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Whether fever and antipyretic treatment are related to progression of organ dysfunction (POD) in sepsis is currently not known.To evaluate the association of fever and antipyretic treatment with POD in sepsis.Prospective cohort study of patients with sepsis. Maximum axillary temperature (T° Max), antipyretic drugs total dose and daily SOFA score were recorded. POD was defined as an increase ≥ 1 point on the SOFA score. A multivariate logistic regression model was used to evaluate the studied association.305 patients were included: 163 were women (53.4%), with a SOFA score of 8 points (6-11); 130 participants (42.62%) had T° Max ≥ 38°C, and 76 (24.9%), POD. Mortality in patients with fever was 26.2% vs. 20% (p = 0.21), and with POD, 73.7% vs. 5.7% (p = 0.01). T° Max ≥ 39°C had an OR of 4.96 (95% CI = 1.97-12.47, p = 0.01); and the use of antipyretics, an OR of 1.04 (95% CI: 0.58-1.86, p = 0.88).An axillary T° Max ≥ 39°C is a risk factor for POD in sepsis. The use of antipyretics was not associated with POD.No se conoce si la fiebre y el tratamiento antipirético se relacionan con progresión de la disfunción orgánica (PDO) en sepsis.Evaluar la asociación de la fiebre y el tratamiento antipirético con la PDO en sepsis.Estudio de cohorte prospectiva de pacientes con sepsis. Se registró temperatura axilar máxima (T° máx.), dosis total de fármacos antipiréticos y puntuación diaria de la escala SOFA. La PDO se definió como el incremento de SOFA ≥ 1 punto. Se utilizó un modelo de regresión logística multivariado para evaluar la asociación estudiada.Se incluyeron 305 pacientes: 163 mujeres (53.4 %) con puntuación SOFA de ocho puntos (6-11); 130 participantes (42.62 %) presentaron T° máx. ≥ 38 °C y 76 (24.9 %), PDO. La mortalidad en los pacientes con fiebre fue de 26.2 % versus 20 % sin fiebre (p = 0.21) y con PDO, de 73.7 % versus 5.7 % (p = 0.01). La T° máx. ≥ 39°C tuvo RM = 4.96 (IC 95 % = 1.97-12.47, p = 0.01) y el uso de antipiréticos, RM = 1.04 (IC 95 % = 0.58-1.86, p = 0.88).La T° máx. axilar ≥ 39°C es un factor de riesgo para PDO en sepsis. El uso de antipiréticos no se asoció a PDO.

Objective Mexico has the second largest prevalence of obesity among adults worldwide, a condition especially affecting the low-income population. There is a pressing need to improve therapeutic options for weight loss. Phentermine is an old and low-cost agent given as an adjuvant therapy for obesity for a 12-week period, at an initial dose of 15 mg or 30 mg. However, there are no precise guidelines on the suitability of both the starting dose and the continuation of treatment for 6 months. The aim of this study was to evaluate the 3- and 6-month efficacy and safety of phentermine in obese Mexican patients to elucidate the aforementioned. Materials and methods In this prospective, multi-center, open-label study, 932 obese adults received 15 mg or 30 mg phentermine once daily for 6 months. Results 30 mg phentermine was more effective than 15 mg phentermine in improving anthropometric variables in the 3-month follow-up, but not after completing the 6-month treatment period. Nearly 40% of 3-month non-responders reached a body weight reduction of at least 5% at 6 months. Conversely, ~ 65% and 25% of 3-month responders maintained or improved, respectively, their body weight reduction with long-term phentermine. Potential tolerance as weight regain was ~ 10% from 3 to 6 months. None of the doses increased cardiovascular risk, although mild-to-moderate adverse events were more frequent with 30 mg phentermine. Conclusion 30 mg phentermine was more effective than 15 mg phentermine after 3 months, but not at 6 months of treatment. An important number of subjects could benefit following the therapy from 3 to 6 months.

Subclinical atherosclerosis (SA) is the presence of coronary calcification in the absence of cardiovascular symptoms, and it usually progresses to atherosclerotic disease. Studies have shown an association of osteoprotegerin gene (OPG) variants with calcification process in cardiovascular diseases; however, to this day there are no studies that evaluate individuals in the asymptomatic stage of atherosclerotic disease. Therefore, the purpose of this study was to analyze the association of four genetic variants and haplotypes of the OPG gene with the development of SA, through TaqMan genotyping assays. We also aimed to identify potential response elements for transcription factors in these genetic variants. The study included 1413 asymptomatic participants (1041 were controls and 372 were individuals with SA). The rs3102735 polymorphism appeared as a protective marker (OR = 0.693; 95% CI = 0.493–0.974; pheterozygote = 0.035; OR = 0.699; 95% CI = 0.496–0.985; pcodominant1 = 0.040) and two haplotypes were associated with SA, one as a decreased risk: GACC (OR = 0.641, 95% CI = 0.414–0.990, p = 0.045) and another as an increased risk: GACT (OR = 1.208, 95% CI = 1.020–1.431, p = 0.029). Our data suggest a lower risk of SA in rs3102735 C carriers in a representative sample of Mexican mestizo population.

Orphan G-protein-coupled receptors (GPCR) comprise a large number of receptors which are widely distributed in the nervous system and represent an opportunity to identify new molecular targets in pain medicine. GPR55 and GPR119 are two orphan GPCR receptors whose physiological function is unclear. The aim was to explore the participation of spinal GPR55 and GPR119 in the processing of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Protein localization and modulation were measured by immunohistochemistry and western blotting, respectively. Intrathecal administration of CID16020046 (selective GPR55 antagonist) or AS1269574 (selective GPR119 agonist) produced a dose-dependent antiallodynic effect, whereas O1062 (GPR55 agonist) and G-protein antagonist peptide dose-dependently prevented the antiallodynic effect of CID16020046 and AS1269574, respectively. Both GPR55 and GPR119 receptors were expressed in spinal cord, dorsal root ganglia and sciatic nerve, but only GPR119 was downregulated after 14 days of spinal nerve ligation. Data suggest that GPR55 and GPR119 participate in the processing of neuropathic pain and could be useful targets to manage neuropathic pain disorders.

