Exercise training restores weight gain and attenuates hepatic inflammation in a rat model of non-celiac gluten sensitivity.

Gluten intolerance is associated with several disorders in the body. Although research has grown in recent years, the understanding of its impact on different tissues and the effects of physical exercise in mitigating health problems in the condition of gluten intolerance are still limited. Therefore, our objective was to test whether gliadin would affect metabolism and inflammation in liver tissue and whether aerobic physical exercise would mitigate the negative impacts of gliadin administration in rodents. Wistar rats were divided into exercised gliadin, gliadin, and control groups. Gliadin was administered by gavage from birth to 60 days of age. The rats in the exercised gliadin group performed an aerobic running exercise training protocol for 15 days. At the end of the experiments, physiological, histological, and molecular analyzes were performed in the study. Compared to the control group, the gliadin group had impaired weight gain and increased gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. On the other hand, compared to the gliadin group, animals in the exercise-gliadin group had a recovery in body weight, improved insulin sensitivity, and a reduction in some gluconeogenesis, lipogenesis, and inflammatory biomarkers in the liver. In conclusion, our results revealed that the administration of gliadin from birth impaired weight gain and induced an increase in hepatic inflammatory cytokines, which was associated with an impairment of glycemic homeostasis in the liver, all of which were attenuated by adding aerobic exercise training in the gliadin group.

Clinical effects and pharmacokinetics of nebulized lidocaine in healthy horses.

Background: Nebulized lidocaine appears promising as a novel corticosteroid-sparing therapeutic for equine asthma, but its safety and pharmacokinetic behavior have yet to be confirmed. Objective: To describe the effect of nebulized lidocaine on upper airway sensitivity, lung mechanics, and lower respiratory cellular response of healthy horses, as well as delivery of lidocaine to lower airways, and its subsequent absorption, clearance, and duration of detectability. Animals: Six healthy university- and client-owned horses with normal physical examination and serum amyloid A, and no history of respiratory disease within 6 months. Methods: Prospective, descriptive study evaluating the immediate effects of 1 mg/kg 4% preservative-free lidocaine following nebulization with the Flexineb®. Prior to and following nebulization, horses were assessed using upper airway endoscopy, bronchoalveolar lavage, and pulmonary function testing with esophageal balloon/pneumotachography and histamine bronchoprovocation. Additionally, blood and urine were collected at predetermined times following single-dose intravenous and nebulized lidocaine administration for pharmacokinetic analysis. Results: Upper airway sensitivity was unchanged following lidocaine nebulization, and no laryngospasm or excessive salivation was noted. Lidocaine nebulization (1 mg/kg) resulted in a mean epithelial lining fluid concentration of 9.63 ± 5.05 µg/mL, and a bioavailability of 29.7 ± 7.76%. Lidocaine concentrations were higher in epithelial lining fluid than in systemic circulation (Cmax 149.23 ± 78.74 µg/L, CELF:Cmaxplasma 64.4, range 26.5-136.8). Serum and urine lidocaine levels remained detectable for 24 and 48 h, respectively, following nebulization of a single dose. Baseline spirometry, lung resistance and dynamic compliance, remained normal following lidocaine nebulization, with resistance decreasing post-nebulization. Compared to the pre-nebulization group, two additional horses were hyperresponsive following lidocaine nebulization. There was a significant increase in mean airway responsiveness post-lidocaine nebulization, based on lung resistance, but not dynamic compliance. One horse had BAL cytology consistent with airway inflammation both before and after lidocaine treatment. Conclusions: Nebulized lidocaine was not associated with adverse effects on upper airway sensitivity or BAL cytology. While baseline lung resistance was unchanged, increased airway reactivity to histamine bronchoprovocation in the absence of clinical signs was seen in some horses following nebulization. Further research is necessary to evaluate drug delivery, adverse events, and efficacy in asthmatic horses.

Time-restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high-fat diet.

