Relationship between pain catastrophizing and pain self-efficacy and presenteeism in workers: a cross-sectional-study focusing on gender differences.

Presenteeism has been noted to be associated with cognitive factors of pain, such as pain catastrophizing (PC) and pain self-efficacy (PS). Pain perception differs by gender, so it is important to consider gender differences when examining the association between cognitive factors of pain and presenteeism. This study aimed to examine the association between presenteeism and cognitive factors of pain, taking gender differences into account. A cross-sectional survey of 305 workers was conducted using a self-administered questionnaire that included items on pain status, PC, PS, and work performance. Multiple logistic regression analysis was used to test whether PC and PS independently influence presenteeism, separately for men and women. Logistic regression analysis showed that PC was extracted in men, and the group with severe PC had higher odds of presenteeism (odds ratio 6.56, 95%confidence interval [CI] 1.83-23.40). Contrarily, PS was extracted in women, with higher odds of presenteeism in the moderate (odds ratio 2.54, 95%CI 1.01-6.39) and low (odds ratio 5.43, 95%CI 1.31-22.50) PS groups than in the high PS. This study showed that the cognitive factors of pain related to presenteeism may differ by gender.

Performance evaluation of a newly designed on-farm blood testing system for determining blood non-esterified fatty acid and ß-hydroxybutyrate concentrations in dairy cows.

The objective of this study was to evaluate a newly designed on-farm blood testing system (OFBTS) for monitoring blood concentrations of non-esterified fatty acids (NEFA) and ß-hydroxybutyrate (BHBA) in dairy cows. Blood samples from 230 Holstein dairy cows between -86 and 343 days in milk were collected. A drop of whole blood was used to determine NEFA and BHBA using the OFBTS. Plasma from the remaining blood was used to determine both analytes using a commercial kit (gold standard). In the repeatability of the OFBTS, the intra-assay CV for NEFA and BHBA were 1.3% and 4.5%, and the inter-assay CV were 1.8% and 2.9%, respectively. The slope and coefficient of determination of OFBTS analysis of NEFA compared to the gold standard were 0.92 and 0.94. Those for BHBA were 0.94 and 0.98. Mean of the difference between the gold standard laboratory assays and OFBTS of NEFA and BHBA were 0.021 and 0.019, respectively. However, the bias became substantial for NEFA in the higher concentration ranges (>1.2 mEq/L). The sensitivity and specificity of NEFA were 93.2% and 99.4% at a cutpoint of 0.4 mEq/L, and 87.9% and 100% at 0.6 mEq/L. Those of BHBA were 86.2% and 99.0% at a cutpoint of 1.0 mM, and 94.7% and 99.5% at 1.2 mM. The reaction time for the NEFA to reach 0.6 mEq/L was 7 min. The BHBA reaction reached 1.2 mM within 2 min. In conclusion, the OFBTS has excellent performance for evaluating blood NEFA or BHBA concentrations.

Static Model-Based Assessment of OATP1B1-Mediated Drug Interactions with Preincubation-Dependent Inhibitors Based on Inactivation and Recovery Kinetics.

Quantitative assessment of drug-drug interactions (DDIs) via organic anion transporting polypeptide (OATP) 1B1 is one of the key issues in drug development. Although OATP1B1 inhibition exhibits unique characteristics, including preincubation dependence for some inhibitors, a limited approach has been attempted based on the static model that considers such preincubation dependence in the prediction of DDIs via OATP1B1. The present study aimed to establish the prediction of DDIs via OATP1B1 using preincubation-dependent inhibitors based on the static model and incorporating both inactivation and recovery of OATP1B1 activity. Cyclosporine A was selected as a preincubation-dependent inhibitor, as well as five substrates that include probes and pharmaceuticals. The inhibition ratio (R value) calculated on the basis of a conventional static model, considering inhibition of OATP1B1 and contribution ratio of OATP1B1 to the overall hepatic uptake, was much lower than the reported AUC ratio, even when IC50 values were estimated after preincubation conditions. Conversely, the R value that was estimated by considering inactivation and recovery parameters was closer to the AUC ratio. The R value that was calculated assuming the complete contribution of OATP1B1 was much higher than the AUC ratio, avoiding false-negative prediction. The R value estimated by considering inactivation and recovery for another combination of a preincubation-dependent inhibitor, asunaprevir, and substrate drug, rosuvastatin, was also closer to the AUC ratio. Thus, R values calculated based on such OATP1B1 kinetics would be potential alternative indexes for the quantitative prediction of OATP1B1-mediated DDIs using preincubation-dependent inhibitors, although this prediction is affected by estimation of the contribution ratio of substrates. SIGNIFICANCE STATEMENT: Static model-based quantitative prediction of organic anion transporting polypeptide 1B1-mediated drug-drug interactions induced by preincubation-dependent inhibitors was newly proposed to avoid false-negative prediction.