Spinal cord injury (SCI) is a condition that puts the patient's life at risk in the acute phase and, during the chronic stage, results in permanent deficits in motor, sensory and autonomic functions. Isolated therapeutic strategies have not shown an effect on this condition. Therefore, this study aimed to evaluate the effects of electroacupuncture (EA) and curcumin, alone or combined, on the oxidative balance, motor function recovery and amount of preserved tissue following a traumatic SCI. Long-Evans rats were divided into five groups: SHAM, SCI, SCI + EA, SCI + Curcumin, and SCI + EA + Curcumin. Nitric oxide was significantly decreased in the Curcumin group; the EA, Curcumin and SCI + EA + Curcumin groups had significantly decreased hydroxyl radical and lipid peroxidation levels. Motor function recovery and the amount of preserved spinal cord tissue were significantly greater in the EA, Curcumin and EA + Curcumin groups. The results show that EA and Curcumin treatment alone or in combination decreased oxidative stress, improved functional motor recovery and increased the amount of preserved spinal cord tissue following a traumatic injury.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very commonly used, but their adverse effects warrant investigating new therapeutic alternatives. Polyalthic acid, a labdane-type diterpenoid, is known to produce gastroprotection, tracheal smooth muscle relaxation, and antitumoral, antiparasitic and antibacterial activity. This study aimed to evaluate the antinociceptive, antiallodynic, antihyperalgesic and anti-inflammatory effect of polyalthic acid on rats. Moreover, the effectiveness of treating hyperalgesia with a combination of polyalthic acid and naproxen was analyzed, as well as the type of drug–drug interaction involved. Nociception was examined by injecting 1% formalin into the right hind paw and thermal hyperalgesia and inflammation by injecting a 1% carrageenan solution into the left hind paw of rats. Allodynia was assessed on an L5/L6 spinal nerve ligation model. Polyalthic acid generated significant antinociceptive (56–320 mg/kg), antiallodynic (100–562 mg/kg), and antihyperalgesic and anti-inflammatory (10–178 mg/kg) effects. Antinociception mechanisms were explored by pretreating the rats with naltrexone, ODQ and methiothepin, finding the effect blocked by the former two compounds, which indicates the participation of opioid receptors and guanylate cyclase. An isobolographic analysis suggests synergism between polyalthic acid and naproxen in the combined treatment of hyperalgesia.

Ulcerative colitis (UC) is a frequent type of inflammatory bowel disease, characterized by periods of remission and exacerbation. Gut dysbiosis may influence pathophysiology and clinical response in UC. The purpose of this study was to evaluate whether gut microbiota is related to the active and remission phases of pancolitis in patients with UC as well as in healthy participants. Fecal samples were obtained from 18 patients with UC and clinical‐endoscopic evidenced pancolitis (active phase n = 9 and remission phase n = 9), as well as 15 healthy participants. After fecal DNA extraction, the 16S rRNA gene was amplified and sequenced (Illumina MiSeq), operational taxonomic units were analyzed with the QIIME software. Gut microbiota composition revealed a higher abundance of the phyla Proteobacteria and Fusobacteria in active pancolitis, as compared with remission and healthy participants. Likewise, a marked abundance of the genus Bilophila and Fusobacteria were present in active pancolitis, whereas a higher abundance of Faecalibacterium characterized both remission and healthy participants. LEfSe analysis showed that the genus Roseburia and Faecalibacterium were enriched in remission pancolitis, and genera Bilophila and Fusobacterium were enriched in active pancolitis. The relative abundance of Fecalibacterium and Roseburia showed a higher correlation with fecal calprotectin, while Bilophila and Fusobacterium showed AUCs (area under the curve) of 0.917 and 0.988 for active vs. remission pancolitis. The results of our study highlight the relation of gut dysbiosis with clinically relevant phases of pancolitis in patients with UC. Particularly, Fecalibacterium, Roseburia, Bilophila, and Fusobacterium were identified as genera highly related to the different clinical phases of pancolitis., The purpose of this study was to evaluate whether gut microbiota is related to the active and remission phases of pancolitis in patients with ulcerative colitis, as well as in healthy participants.