KEY POINTS: Time-restricted feeding (TRF, in which energy intake is restricted to 8 h/day during the dark phase) alone or combined with aerobic exercise (AE) training can prevent weight gain and metabolic disorders in Swiss mice fed a high-fat diet. The benefits of TRF combined with AE are associated with improved hepatic metabolism and decreased hepatic lipid accumulation. TRF combined with AE training increased fatty acid oxidation and decreased expression of lipogenic and gluconeogenic genes in the liver of young male Swiss mice. TRF combined with AE training attenuated the detrimental effects of high-fat diet feeding on the insulin signalling pathway in the liver. ABSTRACT: Time-restricted feeding (TRF) or physical exercise have been shown to be efficient in the prevention and treatment of metabolic disorders; however, the additive effects of TRF combined with aerobic exercise (AE) training on liver metabolism have not been widely explored. In this study TRF (8 h in the active phase) and TRF combined with AE (TRF+Exe) were compared in male Swiss mice fed a high-fat diet, with evaluation of the effects on insulin sensitivity and expression of hepatic genes involved in fatty acid oxidation, lipogenesis and gluconeogenesis. As in previous reports, we show that TRF alone (eating only between zeitgeber time 16 and 0) was sufficient to reduce weight and adiposity gain, increase fatty acid oxidation and decrease lipogenesis genes in the liver. In addition, we show that mice of the TRF+Exe group showed additional adaptations such as increased oxygen consumption ( V̇O2${\dot V_{{{\rm{O}}_{\rm{2}}}}}$ ), carbon dioxide production ( V̇CO2${\dot V_{{\rm{C}}{{\rm{O}}_{\rm{2}}}}}$ ) and production of ketone bodies (ß-hydroxybutyrate). Also, TRF+Exe attenuated the negative effects of high-fat diet feeding on the insulin signalling pathway (insulin receptor, insulin receptor substrate, Akt), and led to increased fatty acid oxidation (Ppara, Cpt1a) and decreased gluconeogenic (Fbp1, Pck1, Pgc1a) and lipogenic (Srebp1c, Cd36) gene expression in the liver. These molecular results were accompanied by increased glucose metabolism, lower serum triglycerides and reduced hepatic lipid content in the TRF+Exe group. The data presented in this study show that TRF alone has benefits but TRF+Exe has additive benefits and can mitigate the harmful effects of consuming a high-fat diet on body adiposity, liver metabolism and glycaemic homeostasis in young male Swiss mice.

Thromboembolism, Bleeding, and Mortality Incidence of Direct Oral Anticoagulants Versus Warfarin Postbariatric Surgery.

BACKGROUND: There is no randomized controlled trial comparing direct oral anticoagulants (DOACs) and warfarin following bariatric surgery to date. The mortality, thromboembolism, and bleeding risk of DOACs in comparison with warfarin following bariatric surgery remains unclear. We aimed to provide a clinical comparison between DOACs and warfarin for these 3 prespecified outcomes. METHODS: A systematic literature search was performed on November 10, 2019, using PubMed, Embase, clinicaltrial.gov, and Cochrane databases. Studies with adult patients who were on either warfarin or DOACs following bariatric surgery and reported the incidence of thromboembolism, bleeding, or mortality were included. Pooled incidence for these prespecified outcomes and its 95% confidence interval (CI) were calculated for each drug separately using the random-effects model, along with a nonadjusted P value comparing the 2 subgroups. RESULTS: A total of 11 studies (805 patients) were included. Comparing DOACs to warfarin, the following pooled incidences were observed for mortality (DOACs: 3.0%; 95% CI 0.4%-18.6% versus warfarin: 1.5%; 95% CI 0.8%-2.9%; P value comparing the 2 subgroups = .38), thromboembolism (DOACs: 4.9%; 95% CI 1%-21.1% versus warfarin: 1.5%; 95% CI 0.8%-2.9%; P value = .18), and bleeding (DOACs: 3.9%; 95% CI 0.7%-18.2% versus warfarin: 11.3%; 95% CI 5.7%-21.4%; P value = .23). CONCLUSION: The results of our meta-analysis remain hypothesis-generating, providing rationale for future randomized controlled trial design or well-designed comparative observational studies. Currently, it does not support the change in the current recommendation from warfarin to DOACs following bariatric surgery.

Minimally invasive versus open surgery for the correction of adult degenerative scoliosis: a systematic review.