Short-lasting inhibition of hepatic uptake transporter OATP1B1 by tyrosine kinase inhibitor pazopanib.

Risk assessment of organic anion transporting polypeptide 1B1 (OATP1B1)-mediated drug-drug interactions (DDIs) is an integral part of drug development, but the difficult aspects in DDI prediction include complex mechanism of OATP1B1 inhibition. Pazopanib, an orally available tyrosine kinase inhibitor, exhibits OATP1B1 inhibition and clinically interacts with some OATP1B1 substrates, although quantitative analysis of DDI potential has not yet been performed. The purpose of the present study was to characterize the inhibitory effect of pazopanib on OATP1B1-mediated transport. Inhibition by pazopanib of OATP1B1-mediated uptake of two typical substrates, [3H]estrone-3-sulfate (E1S) and [3H]estradiol-17ß-glucuronide, assessed in HEK293/OATP1B1 cells, was more obvious after preincubation with pazopanib compared with no preincubation. The reduction in IC50 values was 3-7 times greater and was comparable with the preincubation effect of another long-lasting inhibitor, cyclosporine A (CsA). Preincubation with pazopanib and CsA tended to similarly reduce Vmax and increase Km values of E1S. However, the reduced OATP1B1 activity by preincubation with pazopanib was more rapidly recovered than CsA. In addition, R value, which predicts the maximum increase in the AUC ratio of victim drugs, was calculated to be 1.09. These results suggest that pazopanib is preincubation-dependent but a short-lasting inhibitor against OATP1B1 with low potential of OATP1B1-mediated DDIs.

Characterization of Long-Lasting Oatp Inhibition by Typical Inhibitor Cyclosporine A and In Vitro-In Vivo Discrepancy in Its Drug Interaction Potential in Rats.

Quantitative assessment of potential drug-drug interactions (DDIs) is one of the major focuses in drug development. The aim of the present study was to quantitatively evaluate in vitro-in vivo discrepancy of DDI potential for prototypical organic anion transporting polypeptide (Oatp) inhibitor cyclosporine A (CsA) using rats. Plasma concentration of pravastatin, prototypical Oatp substrate, after oral administration was increased by CsA intravenously administered at 1 d before the pravastatin administration. The ratio of the area under the curve of pravastatin to the control was much higher than the R-values calculated using the plasma unbound concentrations of CsA and the inhibition constant (Ki) assessed in isolated hepatocytes, indicating in vitro-in vivo discrepancy. This interaction with pravastatin persisted for 3 d after CsA administration, demonstrating long-lasting inhibition in vivo. The Ki value for unbound CsA in the presence of serum was comparable with that in its absence. M1, the major metabolite of CsA inhibited pravastatin uptake at much higher concentration compared with its plasma unbound concentration. Thus, the DDI potential of CsA-mediated hepatic Oatp inhibition cannot be extrapolated from in vitro data, and this could be due to the long-lasting Oatp inhibition by CsA, but not the effect of plasma protein or metabolites.

Quantitative assessment of intestinal first-pass metabolism of oral drugs using portal-vein cannulated rats.

