Rational use of short-term anorectic drugs for one-year effective treatment of obesity: An analysis of four studies.

BACKGROUND: Obesity is a complex disease for which pharmacotherapy is often used. Anti-obesity drugs (AODs) are characterized by inducing a variable inter-subject body weight reduction (BWR), the attainment of a plateau after their maximal effect is achieved, and weight regain after drug discontinuation, which complicate individualized treatment of obesity. OBJECTIVE: This exploratory analysis aimed to compare the first-month body weight reduction in kg (1mo-BWRkg) and tolerance development (moT) of four known interventions with low (placebo), intermediate (phentermine or mazindol monotherapy), and high (5 active ingredients fixed-dose combination) efficacy, as predictors of their 6-month body weight reduction efficacy in percent (6mo-BWR%). In addition, a detailed analysis of the 6-to-12-month BWR follow-up in subjects under orlistat or diet and exercise regimens was performed. MATERIALS AND METHODS: The analysis included 662 adult subjects with obesity. After the construction of average efficacy and weight rebound curves, subjects were grouped into various 1mo-BWRkg, moT, and 6mo-BWR% intervals, or 6-month body weight rebound parameters for further evaluation. RESULTS: The 6mo-BWR% efficacy level of interventions was confirmed, although a general high intersubject variation was observed. 1mo-BWRkg + moT was found as an acceptable predictor of 6mo-BWR%. Between 50 and 80% of the 6-to-12-month follow-up completers maintained at least 5% BWR%. CONCLUSION: Short-term AODs are useful adjuvants for the 1-year rational treatment of obesity. 1mo-BWRkg + moT is an acceptable parameter to predict the 6mo-BWR% efficacy of these interventions.

Corrigendum to Article CP203292.

Cecilia Fernández Del Valle-Laisequilla, Cristian Trejo-Jasso, Juan Carlos Huerta-Cruz, Lina Marcela Barranco-Garduño, Juan Rodríguez-Silverio, Héctor Isaac Rocha-González, Juan Gerardo Reyes-García. Efficacy and safety of a fixed-dose combination of D-norpseudoephedrine, triiodothyronine, atropine, aloin, and diazepam in obese patients. Int J Clin Pharmacol Ther. 2018; 56: 531-538. doi: 10.5414/CP203292. Note from the authors: We realized only now that the affiliation of Cecilia Fernández Del Valle-Laisequilla was indicated in the title page, but due to an unintentional mistake in the final version, the affiliation was not declared in the conflict of interest section, which should read: "Cecilia Fernández Del Valle-Laisequilla is Medical Director of Productos Medix S.A. de C.V."

Cachexia measured by bioelectrical impedance vector analysis and risk of infection in women with rheumatoid arthritis.

Rheumatoid arthritis (RA) patients have a higher frequency of infections than the healthy population. The reason has yet to be explained but involves several factors, of which body composition and rheumatoid cachexia are often overlooked. This study aimed to evaluate whether patients with cachexia, measured by bioelectrical impedance vector analysis, are at an increased risk of developing infections compared with patients without cachexia. A secondary analysis of 186 women with RA enrolled in a randomized trial (ClinicalTrials.gov ID: NCT02900898, September 14, 2016) was completed. Medical records and phone calls were used to record infectious events diagnosed and treated during follow-up. Hazard ratios were calculated using Cox proportional hazard regression analysis, and a predictive model of infection was created. After 36 months of follow-up, 62 patients (26.7% non-cachectic and 44.3% cachectic, p < 0.01) developed at least one infectious event. The most common site of was the urinary tract, followed by the lungs and respiratory tract. The presence of cachexia (HR 1.90, 95% CI 1.15-3.13) and the use of glucocorticoids (HR 1.77, 95% CI 1.01-3.09) were associated with infection in univariate and multivariate models. Body mass index (BMI), smoking, and methotrexate use were not associated with a higher frequency of infections. The presence of cachexia and the use of glucocorticoids were identified as predictors of infections in a cohort of female RA patients. More extensive measurements of body composition should be performed beyond BMI in RA patients to better understand its impact and to prevent additional comorbidities and complications. Key Points • The presence of cachexia measured by bioelectrical impedance vector analysis was associated with infectious events in women with rheumatoid arthritis, whereas body mass index did not show an association. • Glucocorticoids were the only drug associated with a higher frequency of infection. None of the disease-modifying antirheumatic drugs, including methotrexate, showed an association.