Despite increase in survival of human immunodeficiency virus (HIV) patients due to highly active antiretroviral therapy, non-infectious complications are still prevalent such as presentation of lung vasculopathy, even in asymptomatic patients. Endothelial nitric oxide synthase (eNOS) is necessary to produce nitric oxide that causes pulmonary endothelial vasodilation. Participation of this protein in the pulmonary circulation in HIV patients has not been elucidated. This work studied the presence and expression of eNOS in pulmonary complex vascular lesions associated with HIV (PCVL/HIV).In lung tissues from patients who died from complications of HIV, we used immunohistochemistry and immune chemiluminescence (imageJ) to determine the different degrees of expression of eNOS in PCVL-HIV in comparison with non-PCVL/HIV. Reagents used were anti-eNOS and an automated system. All data are presented as mean and standard deviation. Differences were analyzed with Wilcoxon; p0.05 was accepted as statistically significant.In 57 tissues, the histological evidence of pulmonary vasculopathy was showed as different types (proliferative, obliterative, and plexiform) and severe presentation of vasculopathy than non-PCVL/HIV. A statistically significant decrease of eNOS was observed in all PCVL/HIV tissue samples.eNOS has a relevant role in the pathogenesis of pulmonary vasculopathy in acquired immunodeficiency syndrome patients. It is necessary to determine in the future the participation of eNOS and other mechanisms involved in PCVL/HIV.A pesar del incremento en la sobrevivencia del paciente con virus de inmunodeficiencia humana (VIH) debido al uso del tratamiento antiretroviral altamente efectivo, las complicaciones no infecciosas siguen ocasionando vasculopatía pulmonar, aun en pacientes asintomáticos. La óxido nítrico sintetasa (ONSe) es necesaria para la producción de óxido nítrico la cual provoca vasodilatación pulmonar. La participación de esta proteína en la circulación pulmonar en los pacientes con VIH aún no se ha dilucidado. Este trabajo estudia la presencia y la expresión de ONSe en las lesiones vasculares pulmonares complejas asociadas al VIH (LVPC/VIH).En tejidos pulmonares de pacientes que fallecieron por complicaciones del VIH, se utilizó inmunohistoquímica e inmunoquimioluminescencia (imageJ) para determinar los diferentes grados de expresión de la ONSe en LVPC/VIH. Los reactivos utilizados son anti-ONSe en sistema automatizado. Todos los datos son presentados en media y desviación estándar. Las diferencias son analizadas con la prueba de Wilcoxon; se aceptó como estadísticamente significativa una p0.05.En 57 pacientes, la histología de la vasculopatía pulmonar mostró diferentes tipos (proliferativo, obliterativo y plexiforme) además de varias presentaciones de vasculopatía en tejidos no-LVPC/VIH. Se observó diferencia estadística en la disminución de ONSe en todos los tejidos LVPC/VIH.La ONSe tiene un papel relevante en la patogénesis de la vasculopatía pulmonar en el VIH. Es necesario determinar en el futuro la participación de ONSe y otros mecanismos involucrados en LVPC/VIH.

The aim of this study was to investigate the antinociceptive potential of (-)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (-)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (-)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (-)-epicatechin was also prevented by the intraperitoneal administration of L-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K channel blocker), 4-aminopyridine (voltage-dependent K channel blocker), and iberiotoxin (large-conductance Ca-activated K channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (-)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.

Background Nerve injury promotes release of 5-HT at the spinal cord. Once released, 5-HT may produce antinociceptive or pronociceptive effects depending of the nature of 5-HT receptors. The purpose of this study was to investigate the participation of spinal 5-HT4 and 5-HT6 receptors in the maintenance of neuropathic pain in rats. Methods Tactile allodynia was measured using von Frey hairs in male Wistar rats subjected to L5-L6 spinal nerve injury. Selective 5-HT4 (GR-113808, 0.01–10 nmol/rat) and 5-HT6 (SB-258585, 1–1000 nmol/rat) receptor antagonists were administered intrathecally to nerve injured rats. Likewise, the most effective dose of 5-HT4 (1 nmol/rat) and 5-HT6 (100 nmol/rat) antagonists were co-administered with their respective agonists (ML-10302, 10–100 nmol/rat and WAY-208466, 100–1000 nmol/rat, respectively). Spinal cord protein expression of both receptors was determined by western blot. Results Intrathecal administration of 5-HT4 or 5-HT6 receptor antagonists, but not vehicle, decreased in a dose-dependent manner tactile allodynia in neuropathic rats. Moreover, intrathecal co-administration with the agonists prevented in a dose-dependent manner the antagonists-induced antiallodynic effect. Both 5-HT4 and 5-HT6 receptors were expressed in the spinal cord of naive, sham and neuropathic rats. Nerve injury did not modify expression of any receptor. Conclusions Data suggests that spinal 5-HT4 and 5-HT6 receptors are expressed in dorsal spinal cord and they participate in the maintenance of neuropathic pain in rats. In this regard, blockade of these receptors could be a useful strategy to treat neuropathic pain states.

Objectives In patients with heart failure, fluid alteration and low muscle strength frequently coexist because of their reduced physical activity and sedentary behavior; however, few studies have evaluated the effects of this coexistence on the prognosis of these patients. The aim of this study was to examine the independent association between fluid alteration and the low handgrip strength (HGS) index with mortality in patients with chronic heart failure. Methods This observational study included 546 (53.3% male) stable outpatients with heart failure. The presence of an abnormal fluid distribution was determined with a bioelectrical impedance ratio (200/5 kHz) ≥0.85. Handgrip strength (HGS) was measured with a hand dynamometer, and the HGS index was calculated by dividing the HGS (kg) by the squared height (meters). A low HGS index was defined if men had Results The mean age of the study population was 60.75 ± 17 y, and 30% were classified with a low HGS index, 9.5% with an abnormal fluid distribution, and 29% with both. During the 36 mo of follow-up, 16.5% of the participants reached the endpoint. In men but not in women, coexistence of a low HGS index and abnormal fluid distribution were independently associated with all-cause mortality with a hazard ratio of 2.8 (95% confidence interval, 1.25–6.4; P = 0.01). Conclusions In men with heart failure, co-existence of a low HGS index and abnormal fluid distribution was independently associated with all-cause mortality.

