuentes, alteraciones que predisponen y conllevan a la futura maloclusión, y las maloclusiones presentes en preescolares. Material y Métodos: Se determinó la frecuencia de las características de la oclusión en la dentición primaria de acuerdo a los principios de Baume. El grupo de estudio comprendió de 61 (76%) niños de edad preescolar. Cada niño fue explorado con luz natural para observar las características de la oclusión propias de su edad. Resultados: De los 61 (76%) niños solo el 12% de ellos presentaron las características de la oclusión primaria, el 67% presentó más de una alteración. La usencia de espacios de desarrollo en el 67%, de los casos, sobremordida horizontal el 15%, mientras que el 38% presento sobremordida vertical, en relación a la oclusión posterior el 3% presento planos terminales distales y el 2% mesial exagerada. De las maloclusiones estudiadas destacó la mordida abierta con el 32% seguidamente la mordida cruzada anterior con el 31%. Conclusiones: 1. La ausencia de espacios de desarrollo en la primera dentición, predice el apiñamiento dental en los permanentes. 2. La diferencia de dimensión en la sobremordida horizontal y vertical de los incisivos, limita el desarrollo y funcionalidad de los maxilares. 3. El plano terminal distal y mesial exagerado, determinan la clase molar II y III de Angle, la presencia de ellas afectan el comportamiento mesial del primer molar permanente. 4. La maloclusión de mordida abierta y la mordida cruzada anterior son signos que afectan complejo craneofaciodental de ambas denticiones.

Objective: Know the frequency in which the prescholar presents: characteristics of primary occlusion, alterations which lead to and predispose future malocclusions, and present malocclusions. Tools and Methodology: The frequency in occlusion characteristics in primary dentures was determined according to Doctor BaumeÆs principles. The study group consisted of 61 (76%) preschool children. Each child was explored with natural light in order to observe occlusion characteristics corresponding to their age. Results: Only 12% of the 61(76%) children presented primary occlusion characteristics, 67% presented more than one alteration. The absence of developmental spaces in 67% of cases was due to a horizontal overbite in 15%, while 38% presented a vertical overbite. Regarding posterior occlusions 3% presented terminal distal planes and 2% an exaggerated mesial. Of the malocclusions studied there was an outstanding 32% of cases with open bite followed by 31% presenting a crossed anterior bite. Conclusions: 1. The absence of developmental spaces in primary dentures predicts the conglomeration of future permanent dentures. 2. The difference in dimension of horizontal and vertical overbites found in incisors limits the development and functionality of maxillaries. 3. The terminal distal plane and exaggerated mesial determine de angle of the second and third molar, their presence affect the displacement of the first permanent molar. 4. The malocclusion of both the open and crossed anterior bite are signs which affect the craniofacial dental complex in both dentures.