Effect of the Melanocortin 4-Receptor Ile269Asn Mutation on Weight Loss Response to Dietary, Phentermine and Bariatric Surgery Interventions.

The loss of function melanocortin 4-receptor (MC4R) Ile269Asn mutation has been proposed as one of the most important genetic contributors to obesity in the Mexican population. However, whether patients bearing this mutation respond differently to weight loss treatments is unknown. We tested the association of this mutation with obesity in 1683 Mexican adults, and compared the response of mutation carriers and non-carriers to three different weight loss interventions: dietary restriction intervention, phentermine 30 mg/day treatment, and Roux-en-Y gastric bypass (RYGB) surgery. The Ile269Asn mutation was associated with obesity [OR = 3.8, 95% CI (1.5-9.7), p = 0.005]. Regarding interventions, in the dietary restriction group only two patients were MC4R Ile269Asn mutation carriers. After 1 month of treatment, both mutation carriers lost weight: -4.0 kg (-2.9%) in patient 1, and -1.8 kg (-1.5%) in patient 2; similar to the mean weight loss observed in six non-carrier subjects (-2.9 kg; -2.8%). Phentermine treatment produced similar weight loss in six carriers (-12.7 kg; 15.5%) and 18 non-carriers (-11.3 kg; 13.6%) after 6 months of pharmacological treatment. RYGB also caused similar weight loss in seven carriers (29.9%) and 24 non-carriers (27.8%), 6 months after surgery. Our findings suggest that while the presence of a single MC4R loss of function Ile269Asn allele significantly increases obesity risk, the presence of at least one functional MC4R allele seems sufficient to allow short-term weight loss in response to dietary restriction, phentermine and RYGB. Thus, these three different interventions may be useful for the short-term treatment of obesity in MC4R Ile269Asn mutation carriers.

Combined First Month Body Weight Loss and Development of Tolerance as Predictors of 6-Month Efficacy of Mazindol in Mild and Moderate Obese Subjects.

The weight loss response to anti-obesity drugs is highly variable and poorly understood, which does not allow us to know, in advance, in which subjects the drug will be effective and in which it will not. The objective of this study was to explore the body weight reduction in kilograms in the first month (1mo-BWRkg) and the development of tolerance as predictors of 6-month efficacy for treatment with 1 mg mazindol twice a day. One hundred ninety-six obese subjects were individually or jointly analyzed. Approximately 60% of subjects developed tolerance to mazindol and achieved increasing proportional levels of 6-month efficacy according to 1mo-BWRkg intervals (<1 kg, 1 to <2 kg, 2 to <4 kg and ≥4 kg). Both moT and 1mo-BWRkg were significantly correlated with the mean percentage body weight reduction (BWR%) after 6-months of treatment. The qualitative analysis of both predictors on the progressive efficacy of mazindol was used to classify patients according to expected efficacy (inefficient, slightly effective, partially effective, or fully effective), based on the mean percentage efficacy and the number of subjects reaching a BWR% of <5%, 5 to <10%, 10 to <15% or ≥15%. In conclusion, combined 1mo-BWRkg and moT were early predictors for the progressive efficacy of 6-month mazindol anti-obesity therapy. This finding represents progress in predictive, preventive, and personalized medicine which could serve for estimating the expectations of individual efficacy with the use of the drug. and highlights the basic principle of personalized medicine, "one size does not fit all".

Effect of vitamin C on immune reconstitution after bone marrow transplantation.