espanolIntroduccion: El exito en nefrolitotomia percutanea (NLP) se define como estatus libre de litos, sin embargo, las complicaciones mayores se presentan con alta frecuencia y han sido reportadas como resultado secundario. Objetivo: Presentar una nueva definicion de exito en NLP que comprenda la tasa libre de litos sin complicaciones mayores y una escala de riesgo para predecir este desenlace. Metodo: Cohorte historica de pacientes sometidos a NLP. Las variables incluidas fueron edad, sexo, urocultivo, indice de comorbilidad de Charlson (ICC) y lito complejo. Se definio exito: sin litos, sin o con complicacion Clavien ≤ 2; exito intermedio: con litos sin o con complicacion Clavien ≤ 2; fracaso: con o sin litos con complicacion Clavien > 2. Se realizo analisis bivariado para identificar los factores asociados con el desenlace. Por regresion logistica multiple se calculo el peso independiente de cada factor. Resultados: Se incluyeron 568 procedimientos, 59 % en el sexo femenino. La mediana de edad fue de 49 anos; 65, 22 y 13 % de los casos tuvieron exito, exito intermedio y fracaso. El sexo femenino, urocultivo positivo, lito complejo e ICC severo se asociaron con fracaso. Conclusion: La probabilidad de exito fue directamente proporcional al numero de factores de riesgo. EnglishIntroduction: Success in percutaneous nephrolithotomy (PCNL) is defined as a stone-free status; however, major complications are highly common and have been reported as a secondary outcome. Objective: To propose a new definition of PCNL success that comprises a stone free rate without major complications and a risk scale to predict this outcome. Methods: Historical cohort of patients undergoing PCNL. The included variables were age, gender, urine culture, Charlson’s comorbidity index (CCI) and complex stones. Success was defined as a stone free status with or without Clavien grade ≤ 2 complication; intermediate success: with stones, with or without Clavien grade ≤ 2 complication; and failure: with or without stones with Clavien grade ≤ 2 complication. Bivariate analysis was performed to identify which factors are associated with the outcome. The independent weight of each factor was calculated by multiple logistic regression analysis. Results: 568 procedures were included, 59% of which were in females. Median age was 49 years; 65%, 22% and 13% of cases were classified as success, intermediate success and failure, respectively. Female sex, positive urine culture, complex stones and severe CCI were associated with failure. Conclusions: The likelihood of success was directly proportional to the number of risk factors.

espanolIntroduccion: La ureteroscopia flexible con litotricia laser (URSLL) es una modalidad minimamente invasiva de tratamiento quirurgico de calculos renales. La seleccion inadecuada de pacientes para este procedimiento genera un desbalance de costo-efectividad. Objetivo: Conocer los factores predictores de estado libre de litos en un solo tiempo quirurgico en pacientes sometidos a URSLL. Metodo: Cohorte retrospectiva de pacientes sometidos a URSLL. Se realizo un analisis univariado y multivariado (regresion logistica) de los predictores de estado libre de calculos en la primera URSLL, global y categorizado por sexo. Resultados: El estado libre de calculos en la primera URSLL fue de 73.62 %. Los predictores de estado libre de calculos en hombres fueron edad y tamano, densidad y multiplicidad del calculo; en las mujeres, el indice de masa corporal y la multiplicidad del calculo. Conclusiones: Los factores pronosticos de estado libre de calculos en la primera URSLL son distintos en hombres y mujeres. Las mujeres con obesidad y sobrepeso probablemente tengan calculos de facil fragmentacion y extraccion asociados con acido urico. EnglishIntroduction: Flexible ureteroscopy and laser fragmentation (FURSL) is a minimally invasive modality for surgical treatment of renal stones. Inadequate selection of patients for this treatment generates a cost-effectiveness unbalance. Objective: To know the stone-free rate predictors in a single surgical time in patients undergoing FURSL. Method: Retrospective cohort of patients undergoing FURSL. Global and gender-categorized univariate and multivariate (logistic regression) analyses were performed to identify stone-free predictors at first FURSL. Results: Stone-free rate at first FURSL was 73.62%. Predictors in males were patient age and stone size, density and multiplicity; in females, body mass index and multiplicity of stones. Conclusions: Stone-free rate predictors at first FURSL are different in males and females. Women with overweight and obesity probably have easy-to-fragment and easy-to-extract stones associated with uric acid.

Background: Fecal calprotectin (FC) can be a valuable tool to optimize health care for patients with inflammatory bowel disease (IBD). The objective of this observational study was to determine the level of knowledge of the FC test in Mexican patients with IBD. Methods: A self-report questionnaire was distributed via Facebook to patients with IBD. The survey consisted of 15 questions in two categories: the first category assessed knowledge of IBD diagnosis, and the second category assessed knowledge of the FC test. Results: In total, 460 patients with IBD participated, of which 83.9% (386) had ulcerative colitis (UC) and 16.0% (74) had Crohn’s disease (CD). Regarding IBD diagnosis, 41.9% of participants stated that they did not know of a non-invasive test for fecal matter to identify inflammation of the colon. Regarding the FC test, 57.5% (UC) and 58.1% (CD) stated that they did not know about the test. Additionally, 65.8% (UC) and 51.3% (CD) of participants stated that they had never received the FC test and 82.6% (UC) and 77.0% (CD) recognized that the FC test was difficult to access in their medical practice. Furthermore, 66% (UC) and 52.7% (CD) of participants noted that their specialist doctor had never suggested the FC test to them, yet 89.1% (UC) and 87.8% (CD) stated that they would prefer FC analysis for their IBD follow-up assessments. Conclusions: There is little knowledge of the FC biomarker among Mexican patients with IBD. This suggests the need for greater dissemination of its use and scope as a biomarker in IBD.

Objective A fixed-dose combination (FDC) of D-norpseudoephedrine, tri-iodothyronine, atropine, aloin, and diazepam is used in Mexico for the short-term treatment of obesity; however, its efficacy and safety have been scarcely studied. The aim of this study was to analyze the efficacy and safety of this FDC in Mexican adult overweight and obese patients by a prospective, uncontrolled, multicenter, phase IV open-label study. Materials and methods 3,290 patients with a body mass index (BMI) ˃ 27 kg/m2 were included in the current study. Primary outcome was the absolute body weight loss, whilst secondary outcomes were the improvement of anthropometric and cardiometabolic parameters as well as the description of adverse events. Results The FDC decreased the body weight and BMI by -9.0 ± 5.6 kg and -3.4 ± 2.2 kg/m2, respectively, at 6 months. In addition, 43.3% and 14.3% of subjects achieved at least 5% or 10% weight loss at 6 months, respectively. The FDC also significantly improved waist circumference, hip circumference, body fat, visceral fat, systolic blood pressure, diastolic blood pressure, diabetes risk, and mortality risk, at 3 and 6 months. Moreover, the FDC seems to have better results in the following order: obese grade 3 ≈ obese grade 2 ˃ obese grade 1 ˃ overweight patients. Mild mouth dryness, anxiety, and headache were the main reported adverse events. Conclusion Data suggest that the FDC is effective and well tolerated for the short-term therapy of overweight and obesity in Mexican patients. .