While open surgery has been the primary surgical approach for adult degenerative scoliosis, minimally invasive surgery (MIS) represents an alternative option and appears to be associated with reduced morbidity. Given the lack of consensus, we aimed to conduct a systematic review on available literature comparing MIS versus open surgery for adult degenerative scoliosis. PubMed, Embase, and Cochrane databases were searched through December 16, 2019, for studies that compared both MIS and open surgery in patients with degenerative scoliosis. Four cohort studies reporting on 350 patients met the inclusion criteria. In two studies, patients undergoing open surgery were younger and had more severe disease at baseline as compared with MIS. Patients who underwent MIS had less blood loss, shorter length of stay, and a reduced rate of complications and infections. Both MIS and open surgery resulted in a significant change in pain and disability scores and both approaches provided significant correction of deformity in all studies, although open surgery was associated with a greater change in pelvic incidence-lumbar lordosis mismatch (PI-LL) and sagittal vertical axis (SVA) in two and three studies, respectively. In patients with adult degenerative scoliosis undergoing surgery, both MIS and open approaches appeared to offer comparable improvements in pain and function. However, MIS was associated with better safety outcomes, while open surgery provided greater correction of spinal deformity. Further studies are needed to identify specific subset of patients who may benefit from one approach versus the other.

Aging is associated with increased TRB3, ER stress, and hepatic glucose production in the liver of rats.

TRB3, a mammalian homolog of Drosophila tribbles, plays an important role in multiple tissues and it has been implicated in stress response regulation and metabolic control. However, the role of hepatic TRB3 and its relationship with endoplasmic reticulum stress (ER stress) during aging has not been elucidated. Thus, the present study aimed to explore the association of aging with TRB3 and ER stress on the hepatic glucose production in Wistar rats. We found the TRB3 protein content to be higher in livers of old rats (27 months) compared to young (3 months) and middle-aged (17 months) rats. The increased content of hepatic TRB3 of the old rats was associated with insulin resistance (decreased protein kinase B (Akt) and Forkhead Box O1 (FoxO1) phosphorylation) and increased enzymes of gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6-phosphatase (G6Pase)). Moreover, aging was associated with activation of the endoplasmic reticulum stress pathway-related molecules, with an increase in phosphorylation of Inositol-requiring enzyme 1 (p-IRE1α), the protein kinase RNA-like endoplasmic reticulum kinase (p-PERK), eukaryotic translation initiation factor-α (p-eIF2α), binding immunoglobulin protein (BiP), and the C/EBP homologous protein (CHOP) contents in rats. These molecular changes resulted in increased liver glucose production in response to the pyruvate challenge and hyperglycemia of the old rats. In conclusion, our results suggested that, by interfering with insulin signaling in the liver, TRB3 was associated with ER stress and increased hepatic glucose production in aging rats.

Pharmacovigilance in developing countries (part II): a path forward.

In recent years, attention to pharmacovigilance has gained momentum in developing countries, however awareness of, and policies or systems for pharmacovigilance in most developing countries still lags sharply behind developed countries. This article proposes different strategies to encourage the introduction and sustain the advancement of robust pharmacovigilance systems in developing countries. To this end, this article seeks to accomplish the ultimate goal of pharmacovigilance in a developing country context; ensuring patient safety and promoting safe and rational use of drugs.

Headache Resolution After Rathke Cleft Cyst Resection: A Meta-Analysis.

OBJECTIVE: Rathke cleft cysts (RCC) are benign lesions of the sella that often present with headache. It is not currently well established whether surgical resection of RCC results in resolution of headache. We conducted a meta-analysis to examine the effect of RCC resection on headache resolution. METHODS: PubMed, EMBASE, and Cochrane databases were searched through June 2017 for articles that evaluated the effect of RCC resection on headache resolution. Pooled effect estimates were calculated using fixed-effects and random-effects models. RESULTS: Ten case series with 276 patients were included. Transsphenoidal surgery (TSS) was used to resect RCC in all of the studies. Only 1 patient in 1 study underwent transcranial surgery. Using the fixed effect model, the overall headache resolution prevalence was 71.7% (95% confidence interval [CI] 65.3%, 77.3%) among patients who underwent resection of RCC (I2 = 76.9%; P-heterogeneity < 0.01). Subgroup analysis based on center (P-interaction < 0.01) and continent (P < 0.01) showed a higher resolution in studies conducted in a single center (79.8%; 95% CI 73.7%, 84.8%) than in multiple centers (40.0%; 95% CI 26.9%, 54.8%) and a higher resolution in studies conducted in Asia (85.0%) than in Europe (61.5%) or North America (65.7%). Metaregression analysis was significant on mean follow-up time (slope = 0.03; P = 0.02), percentage of women (slope -0.05; P < 0.01), journal impact factor (slope 0.73; P < 0.01), and study quality (slope -0.99; P < 0.01) but not on mean age (P = 0.10). None of the above-mentioned results were significant when the random effects model was used. No evidence of publication bias was observed. CONCLUSION: This meta-analysis demonstrates that the resection of RCC in patients presenting with headache is associated with headache resolution.