BACKGROUND: Vitamin C is an essential nutrient for the adequate function and maturation of the immune system. In vitro studies show that the development, proliferation, and functioning of T cells requires vitamin C, especially for natural killer (NK) cells. Their deficiency during the acute phase post-transplantation could cause greater morbidity and mortality in these patients. A prospective clinical trial using high-dose vitamin C was performed to determine if vitamin C supplementation improves reconstitution of NK lymphocytes after hematopoietic stem cell transplantation (HSCT). MATERIALS AND METHODS: We enrolled 24 patients who underwent autologous HSCT for multiple myeloma and lymphoma. Patients were randomized to receive standard treatment or standard treatment plus 20 g vitamin C once daily (1 - 10 days) and 500 mg twice daily (11 - 100 days) after transplantation. RESULTS: NK and CD3+ lymphocytes showed an increase from days +30 to +100 only in the vitamin C-treated group. Patients in the vitamin C group had a lower frequency of infections. No severe adverse events were reported. CONCLUSION: Our results suggest that high-dose vitamin C supplementation is an effective and safe therapeutic option to decrease the frequency of infections and enhance immune reconstitution after HSCT.

Metformin improves the weight reduction effect of mazindol in prediabetic obese Mexican subjects.

OBJECTIVE: Obesity is the strongest risk factor for type 2 diabetes (T2D). We aimed to explore 7% weight reduction rates of mazindol alone or combined with metformin in non-diabetic obese Mexican subjects who had additional risk factors for T2D. MATERIALS AND METHODS: In this randomized double-blind study, 137 participants received 1 mg mazindol (n = 65) alone or combined with 500 mg metformin (n = 72), twice a day, for 6 months. RESULTS: Mazindol and mazindol-metformin were similarly effective. However, when subjects were subclassified into non-diabetics and prediabetics, according to glycated hemoglobin (HbA1c) - < 5.7% and 5.7 - 6.4%, respectively - and/or fasting plasma glucose (FPG) - < 100 mg/dL and 100 - 125 mg/dL, respectively -, differences were evident. Prediabetics in the mazindol-metformin group had a higher rate of 7% weight reduction (78.4%, n = 37) compared to prediabetics treated with mazindol (48.3%, n = 29). Furthermore, mazindol-metformin treatment induced significant reductions in fasting plasma insulin, HOMA-IR, and HbA1c in prediabetics compared to mazindol. No differences were found in any parameter between non-diabetics treated with mazindol (n = 36) and mazindol-metformin (n = 35). CONCLUSION: Our results highlight the effectiveness of mazindol-metformin to achieve higher rates of 7% weight reduction and to improve the glycemic profile in prediabetic obese subjects, which could be useful to prevent or delay T2D in these subjects.

SOFA Score Plus Impedance Ratio Predicts Mortality in Critically Ill Patients Admitted to the Emergency Department: Retrospective Observational Study.

BACKGROUND: The Sequential Organ Failure Assessment (SOFA) is a scoring system used for the evaluation of disease severity and prognosis of critically ill patients. The impedance ratio (Imp-R) is a novel mortality predictor. AIMS: This study aimed to evaluate the combination of the SOFA + Imp-R in the prediction of mortality in critically ill patients admitted to the Emergency Department (ED). METHODS: A retrospective cohort study was performed in adult patients with acute illness admitted to the ED of a tertiary-care referral center. Baseline SOFA score and bioelectrical impedance analysis to obtain the Imp-R were performed within the first 24 h after admission to the ED. A Cox regression analysis was performed to evaluate the mortality risk of the initial SOFA score plus the Imp-R. Harrell's C-statistic and decision curve analyses (DCA) were performed. RESULTS: Out of 325 patients, 240 were included for analysis. Overall mortality was 31.3%. Only 21.3% of non-surviving patients died after hospital discharge, and 78.4% died during their hospital stay. Of the latter, 40.6% died in the ED. The SOFA and Imp-R values were higher in non-survivors and were significantly associated with mortality in all models. The combination of the SOFA + Imp-R significantly predicted 30-day mortality, in-hospital mortality, and ED mortality with an area under the curve (AUC) of 0.80 (95% CI: 74-0.86), 0.79 (95% CI: 0.74-0.86) and 0.75 (95% CI: 0.66-0.84), respectively. The DCA showed that combining the SOFA + Imp-R improved the prediction of mortality through the lower risk thresholds. CONCLUSIONS: The addition of the Imp-R to the baseline SOFA score on admission to the ED improves mortality prediction in severely acutely ill patients admitted to the ED.