Background: Obesity is a pandemic disease. Lifestyle modifications as diet and exercise remain as the first-line intervention for obesity; however, many patients fail to attain adequate weight loss and require drug treatment. Mazindol is a short-term useful agent in the treatment of obesity, whose safety profile has not been analyzed in Mexican population. Objective: The current study was performed to investigate the reports of adverse events, received in the supplier laboratory for 8 years (2009-2016) with the purpose of determine potential issues of safety, related to Mazindol (MZ1®). Methods: Adverse events were arranged in frequency tables and stratified by intensity and causality. Subgroups of sex, age and BMI with a higher frequency of side-effects were identified, as well as the main comorbidities and concomitant medications. Results: One thousand three hundred eighty-six adverse events from 581 reports were received from 2009 to 2016. Most of reports were generated by patients in the fourth decade of life in both groups (25.5%). The most frequent adverse events were dry mouth (17.2%), polydipsia (10.6%) and constipation (9.0%). Most of them were both mild (90.5%) and possible (59.2%). Constipation was an important cause of withdrawal. Conclusions: Data seems to indicate that 1 mg Mazindol is well tolerated for obesity treatment and its adverse events profile is acceptable. However, it is necessary to emphasize in the use appropriate of the drug, following the dosage schedule and indications approved.

ResumenIntroducciónLos tumores del estroma gastrointestinal son lesiones mesenquimatosas derivadas de las células intersticiales de Cajal. El tratamiento más efectivo en la enfermedad primaria localizada es la cirugía. Con imatinib como tratamiento neoadyuvante en las lesiones de alto riesgo o en enfermedad metastásica, la supervivencia a 5 años ha aumentado a cerca del 80%. El objetivo del presente trabajo consiste en analizar los factores pronósticos que determinan la recurrencia y la supervivencia libre de enfermedad en este tipo de tumores.Material y métodosEstudio observacional, retrospectivo y longitudinal. Pacientes del Hospital de Oncología, CMN Siglo XXI, con confirmación histológica y tratamiento quirúrgico de la lesión primaria.ResultadosSe identificaron 66 pacientes; la localización más frecuente fue el estómago (66.6%), seguido por el intestino delgado (28.7%) y el colon (1.54%). El 7.57% presentó metástasis en el momento del diagnóstico: 4.54% (3) en hígado y 3.03% (2) en peritoneo. El tamaño promedio de los tumores fue de 10.84cm (2.2 a 38cm). La tasa de supervivencia global a 5 años fue del 82%, y la tasa de supervivencia libre de recurrencia a 5 años del 61%. En el caso de la supervivencia global, la localización de la lesión fue el único factor que mostró significación estadística, con p=0.0054ConclusiónLa localización del tumor, el tamaño, el número de mitosis, el grupo de riesgo y el tratamiento adyuvante con imatinib fueron estadísticamente significativos como factores pronósticos de recurrencia de la enfermedad. La localización de la lesión fue el único factor que mostró significación estadística como factor pronóstico de supervivencia global.AbstractIntroductionGastrointestinal stroma tumours are mesenchymal lesions derived from Cajal interstitial cells. The most effective treatment in primary localised disease is surgery. With imatinib as neoadjuvant treatment in high-risk lesions or metastatic disease, 5-year survival has increased to nearly 80%. The purpose of this work is to analyse prognostic factors that determine recurrence and disease-free survival in this type of tumour.Material and methodsObservational, retrospective, longitudinal study of patients from the Oncology Hospital, CMN Siglo XXI, with histological confirmation and surgical treatment of the primary lesion.ResultsSixty-six patients were identified. The most common tumour site was the stomach (66.6%), followed by small bowel (28.7%), and colon (1.54%). At the time of diagnosis, 7.57% had metastasis: 4.54% (3) in the liver and 3.03% (2) in the peritoneum. The mean size of tumours was 10.84cm (2.2 to 38cm). Overall 5-year survival was 82%, and 5-year recurrence-free survival was 61%. In the case of overall survival, the site of the lesion was the only factor showing statistical significance, with P=.0054.ConclusionTumour location and size, number of mitoses, risk group, and adjuvant treatment with imatinib were statistically significant as prognostic factors of disease recurrence. Lesion location was the only factor that showed statistical significance as a prognostic factor of overall survival.

From the advent of the highly effective antiretroviral treatment, the life expectancy of patients with human immunodeficiency virus has increased significantly. At present, the causes of death are non-infectious complications. Between them, the pulmonary arterial hypertension has a special importance. It is important early detection to establish the therapeutic, with the objective of preventing a fatal outcome to future.