Pharmacovigilance in developing countries (part I): importance and challenges.

The thalidomide disaster was the significant historical event that acted as a catalyst for pharmacovigilance activity. Following this event developed countries initiated drug monitoring systems that evolved and now extend their scope to broader drug-related safety issues; however, this was not the case in developing countries. Pharmacovigilance is still a relatively new concept with low priority in developing countries although various issues are raising concerns that magnify the need for systems to monitor post marketing drug safety in these countries. This article analyzes the barriers to introducing robust pharmacovigilance systems in developing countries.

Assessment of the standard pediatric unfractionated heparin dosing protocol.

Current dosing guidelines for unfractionated heparin therapy in pediatric patients are based on recommendations of only one study that evaluated a weight-based dosing nomogram. To test the hypothesis that adhering to a strict weight-based nomogram yields better therapeutic results in pediatric patients, we prospectively monitored 25 consecutive pediatric patients who received unfractionated heparin based on the nomogram, and compared them to control patients whose treatment did not follow the standard nomogram. The mean time needed to achieve the target activated partial thromboplastin time was significantly shorter in the study group than the control group (18.32 ± 9.98 vs. 43.8 ± 30 h). A higher proportion of the study group reached the target activated partial thromboplastin time at 12, 24, and 36 h, compared to controls: 44% vs. 6%, 72% vs. 28%, 100% vs. 58%, respectively. Within the study group, patients under 1 year of age needed more time to achieve the target activated partial thromboplastin time than those over 1-year old. The performance of the standard dosing nomogram was excellent with regard to early anticoagulation target achievement, without increasing the risk of bleeding. Further studies are warranted to refine this nomogram for pediatric patients who are less than 1-year old.

Clinical efficacy and pharmacokinetics of antimony in cutaneous leishmaniasis patients treated with sodium stibogluconate.

The efficacy and pharmacokinetics of antimony were explored in 12 young male patients with cutaneous leishmaniasis following intramuscular administration of sodium stibogluconate equivalent to 600 mg of antimony (Sb). Patients' cure rate was evaluated up to 6 weeks after treatment. Blood samples were collected at different time periods on the first and last days of a 3-week treatment. Twenty-four-hour urine samples were also collected on both occasions for the estimation of renal clearance (CL(r)). The blood concentrations of the Sb time profile were best described by a 2-compartment model with a first-order absorption rate. The mean absorption half-life was 0.21 ± 0.023 and 0.36 ± 0.18 hours for the first and last doses, respectively. A rapid distribution phase was followed by a slower elimination phase of a half-life of 9.4 ± 1.9 and 9.69 ± 2.3 hours for both days, respectively. An accumulation index of 2.33 was calculated. The fraction of dose excreted in urine was 0.386 ± 0.11 and 0.326 ± 0.05 on both occasions, respectively. The mean CL(r) was 4.88 ± 1.13 and 4.58 ± 1.05 L/h. In the current study, all of the patients were completely healed by week 6 after the end of treatment, as judged by the treating physician. In conclusion, the blood profile of antimony seems to be multicompartmental in nature.

Pharmacokinetics of vancomycin in adult cancer patients.

BACKGROUND AND OBJECTIVES: gram-positive infections are prevalent among cancer patients and vancomycin therapy is often initiated empirically. A typical vancomycin pharmacokinetics is observed in such patients. The aim of the study was to evaluate the pharmacokinetics of vancomycin in this patient population and compare it to that of normal population. METHOD AND RESULTS: the pharmacokinetics of vancomycin was examined retrospectively in two groups of patients - 18 cancer patients (age 43.4 ± 22.1 years) and 13 patients without cancer (age 48.5 ± 20.2 years). Following the administration of intermittent intravenous infusion of 15 mg/kg of vancomycin, peak and trough vancomycin serum concentration were determined after the third dose or at steady state as per standard of care. Vancomycin data were analyzed according to a one-compartment open model. Pharmacokinetic parameters such as clearance (CL), volume of distribution (Vd), and K elimination (ke) were calculated. Both Vd and CL were significantly higher in the cancer group (Mean Vd was 70 ± 45 L in the cancer group and 31.1 ± 8.3 L in the noncancer group, p-value 0.002; CL mean was 110.1 ± 42 mL/min in the cancer group and 71.2 ± 22.2 mL/min in the noncancer group, p-value 0.005). There was no significant difference in K elimination and half-life (t(1/2)). CONCLUSION: cancer patients may require higher than usual dosing regimens to ensure optimal therapeutic concentrations, since vancomycin CL and Vd is significantly higher in these patients, a dosing schedule as high as 60 mg/kg/day may be needed for cancer patients.