GPR55 and GPR119 Receptors Contribute to the Processing of Neuropathic Pain in Rats.

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.

Weight Loss at First Month and Development of Tolerance as Possible Predictors of 30 mg Phentermine Efficacy at 6 Months.

The efficacy of anti-obesity drugs usually does not consider the high degree of interindividual variability in responses to the drug which could affect the decision to withdraw the drug early due to ineffectiveness or to continue therapy according to specific expectations of success. The aim of this study was to analyze body weight loss in kilograms during the first month (1 mo-BWLkg) of treatment with 30 mg phentermine and development of tolerance to phentermine, on its 6-month efficacy. One hundred sixty-six subjects with obesity were individually or jointly analyzed in the study. Subjects with 1 mo-BWLkg of <1 kg, 1-3 kg, 3-5 kg, and ≥5 kg reached 6-month mean percentage body weight reductions (BWR%) of approximately 3%, 5%, 10%, and 15%, respectively. Development of late tolerance (4-6 months) to phentermine had a lower impact than early tolerance (2-3 months). Subjects with 1 mo-BWLkg < 3 kg who developed early tolerance did not achieve relevant BWR% (≥5%) at month 6, while the rest of the subgroups achieved increasing and progressive BWR%, according to their 1 mo-BWLkg range and time of onset of tolerance. The 1 mo-BWLkg and development of tolerance to phentermine could be useful to predict the expected 6-month efficacy trends in obese patients treated with 30 mg phentermine.

Effectiveness of ultrasound in the detection of axillary metastasis in patients with breast cancer without clinical evidence of axillary disease: Clinical impact / Efectividad de la ecografía en la detección de metástasis axilares en pacientes con cáncer de mama sin evidencia clínica de enfermedad axilar: impacto clínico

Introduction Preoperative ultrasound in patients with breast cancer without evidence of clinical axillary disease represents an attempt to reliably identify axillary lymph node metastasis. However, the usefulness of ultrasound for the detection of axillary disease should be evaluated. Materials and methods The study included a retrospective cohort of 826 patients with diagnosed invasive breast cancer, treated at the National Cancer Institute of Mexico, from 2014 to 2018. All patients underwent ipsilateral axillary ultrasound for staging purposes. Besides the descriptive analysis of the preoperative ultrasound, findings of the cohort were compared with their corresponding cytology and histopathology reports. Results Diagnostic index for axillary ultrasound was calculated as follows: 32.8% sensitivity, 82.5% specificity, 37.1% positive predictive value (PPV), 79.6% negative predictive value (NPV), 70.6% diagnostic accuracy, 1.86 positive likelihood ratio (LR+), and 0.81 negative likelihood ratio (LR−). Loss of fatty hilum was associated with a higher risk of axillary metastasis on the multivariate analysis (OR 3.645; 95% CI, 1.664–7.985, p<0.001). Conclusions The utility of axillary ultrasound as a method of determining the nodal status prior to surgery in patients with breast cancer without clinical evidence of axillary disease was not demonstrated in this study. (AU)

Introducción La ecografía preoperatoria en pacientes con cáncer de mama sin evidencia de enfermedad clínica axilar representa un intento de identificar de manera confiable metástasis a ganglios linfáticos axilares. Sin embargo, se debe evaluar la utilidad de la ecografía para la detección de la enfermedad axilar. Material y métodos El estudio incluyó una cohorte retrospectiva de 826 pacientes con cáncer de mama invasivo diagnosticado en el Instituto Nacional de Cancerología de México, de 2014 a 2018. Todos los pacientes se sometieron a una ecografía axilar ipsilateral con fines de estadificación. Además del análisis descriptivo de la ecografía preoperatoria, los resultados de la cohorte se compararon con sus correspondientes informes de citología e histopatología. Resultados Los índices diagnósticos para la ecografía axilar fueron: 32,8% de sensibilidad, 82,5% de especificidad, 37,1% de valor predictivo positivo (VPP), 79,6% de valor predictivo negativo (VPN), 70,6% de precisión diagnóstica, 1,86 de razón de verosimilitud positiva (LR+) y 0,81 de razón de verosimilitud negativa (LR−). La pérdida de hilio graso se asoció con un mayor riesgo de metástasis axilares en el análisis multivariado (RM: 3.645; IC al 95%: 1.664-7.985; p<0,001). Conclusiones La utilidad de la ecografía axilar como método para determinar el estado ganglionar antes de la cirugía en pacientes con cáncer de mama sin evidencia clínica de enfermedad axilar no se demostró en este estudio. (AU)

Three- and six-month efficacy and safety of phentermine in a Mexican obese population.