Metabotropic P2Y receptors subfamily consists of eight functional mammalian receptors. Specifically, P2Y1, P2Y6 and P2Y11 receptors have been described in the sensory nervous system, but their participation, at peripheral level, in behavioral pain models is scarcely understood. This study assessed the role of peripheral P2Y1, P2Y6 and P2Y11 receptors in formalin-induced inflammatory pain. Ipsilateral, but not contralateral peripheral pre-treatment with the endogenous P2Y1 (ADP, 100-1000nmol/paw), P2Y6 (UDP, 180-300nmol/paw) and P2Y11 (ATP, 100-1000nmol/paw), or selective P2Y1 (MRS2365, 0.1-10nmol/paw), P2Y6 (PSB0474, 0.1-0.10pmol/paw) and P2Y11 (NF546, 0.3-3nmol/paw) receptor agonists increased 0.5% formalin-induced flinching behavior. Concordantly, peripheral pre-treatment with the selective P2Y1 (MRS2500, 0.01-10pmol/paw), P2Y6 (MRS2578, 3-30nmol/paw) and P2Y11 (NF340, 1-10nmol/paw) receptor antagonists significantly decreased 1% formalin-induced flinching behavior. Furthermore, the pronociceptive effect of ADP (100nmol/paw) or MRS2365 (10nmol/paw), UDP (300nmol/paw) or PSB0474 (10pmol/paw) and ATP (1000nmol/paw) or NF546 (3nmol/paw) was blocked by the selective P2Y1 (MRS2500, 0.01nmol/paw), P2Y6 (MRS2578, 3nmol/paw), and P2Y11 (NF340, 1nmol/paw) receptor antagonists, respectively. Western blot analysis confirmed the presence of P2Y1 (66kDa), P2Y6 (36kDa) and P2Y11 (75kDa) receptors in dorsal root ganglia (DRG) and sciatic nerve. Results suggest that peripheral activation of P2Y1, P2Y6 and P2Y11 receptors plays a pronociceptive role in formalin-induced pain.

Nerve injury promotes release of 5-HT at the spinal cord. Once released, 5-HT may produce antinociceptive or pronociceptive effects depending of the nature of 5-HT receptors. The purpose of this study was to investigate the participation of spinal 5-HTTactile allodynia was measured using von Frey hairs in male Wistar rats subjected to L5-L6 spinal nerve injury. Selective 5-HTIntrathecal administration of 5-HTData suggests that spinal 5-HT

Gastroeophageal reflux is a condition in which the acidified liquid content of the stomach backs up into the esophagus. The antiacid magaldrate and prokinetic domperidone are two drugs clinically used for the treatment of gastroesophageal reflux symptoms. However, the evidence of a superior effectiveness of this combination in comparison with individual drugs is lacking. A double-blind, randomized and comparative clinical trial study was designed to characterize the efficacy and safety of a fixed dose combination of magaldrate (800 mg)/domperidone (10 mg) against domperidone alone (10 mg), in patients with gastroesophageal reflux symptoms. One hundred patients with gastroesophageal reflux diagnosed by Carlsson scale were randomized to receive a chewable tablet of a fixed dose of magaldrate/domperidone combination or domperidone alone four times each day during a month. Magaldrate/domperidone combination showed a superior efficacy to decrease global esophageal (pyrosis, regurgitation, dysphagia, hiccup, gastroparesis, sialorrhea, globus pharyngeus and nausea) and extraesophageal (chronic cough, hoarseness, asthmatiform syndrome, laryngitis, pharyngitis, halitosis and chest pain) reflux symptoms than domperidone alone. In addition, magaldrate/domperidone combination improved in a statistically manner the quality of life of patients with gastroesophageal reflux respect to monotherapy, and more patients perceived the combination as a better treatment. Both treatments were well tolerated. Data suggest that oral magaldrate/domperidone mixture could be a better option in the treatment of gastroesophageal reflux symptoms than only domperidone.

According to the high consumption of the mixture of B vitamins and diclofenac in several countries, this combination has constituted a frequently used option in pain therapy from inflammatory origin. Although the evidence obtained from inflammatory pain animal models has shown the existence of analgesic synergy between diclofenac and the B vitamins mixture, the corresponding clinical evidence is scarce. A double-blind, randomized clinical trial study was designed to characterize the analgesic effect and safety of diclofenac and B vitamins against diclofenac alone in patients with severe osteoarthritis. Forty eight patients programmed to total knee arthroplasty with a pain level ≥7 in a 1-10 cm visual analogue scale were allocated to receive a single intramuscular injection of sodium diclofenac (75 mg) alone or combined with thiamine (100 mg), pyridoxine (100 mg) and cyanocobalamin (5 mg), and the pain level was evaluated during 12 h post-injection. Diclofenac+B vitamins mixture showed a superior analgesic effect during the assessed period and also a better assessment of the pain relief perception by patients than diclofenac alone. This study constitutes a clinical support on the improvement of the analgesic effect of diclofenac by B vitamins in patients with osteoarthritis programmed to total knee arthroplasty, as a clinical model of inflammatory pain.

Preclinical Research Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug (NSAID) effective in the treatment of moderate to severe pain. Tizanidine, an α-2-adrenoceptor agonist with myospasmolytic action, is indicated for the treatment of back pain either as monotherapy or in combination with NSAIDs. However, side effects may limit their use. As both drugs produce side effects that are dose dependent, a combination of these drugs appears in order to reduce the dose required for efficacy and, consequently, side effects. In this study, we evaluated the potential synergistic effect of these drugs in the thermal paw stimulation model and their effect on gastric ulcer production in response in the rat. Dose-response curves for ketorolac and tizanidine were constructed and from these, an ED40 value was obtained. Isobolographic analysis was carried out based on 0.5:0.5 proportions. In addition, protective effect of tizanidine against ketorolac-induced gastric damage was evaluated. A synergistic interaction in thermal hyperalgesia and gastroprotective activity was observed, suggesting a good therapeutic potential of this combination in the treatment of pain.

Dipyrone, also known as metamizol, and tramadol are drugs that are widely used for the treatment of pain; however, side effects can limit their use. As dipyrone and tramadol produce side effects that are dose dependent, it seems appropriate to combine these drugs to reduce their dose requirements and, consequently, side effects. The purpose of this study was to evaluate whether dipyrone and tramadol produce antihyperalgesic effects in the thermal paw stimulation model in the rat, and whether there is a synergistic interaction between them. Using this model, dose-response curves were constructed for dipyrone (10–178 mg/kg, p.o.) and tramadol (1–32 mg/kg p.o.). From these curves, an ED50 value was obtained and isobolographic analyses were carried out based on 1:1 and 0.6:0.4 (dipyrone:tramadol) potency ratio proportions. When the proportion was 1:1, an additive interaction was obtained, whereas the 0.6:0.4 proportion showed a synergistic interaction. These results suggest a good therapeutic potential of this combination. Drug Dev Res 70:450–454, 2009. © 2009 Wiley-Liss, Inc.

