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."

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.

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.

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.

Possible involvement of peripheral TRP channels in the hydrogen sulfide-induced hyperalgesia in diabetic rats.

BACKGROUND: Peripheral diabetic neuropathy can be painful and its symptoms include hyperalgesia, allodynia and spontaneous pain. Hydrogen sulfide (H2S) is involved in diabetes-induced hyperalgesia and allodynia. However, the molecular target through which H2S induces hyperalgesia in diabetic animals is unclear. The aim of this study was to determine the possible involvement of transient receptor potential (TRP) channels in H2S-induced hyperalgesia in diabetic rats. RESULTS: Streptozotocin (STZ) injection produced hyperglycemia in rats. Intraplantar injection of NaHS (an exogenous donor of H2S, 3-100 µg/paw) induced hyperalgesia, in a time-dependent manner, in formalin-treated diabetic rats. NaHS-induced hyperalgesia was partially prevented by local intraplantar injection of capsazepine (0.3-3 µg/paw), HC-030031 (100-316 µg/paw) and SKF-96365 (10-30 µg/paw) blockers, at 21 days post-STZ injection. At the doses used, these blockers did not modify formalin-induced nociception. Moreover, capsazepine (0.3-30 µg/paw), HC-030031 (100-1000 µg/paw) and SKF-96365 (10-100 µg/paw) reduced formalin-induced nociception in diabetic rats. Contralateral injection of the highest doses used did not modify formalin-induced flinching behavior. Hyperglycemia, at 21 days, also increased protein expression of cystathionine-ß-synthase enzyme (CBS) and TRPC6, but not TRPA1 nor TRPV1, channels in dorsal root ganglia (DRG). Repeated injection of NaHS enhanced CBS and TRPC6 expression, but hydroxylamine (HA) prevented the STZ-induced increase of CBS protein. In addition, daily administration of SKF-96365 diminished TRPC6 protein expression, whereas NaHS partially prevented the decrease of SKF-96365-induced TRPC6 expression. Concordantly, daily intraplantar injection of NaHS enhanced, and HA prevented STZ-induced intraepidermal fiber loss, respectively. CBS was expressed in small- and medium-sized cells of DRG and co-localized with TRPV1, TRPA1 and TRPC6 in IB4-positive neurons. CONCLUSIONS: Our data suggest that H2S leads to hyperalgesia in diabetic rats through activation of TRPV1, TRPA1 and TRPC channels and, subsequent intraepidermal fibers loss. CBS enzyme inhibitors or TRP-channel blockers could be useful for treatment of painful diabetic neuropathy.

Efficacy and safety of a fixed-dose combination of D-norpseudoephedrine, triiodothyronine, atropine, aloin, and diazepam in obese patients
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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.
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Mortality in adult patients with fluid overload evaluated by BIVA upon admission to the emergency department.

PURPOSE OF THE STUDY: The aim of this study was to investigate the association of fluid overload, measured by bioelectrical impedance vector analysis (BIVA) and also by accumulated fluid balance, with 30-day mortality rates in patients admitted to the emergency department (ED). DESIGN: We conducted a prospective observational study of fluid overload using BIVA, taking measures using a multiple-frequency whole-body tetrapolar equipment. Accumulated fluid balances were obtained at 24, 48 and 72 hours from ED admission and its association with 30-day mortality. PATIENTS: 109 patients admitted to the ED classified as fluid overloaded by both methods. RESULTS: According to BIVA, 71.6% (n=78) of patients had fluid overload on ED admission. These patients were older and had higher Sequential Organ Failure Assessment scores. During a median follow-up period of 30 days, 32.1% (n=25) of patients with fluid overload evaluated by BIVA died versus none with normovolaemia (p=0.001). There was no statistically significant difference in mortality between patients with and without fluid overload as assessed by accumulated fluid balance (p=0.81). CONCLUSIONS: Fluid overload on admission evaluated by BIVA was significantly related to mortality in patients admitted to the ED.

Antiallodynic interaction and motor performance of the pregabalin/thioctic acid and pregabalin/α-tocopherol combinations in neonatal streptozotocin-induced diabetic rats.