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.

Evaluation of the Antinociceptive, Antiallodynic, Antihyperalgesic and Anti-Inflammatory Effect of Polyalthic Acid.

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.

All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: A real-world observational study.

The aim of our study was to evaluate all-cause mortality risk in patients with laboratory-confirmed COVID-19 in Mexico City treated with repurposed antivirals and antibiotics. This real-world retrospective cohort study contemplated 395,343 patients evaluated for suspected COVID-19 between February 24 and September 14, 2020 in 688 primary-to-tertiary medical units in Mexico City. Patients were included with a positive RT-PCR for SARS-CoV-2; those receiving unspecified antivirals, excluded; and groups of antivirals prescribed in < 30 patients, eliminated. Survival and mortality risks were determined for patients receiving antivirals, antibiotics, both, or none. We assessed the effect of early (<2 days) versus late (>2 days) use of antivirals on mortality in a sub-cohort of patients. Multivariable adjustment, propensity score matching, generalized estimating equations, and calculation of E-values were performed to limit confounding. 136,855 patients were analyzed; mean age 44.2 (SD:16.8) years; 51.3 % were men. 16.6 % received antivirals (3 %), antibiotics (10 %), or both (3.6 %). Antivirals studied were Oseltamivir (n=8414), Amantadine (n=319), Lopinavir-Ritonavir (n=100), Rimantadine (n=61), Zanamivir (n=39), and Acyclovir (n=36). Survival with antivirals (73.7 %, p<0.0001) and antibiotics (85.8 %, p<0.0001) was lower than no antiviral/antibiotic (93.6 %). After multivariable adjustment, increased risk of death occurred with antivirals (HR=1.72, 95 % CI: 1.61-1.84) in ambulatory (HR=4.7, 95 % CI: 3.94-5.62) and non-critical (HR=2.03, 95 % CI: 1.86-2.21) patients. Oseltamivir increased mortality risk in the general population (HR=1.72, 95 % CI: 1.61-1.84), ambulatory (HR=4.79, 95 % CI: 4.01-5.75), non-critical (HR=2.05, 95 % CI: 1.88-2.23), and pregnancy (HR=8.35, 95 % CI: 1.77-39.30); as well as hospitalized (HR=1.13, 95 % CI: 1.01-1.26) and critical patients (HR=1.22, 95 % CI: 1.05-1.43) after propensity score-matching. Early versus late oseltamivir did not modify the risk. Antibiotics were a risk factor in general population (HR=1.13, 95 % CI: 1.08-1.19) and pediatrics (HR=4.22, 95 % CI: 2.01-8.86), but a protective factor in hospitalized (HR=0.81, 95 % CI: 0.77-0.86) and critical patients (HR=0.67, 95 % CI: 0.63-0.72). No significant benefit for repurposed antivirals was observed; oseltamivir was associated with increased mortality. Antibiotics increased mortality risk in the general population but may increase survival in hospitalized and critical patients.

Comparison of Bioelectrical Impedance Analysis Parameters for the Detection of Fluid Overload in the Prediction of Mortality in Patients Admitted at the Emergency Department.