The relaxing activity of Croton reflexifolius H.B.K (Euphorbiaceae) leaves was assessed in isolated guinea pig tracheal rings. The dichloromethane extract of C. reflexifolius was the most active re...

Ketoprofen is a nonsteroidal antiinflammatory drug (NSAID) widely used in therapeutics. However, gastrointestinal toxicity may limit its use. To reduce the requirements of NSAIDs and hence their toxicity, these compounds have been combined with several drugs. B vitamins increase the analgesic activity of NSAIDs, but conflicting results have been obtained. The purpose of this study was to establish whether a vitamin B mixture can increase the antinociceptive effect of ketoprofen in the thermal paw stimulation model and in antiinflammatory activity in carrageenan-induced paw edema in the rat. Ketoprofen produced a dose-dependent antinociception, whereas a mixture of B vitamins produced a very limited antinociceptive effect. However, B vitamins were able to increase the antinociceptive effect of ketoprofen, reaching effects similar to those obtained with the maximal dose of ketoprofen tested. Ketoprofen produced a dose-dependent antiinflammatory activity and B vitamins also produced significant antiinflammatory effects. When ketoprofen was combined with a mixture of B vitamins, an increase in the antiinflammatory action was observed. These results indicate that coadministration of B vitamins with ketoprofen can increase both antihyperalgesic and antiinflammatory effects. Thus, B vitamins are effective as analgesic adjuvants in the models tested. Drug Dev. Res. 64:66–70, 2005. © 2005 Wiley-Liss, Inc.

Vitamin B2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far there are no preclinical studies about the analgesic properties of this vitamin. The current study was designed to investigate the possible antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation models, respectively. Oral riboflavin produced a dose-related antinociceptive (6.25-50 mg/kg), antihyperalgesic (25-150 mg/kg) and anti-inflammatory (50-150 mg/kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin (150-600 mg/kg), reduced tactile allodynia in neuropathic rats. Riboflavin-induced antinociception in the formalin test was reversed by pretreatment with NG-L-nitro-arginine methyl ester and glibenclamide, but not by NG-D-nitro-arginine methyl ester or naloxone. Our results indicate that riboflavin is able to produce antinociception and anti-inflammatory, but not antiallodynic, effect in the rat. The effect of riboflavin could be due to the activation of K+ channels or nitric oxide release, but not activation of opioid mechanisms.

Background and Aims Despite increase in survival of HIV patients due to highly active antiretroviral therapy (HAART), non-infectious complications are still prevalent such as presentation of lung vasculopathy, even in asymptomatic patients. Endothelin-1 (ET-1) is a potent vasoconstrictor that causes pulmonary vasculopathy. Participation of this protein in the pulmonary circulation in HIV patients has not been elucidated. In this work we studied the presence and expression of ET-1 in pulmonary complex vascular lesions associated with human immunodeficiency virus (PCVL/HIV). Methods We used immunohistochemistry and immunochemiluminescence (imagej) to determine the different degrees of expression of ET-1 in PCVL/HIV in comparison with non-PCVL/HIV. Reagents used were anti-endothelin-1 and an automated system. All data are presented as mean and standard deviation (SD). Differences were analyzed with one-way ANOVA; p Results Lung tissues from 56 patients who died from complications of HIV pulmonary infection and with PCVL were studied. Histological evidence of pulmonary vasculopathy was shown as different types (proliferative, obliterative and plexiform). A statistically significant increase in ET-1 expression was observed in all PCVL/HIV tissue samples and is associated directly with different grades of severity of endothelial dysfunction. Conclusions ET-1 has a relevant role in the pathogenesis of pulmonary vasculopathy in acquired immunodeficiency syndrome (AIDS) patients. It is necessary to determine in the future the participation of ET-1 and other mechanisms involved in PCVL/HIV.

From the advent of the highly effective antiretroviral treatment, the life expectancy of patients with human immunodeficiency virus has increased significantly. At present, the causes of death are non-infectious complications. Between them, the pulmonary arterial hypertension has a special importance. It is important early detection to establish the therapeutic, with the objective of preventing a fatal outcome to future.

The relationship between blood levels of ketoprofen and its anti-hyperalgesic effects was examined in rat using the carrageenan-evoked thermal hyperalgesia model. Female adult Wistar rats were injected with carrageenan into the plantar surface of the right hind paw. Immediately after, rats were administered with ketoprofen po and hindpaw withdrawal latency measured and micro-whole blood samples were obtained over six hours via a cannula inserted in the caudal artery. Ketoprofen levels were measured by HPLC. Ketoprofen concentration increased in a dose-dependent manner and was reflected in dose-dependent anti-hyperalgesic effect. The pharmacokinetic and pharmacodynamic parameters expressed as mean ± s.e.m. following administration of 1, 3.2, and 10 mg/kg ketoprofen were: Cmax 1.27 ± 0.08, 3.44 ± 0.20 and 11.76 ± 0.81 μg/mL; AUClast 4.16 ± 0.17, 11.63 ± 0.65 and 28.15 ± 1.32 μg h/mL; and Emax observed (AUCE ): 65.41 ± 7.79, 92.06 ± 6.46 and 98.42 ± 7.53%. A direct relationship between blood concentrations and the anti-hyperalgesic effect of ketoprofen followed a maximum effect model equation. The results indicate that the anti-hyperalgesic effect of ketoprofen in the carrageenan pain model can be predicted by the pharmacokinetic properties of ketoprofen.