The effect of chronic cadmium exposure on the pharmacokinetics of theophylline and ciprofloxacin in rats.

Cadmium has been associated with a number of adverse health effects but the impact of those effects on the pharmacokinetics of different drugs has not been investigated. Therefore, the pharmacokinetics of theophylline and ciprofloxacin were studied in cadmium-exposed and control rats (72 rats) following i.p. (6.5mg/kg) and p.o. (10mg/kg) administration, respectively. The third-generation offsprings of rats exposed to 100 microg/mL of cadmium chloride in drinking water were used in this study. Following 8 weeks of exposure, animals received the drugs as a single dose. Blood samples were withdrawn at different time-points and the plasma concentrations of both drugs were analyzed by HPLC. The pharmacokinetic parameters of theophylline and ciprofloxacin were altered significantly in the cadmium-exposed animals. For theophylline, a statistically significant increase (p<0.0001) in C(max) (69%) and AUC(0-)(infinity) (68%) of theophylline in the cadmium-exposed rats as compared to the control were observed. A corresponding significant (p<0.0001) reduction of 41% in clearance (CL/F) of theophylline was detected in the exposed group. Neither the half-life nor the mean residence time (MRT) showed any significant change due to the exposure to cadmium. For ciprofloxacin, no significant difference was seen in the C(max) of the exposed group as compared to the control animals. However, a delay in T(max) was observed in the exposed group (from 0.16(+/-0.003) to 0.37(+/-0.14)h). A small, but significant increase in t(1/2) (p<0.05) was detected (1.74(+/-0.25) vs. 1.45(+/-0.12)h). A significant reduction (p<0.05) of CL/F from 30.54(+/-1.9) to 24.01(+/-3.81)mL/min/kg was seen in the treated group. The current investigation showed that chronic exposure to cadmium could have a very significant impact on altering the pharmacokinetic parameters of various drugs. Therefore, in cadmium-polluted areas, dose adjustments and drug monitoring, especially for drugs with a narrow therapeutic window, should be carried out.

Effects of fluconazole on the pharmacokinetics and pharmacodynamics of antimony in cutaneous leishmaniasis-infected hamsters.

Pentavalent antimony (Sb(V)) compounds are the drugs of choice for the treatment of all forms of leishmaniasis. For 20 years there has been an interest in antifungal azoles for treating leishmaniasis, with variable success. In the current study, we examined the effects of co-administration of fluconazole (FLZ) on the pharmacokinetics and pharmacodynamics of Sb(V) in cutaneous leishmaniasis-infected hamsters. Hamsters were divided into four groups. All hamsters were injected with 0.1 mL of 1x10(8)promastigotes/mL into the right foot on Day 1. Treatment was started 5 days after the infection. The antimony group received 80 mg/kg/day of Pentostam intramuscularly whilst the FLZ group received FLZ 20 mg/kg/day orally for 14 days. The combination group received both Pentostam and FLZ at the above mentioned doses for 14 days. Animals in the control group received no treatment. The infected footpads were measured on Days 1 and 14. A pharmacokinetic study was conducted on Days 1 and 14 of treatment, representing single- and multiple-dose pharmacokinetics, respectively. Blood samples were collected at different time intervals up to 24h. Sb(V) was determined using flameless atomic absorption spectrophotometry. Pharmacokinetic parameters were calculated using a non-compartmental analysis. In the single-dose study, there was no statistically significant difference in any of the pharmacokinetic parameters of Sb(V) when given alone or with FLZ. However, on Day 14 a significant increase in peak plasma concentration (C(max)) (three-fold) and area under the concentration-time curve (AUC) (four-fold) of antimony was observed when Sb(V) was co-administered with FLZ. A statistically significant prolongation of the terminal half-life from 1.63 to 8.67 h (P<0.05) was also observed. A significant reduction in clearance was detected. However, FLZ had no effect on the pharmacodynamics of Sb(V) as measured by footpad sizes. In conclusion, FLZ did not improve the therapeutic effect of Sb(V) when given concomitantly despite the significant increase in blood concentration and prolongation of the elimination half-life of Sb(V).