BACKGROUND: Fluid overload (FO) in critically ill patients is associated with increased adverse events. This study aims to compare different bioelectrical impedance analysis (BIA) parameters that demonstrate FO and their association with 30-day mortality in critical patients admitted to the emergency department (ED). METHODS: Five components of the BIA were obtained by multifrequency device-total body water (TBW), extracellular water (ECW), intracellular water (ICW), resistance (R), and reactance (Xc)-to calculate parameters (impedance vectors, impedance ratio, and the ratios of ECW to TBW, ECW to ICW, ECW to body surface area, TBW to height2 , ICW to height2 , Xc to height, and R to height) that have been used for the detection of FO. A concordance analysis (κ) was performed comparing every parameter with each other. Furthermore, different regression models (Cox regression) were created associating the FO for each parameter with 30-day mortality, adjusted for age, body mass index, sex, Sequential Organ Failure Assessment score, and serum albumin level. RESULTS: A total of 142 patients were included in the study. Only FO by impedance vector analysis (relative risk [RR] = 6.4; 95% CI, 1.5-27.9; P = .01), impedance ratio (RR = 2.7; 95% CI, 1.1-7.1; P = .04), and R (RR = 2.6; 95% CI, 1.2-5.5; P = .02) increased the probability of 30-day mortality. CONCLUSIONS: Different parameters that determine FO by BIA were associated with the mortality of patients admitted to the ED, but the impedance vector analysis was superior to any other parameter of the BIA.

Efficacy and safety of the metformin-mazindol anorectic combination in rat.

The current study investigates the anorectic interaction and safety of the mazindol-metformin combination in rats. Isobologram and interaction index were used to determine anorectic interaction between mazindol and metformin in the sweetened milk model. The safety profile of the mazindol-metformin combination was determined by measuring anxiety, blood pressure, hematic biometry and blood chemistry. An acute dose of mazindol and metformin administered per os, individually or as a mixture, has reduced the milk consumption in rats in a dose-dependent manner. Theoretical effective dose 40 (ED40t) did not differ from the experimental effective dose 40 (ED40e) obtained with the mazindol-metformin mixture in the anorexia experiments, by Student's t-test. In addition, the interaction index confirmed the additive anorectic effect between both drugs. A single oral dose of ED40e mazindol-metformin mixture induced anxiolysis in the elevated plus-maze test. Moreover, oral administration of mazindol-metformin combination for 3 months significantly decreased glycemia, but not blood pressure nor other parameters of hematic biometry and blood chemistry. Results suggest that mazindol-metformin combination exerts an additive anorectic effect, as well as anxiolytic and hypoglycemic properties. Mazindol-metformin combination might be useful in obese patients with anxiety disorders or diabetes risk factors.

Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the main types of drugs used to treat pain, they have several adverse effects, and such effects can be reduced by combining two analgesic drugs. The aim of this study was to evaluate the nociceptive activity of methyleugenol combined with either diclofenac or ketorolac, and determine certain parameters of pharmacokinetics. For the isobolographic analysis, the experimental effective dose 30 (ED30) was calculated for the drugs applied individually. With these effective doses, the peak plasma concentration (Cmax) was found and the other parameters of pharmacokinetics were established. Methyleugenol plus diclofenac and methyleugenol plus ketorolac decreased licking behavior in a dose-dependent manner in phase II, with an efficacy of 32.9 ± 9.3 and 39.8 ± 9.6%, respectively. According to the isobolographic analysis, the experimental and theoretical ED30 values were similar for methyleugenol plus diclofenac, suggesting an additive effect, but significantly different for methyleugenol plus ketorolac (3.6 ± 0.5 vs. 7.7 ± 0.6 mg/kg, respectively), indicating a probable synergistic interaction. Regarding pharmacokinetics, the only parameter showing a significant difference was Cmax for the methyleugenol plus diclofenac combination. Even with this difference, the combinations studied may be advantageous for treating inflammatory pain, especially for the combination methyleugenol plus ketorolac.

Antiallodynic effect of PhAR-DBH-Me involves cannabinoid and TRPV1 receptors.