The present study aimed to evaluate the antinociceptive activity (in inflammatory and neuropathic pain models) and gastroprotective effect of the 3,5-diprenyl-4-hydroxyacetophenone (HYDP), isolated from Ageratina pichinchensis . The gastroprotective activity of this plant was previously reported by our workgroup, finding encesanescin to be one active compound. The present results show that HYDP reduced nociception in a dose-dependent manner in carrageenan and L5/L6 spinal nerve ligation, with efficacies of 72.6 and 57.1%, respectively, at doses of 100 and 562 mg/kg. HYDP also showed gastroprotective activity in the model of ethanol-induced gastric lesion, with a 75.59% maximum inhibition of ulcers at a dose of 100 mg/kg. This gastroprotective effect was attenuated by N G -nitro- l -arginine methyl ester, indomethacin and N-ethylmaleimide, indicating that NO, prostaglandins and sulfhydryl groups are involved in the mechanisms of action. This is the first evidence, to our knowledge, of the antinociceptive and gastroprotective activities of HYDP.

The oleanane-type triterpene chichipegenin and the sterols peniocerol and macdougallin, isolated from Myrtillocactus geometrizans, showed anti-inflammatory activities in both the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema model and the carrageenan-induced rat paw edema model. All tested compounds inhibited the TPA-induced edema in a dose-dependent manner, with ED50 values less than or equal to that shown by indomethacin. Among them, peniocerol was the most active compound. However, only peniocerol and macdougallin reduced carrageenan-induced rat paw edema. On the other hand, peniocerol and macdougallin showed cytotoxicity against several human cancer cell lines. These results indicate that compounds isolated from M. geometrizans possess antiinflammatory and cytotoxic properties, and the presence of chichipegenin in the aerial parts could justify the medicinal uses attributed to the plant.

Tithonia diversifolia is a medicinal plant from the Municipality of Suchiapa, Chiapas, Mexico, that according to local folk medicine is considered useful in the treatment of gastric ulcers. The aim of the present study was to investigate the gastroprotective activity of T. diversifolia by using an ethanol-induced gastric ulcer experimental model in male Wistar rats. The results showed that T. diversifolia had gastroprotective activity, and that the dichloromethane extract had the highest protective activity (close to 90% when using doses between 10 to 100 mg/kg), and that further the compound tagitinin C isolated from this extract was the main active gastroprotective agent. Rats treated with tagitinin C suspended in Tween 80 at 1, 3, 10 and 30 mg/kg showed 37.7, 70.1, 100, and 100% gastroprotection, respectively. The effect elicited by tagitinin C (30 mg/kg) was not attenuated by pretreatment with either N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups, or indomethacin (10 mg/kg, s.c.), a blocker of prostaglandin synthesis, which suggests that the gastroprotective mechanism of action of this sesquiterpene lactone does not involve NO, sulfhydryl groups or prostaglandins.

Diclofenac and tramadol are drugs widely used for the treatment of pain. However, side effects may limit their use. As both drugs produce side effects that are dose-dependent, it seems appropriate to combine them in order to reduce the requirements for efficacy and, consequently, side effects. The purpose of this study was to evaluate the possible synergistic effect of these drugs in three experimental models of nociception in the rat. Dose-response curves for diclofenac and tramadol were constructed in three models, thermal hyperalgesia, formalin, and hot plate. From these curves, ED40 or ED30 (according to the model employed) values were obtained and isobolographic analyses were carried out based on 0.5:0.5 proportions. Synergistic interactions were observed in the thermal hyperalgesia and hot plate models and an additive interaction was obtained in the formalin test. These results suggest a good therapeutic potential of this combination in the treatment of pain. Drug Dev Res 72: 391–396, 2011. © 2011 Wiley-Liss, Inc.

Eupatorium aschenbornianum is considered useful in the treatment of gastric ulcer. In the current study the validity of this practice was tested by using the experimental model of an ethanol induced gastric ulcer in rats. The results show that E. aschenbornianum had gastroprotective activity, that the hexane extract had the highest protective activity (85.65 ± 4.76%), and that encecanescin isolated from this extract was the main active gastroprotective agent. The effect elicited by encecanescin was attenuated by N G -nitro- l -arginine methyl ester, N-ethylmaleimide and indomethacin, which suggests that NO, prostaglandins and sulfydryl groups are involved in the mechanisms of gastroprotective action.

The pharmacokinetics of meloxicam, a potent analgesic and antiinflammatory drug used in several rheumatic diseases, has been studied in rats that received oral doses of 3.2, 5.6 or 10 mg/kg of meloxicam. Blood samples were obtained at selected times during 24 h after administration, and meloxicam concentrations were determined by a validated high-performance liquid chromatography (HPLC) method, using micro-whole-blood samples, developed in our laboratory. After administration of meloxicam, blood concentrations increased reaching a dose-dependent maximal concentration in about 2 h. Then, concentrations decayed with a half-life of 9 h. An increase in C(max) and AUC as a function of the dose was observed, and no statistically significant difference was observed in AUC/dose or C(max)/dose between doses. However, linearity could not be concluded because of the wide variability observed.

The oleanane-type triterpene chichipegenin and the sterols peniocerol and macdougallin, isolated from Myrtillocactus geometrizans, showed anti-inflammatory activities in both the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema model and the carrageenan- induced rat paw edema model. All tested compounds inhibited the TPA-induced edema in a dose-dependent manner, with ED50 values less than or equal to that shown by indomethacin. Among them, peniocerol was the most active compound. However, only peniocerol and macdougallin reduced carrageenan-induced rat paw edema. On the other hand, peniocerol and macdougallin showed cytotoxicity against several human cancer cell lines. These results indicate that compounds isolated from M. geometrizans possess antiinflammatory and cytotoxic properties, and the presence of chichipegenin in the aerial parts could justify the medicinal uses attributed to the plant.