Painful peripheral neuropathy can be associated with nerve damage caused by diabetes mellitus. Although pregabalin is the first-line therapy for peripheral neuropathy, it shows substantial discontinuation rates, mainly because of nervous system side effects as motor incoordination. Multimodal therapy may improve the motor side effect profile of pregabalin. The aim of this study was to evaluate the interaction of pregabalin + thioctic acid or pregabalin + α-tocopherol on allodynia and motor performance in neonatal streptozotocin-induced diabetic rats. Efficacy of drugs separately or in combination was tested by tactile allodynia using von Frey filaments. Isobolographic and interaction index analysis were used to determine the antiallodynic interaction between pregabalin and either thioctic acid or α-tocopherol. Motor performance was measured using a rotarod test. Pregabalin, thioctic acid, and α-tocopherol reduced, in a dose-dependent fashion, tactile allodynia. Pregabalin + thioctic acid and pregabalin + α-tocopherol combinations also dose-dependently reduced allodynic behavior in diabetic rats. Isobolographic analysis revealed an additive interaction for both combinations. Consistently, the interaction indices confirmed the additive effect between pregabalin + thioctic acid and pregabalin + α-tocopherol. In addition, the administration of either combination improved motor incoordination induced by pregabalin. Data suggests that thioctic acid or α-tocopherol could positively impact the therapeutic profile of pregabalin, because they might be useful for reducing motor incoordination associated to pregabalin in patients with peripheral neuropathy.

Role of anoctamin-1 and bestrophin-1 in spinal nerve ligation-induced neuropathic pain in rats.

BACKGROUND: Calcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors. RESULTS: L5/L6 spinal nerve ligation induced mechanical tactile allodynia. Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia. Intrathecal administration of selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) also dose-dependently diminished tactile allodynia and thermal hyperalgesia. Anoctamin-1 and bestrophin-1 mRNA and protein were expressed in the dorsal spinal cord and DRG of naïve, sham and neuropathic rats. L5/L6 spinal nerve ligation rose mRNA and protein expression of anoctamin-1, but not bestrophin-1, in the dorsal spinal cord and DRG from day 1 to day 14 after nerve ligation. In addition, repeated administration of CaCCs inhibitors (T16Ainh-A01, CaCCinh-A01 or NFA) or anti-anoctamin-1 antibody prevented spinal nerve ligation-induced rises in anoctamin-1 mRNA and protein expression. Following spinal nerve ligation, the compound action potential generation of putative C fibers increased while selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) attenuated such increase. CONCLUSIONS: There is functional anoctamin-1 and bestrophin-1 expression in rats at sites related to nociceptive processing. Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia. As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.

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.

Role of spinal P2Y6 and P2Y11 receptors in neuropathic pain in rats: possible involvement of glial cells.

BACKGROUND: The participation of spinal P2X receptors in neuropathic pain is well recognized. However, the role of P2Y receptors has been less studied. The purpose of this study was to investigate the contribution of spinal P2Y6,11 receptors following peripheral nerve damage induced by spinal nerve ligation. In addition, we determined the expression of P2Y6,11 receptors in the dorsal spinal cord in presence of the selective P2Y6,11 receptors antagonists. Furthermore, we evaluated the participation of spinal microglia and astrocytes in the pronociceptive role of P2Y6,11 receptors. RESULTS: Spinal administration of the selective P2Y6 (MRS2578, 10-100 µM) and P2Y11 (NF340, 0.3-30 µM) receptor antagonists reduced tactile allodynia in spinal nerve ligated rats. Nerve injury increased the expression of P2Y6,11 receptors at 7, 14 and 21 days after injury. Furthermore, intrathecal administration of MRS2578 (100 µM/day) and NF340 (30 µM/day) for 3 days significantly reduced spinal nerve injury-induced increase in P2Y6,11 receptors expression, respectively. Spinal treatment (on day 14 after injury) with minocycline (100 µg/day) or fluorocitrate (1 nmol/day) for 7 days reduced tactile allodynia and spinal nerve injury-induced up-regulation in Iba-1 and GFAP, respectively. In addition, minocycline reduced nerve injury-induced up-regulation in P2Y6,11 receptors whereas that fluorocitrate diminished P2Y11, but not P2Y6, receptors up-regulation. Intrathecal treatment (on day 21 after injury) with the selective P2Y6 (PSB0474, 3-30 µM) and P2Y11 (NF546, 1-10 µM) receptor agonists produced remarkable tactile allodynia in nerve ligated rats previously treated with minocycline or fluorocitrate for 7 days. CONCLUSIONS: Our data suggest that spinal P2Y6 is present in spinal microglia while P2Y11 receptors are present in both spinal microglia and astrocytes, and both receptors are up-regulated in rats subjected to spinal nerve injury. In addition, our data suggest that the spinal P2Y6 and P2Y11 receptors participate in the maintenance of 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.

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.

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".

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.

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.