The antiallodynic effect of PhAR-DBH-Me was evaluated on two models of neuropathic pain, and the potential roles of CB1, CB2, and TRPV1 receptors as molecular targets of PhAR-DBH-Me were studied. Female Wistar rats were submitted to L5/L6 spinal nerve ligation (SNL) or repeated doses of cisplatin (0.1 mg/kg, i.p.) to induce experimental neuropathy. Then, tactile allodynia was determined, and animals were treated with logarithmic doses of PhAR-DBH-Me (3.2-100 mg/kg, i.p.). To evaluate the mechanism of action of PhAR-DBH-Me, in silico studies using crystallized structures of CB1, CB2, and TRPV1 receptors were performed. To corroborate the computational insights, animals were intraperitoneally administrated with antagonists for CB1 (AM-251, 3 mg/kg), CB2 (AM-630, 1 mg/kg), and TRPV1 receptors (capsazepine, 3 mg/kg), 15 min before to PhAR-DBH-Me (100 mg/kg) administration. Vagal stimulation evoked on striated muscle contraction in esophagus, was used to elicited pharmacological response of PhAR-DBH-ME on nervous tissue. Systemic administration of PhAR-DBH-Me reduced the SNL- and cisplatin-induced allodynia. Docking studies suggested that PhAR-DBH-Me acts as an agonist for CB1, CB2, and TRPV1 receptors, with similar affinity to the endogenous ligand anandamide. Moreover antiallodynic effect of PhAR-DBH-Me was partially prevented by administration of AM-251 and AM-630, and completely prevented by capsazepine. Finally, PhAR-DBH-Me decreased the vagally evoked electrical response in esophagus rat. Taken together, results indicate that PhAR-DBH-Me induces an antiallodynic effect through partial activation of CB1 and CB2 receptors, as well as desensitization of TRPV1 receptors. Data also shed light on the novel vanilloid nature of the synthetic compound PhAR-DBH-Me.

Factors associated with residual symptom burden in patients with peritoneal dialysis: a cohort study / Factores asociados a carga sintomática residual en pacientes con diálisis peritoneal: estudio de cohorte

BACKGROUND: Patients on peritoneal dialysis have residual symptoms that reduce their quality of life. OBJECTIVE: To determine the associated factors of residual symptom burden in patients with continuous ambulatory peritoneal dialysis (CAPD). MATERIAL AND MEHOTDS: An observational, longitudinal, prospective and analytical study was carried out in patients with chronic kidney disease, who were candidates for peritoneal dialysis. The Palliative Care Outcome Scale-Symptoms Renal (POS-S Renal) questionnaire was applied in predialysis and 3 months after CAPD. The residual symptom burden was determined three months after CAPD with a value ≥ 8 points of the POS-S Renal questionnaire. The clinical and biochemical variables coded in a dichotomous manner were compared with the residual symptom burden. Relative risk (RR) with 95% confidence intervals and logistic regression models were calculated. RESULTS: Seventy patients were included. The mean of glomerular filtration rate (GFR) was 4.7 ± 2 ml/min/1.73 m2. The median of the POS-S Renal score in predialysis was 30 points, and 3 months after CAPD was 8 points. The slight symptom burden predialysis presented a RR of 0.18. CONCLUSIONS: The slight symptom burden predialysis is a protective factor independent for residual symptom burden three months after CAPD.

INTRODUCCIÓN: Los pacientes en diálisis peritoneal presentan síntomas residuales que reducen su calidad de vida. OBJETIVO: Determinar los factores asociados a la carga sintomática residual en pacientes con diálisis peritoneal continua ambulatoria (DPCA). MATERIAL Y MÉTODOS: Estudio observacional, longitudinal, prospectivo y analítico. Se incluyeron pacientes con enfermedad renal crónica candidatos a diálisis peritoneal. Se les aplicó el cuestionario Palliative Care Outcome Scale-Symptoms Renal (POS-S Renal) en prediálisis y a los 3 meses de DPCA. Se determinó la carga sintomática residual a los 3 meses de DPCA con un valor ≥ 8 puntos del cuestionario POS-S Renal. Las variables clínicas y bioquímicas codificadas de forma dicotómica fueron comparadas con la carga sintomática residual. Se calcularon el riesgo relativo (RR), los intervalos de confianza del 95% y los modelos de regresión logística. RESULTADOS: Se incluyeron 70 pacientes. La media de la tasa de filtrado glomerular fue de 4.7 ± 2 ml/min/1.73 m2. La mediana de la puntuación POS-S Renal en prediálisis fue de 30 puntos y a los 3 meses de la DPCA fue de 8 puntos. La carga sintomática leve prediálisis presentó un RR de 0.18. CONCLUSIONES: La carga sintomática leve prediálisis es un factor protector independiente de la carga sintomática residual a los 3 meses de la DPCA.