PURPOSE: To evaluate the impact of intestinal first-pass metabolism (Fg) by cytochrome P4503A (CYP3A) and uridine 5'-diphosphate-glucuronosyltransferases (UGT) on in vivo oral absorption of their substrate drugs. METHODS: CYP3A and UGT substrates were orally administered to portal-vein cannulated (PV) rats to evaluate their intestinal availability (Fa · Fg). In the case of CYP3A substrates, vehicle or 1-aminobenzotriazole (ABT), a potent inhibitor of CYP enzymes, was pretreated to assess Fg separately from Fa (Enzyme-inhibition method). On the other hand, since potent inhibitors of UGT have not been identified, Fg of UGT substrate was calculated from total amount of metabolites generated in enterocytes (Metabolite-distribution method). RESULTS: After oral administration of CYP3A substrates in ABT-pretreated rats, the portal and systemic plasma concentrations of the metabolite were nearly the same, indicating almost complete inhibition of intestinal CYP3A-mediated metabolism. Using Enzyme-inhibition method, Fg of midazolam (1 mg/kg) was calculated as 0.71. Additionally, total amount of raloxifene-6-glucuronide generated in enterocytes after oral administration of raloxifene was estimated using Metabolite-distribution method and Fg of raloxifene (0.98 µmol/kg) was calculated as 0.21. CONCLUSIONS: PV rats enabled in vivo quantitative assessment of intestinal first-pass metabolism by CYP3A and UGT. This method is useful for clarifying the cause of low bioavailability.

In vivo assessment of the impact of efflux transporter on oral drug absorption using portal vein-cannulated rats.

The purpose of this study was to evaluate the impact of intestinal efflux transporters on the in vivo oral absorption process. Three model drugs-fexofenadine (FEX), sulfasalazine (SASP), and topotecan (TPT)-were selected as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and P-gp and BCRP substrates, respectively. The drugs were orally administered to portal vein-cannulated rats after pretreatment with zosuquidar (ZSQ), P-gp inhibitor, and/or Ko143, BCRP inhibitor. Intestinal availability (Fa·Fg) of the drugs was calculated from the difference between portal and systemic plasma concentrations. When rats were orally pretreated with ZSQ, Fa·Fg of FEX increased 4-fold and systemic clearance decreased to 75% of the control. In contrast, intravenous pretreatment with ZSQ did not affect Fa·Fg of FEX, although systemic clearance decreased significantly. These data clearly show that the method presented herein using portal vein-cannulated rats can evaluate the effects of intestinal transporters on Fa·Fg of drugs independently of variable systemic clearance. In addition, it was revealed that 71% of FEX taken up into enterocytes underwent selective efflux via P-gp to the apical surface, while 79% of SASP was effluxed by Bcrp. In the case of TPT, both transporters were involved in its oral absorption. Quantitative analysis indicated a 3.5-fold higher contribution from Bcrp than P-gp. In conclusion, the use of portal vein-cannulated rats enabled the assessment of the impact of efflux transporters on intestinal absorption of model drugs. This experimental system is useful for clarifying the cause of low bioavailability of various drugs.

Functional expression of carnitine/organic cation transporter OCTN1 in mouse brain neurons: possible involvement in neuronal differentiation.

The aim of the present study is to clarify the functional expression and physiological role in brain neurons of carnitine/organic cation transporter OCTN1/SLC22A4, which accepts the naturally occurring antioxidant ergothioneine (ERGO) as a substrate in vivo. After intracerebroventricular administration, the distribution of [(3)H]ERGO in several brain regions of octn1(-/-) mice was much lower than that in wild-type mice, whereas extracellular marker [(14)C]mannitol exhibited similar distribution in the two strains. The [(3)H]ERGO distribution in wild-type mice was well correlated with the amount of ERGO derived from food intake and the OCTN1 mRNA level in each brain region. Immunohistochemical analysis revealed colocalization of OCTN1 with neuronal cell markers microtubule-associated protein 2 (MAP2) and ßIII-tubulin in mouse brain and primary cultured cortical neurons, respectively. Moreover, cultured cortical neurons exhibited time-dependent and saturable uptake of [(3)H]ERGO. These results demonstrate that OCTN1 is functionally expressed in brain neurons. The addition of ERGO simultaneously with serum to culture medium of cortical neurons attenuated mRNA and protein expressions of MAP2, ßIII-tubulin and synapse formation marker synapsin I, and induced those of sex determining region Y-box 2 (Sox2), which is required to maintain the properties of undifferentiated neural stem cells. In neuronal model Neuro2a cells, knockdown of OCTN1 by siRNA reduced the uptake of [(3)H]ERGO with concomitant up-regulation of oxidative stress marker HO-1 and Sox2, and down-regulation of neurite outgrowth marker GAP43. Interestingly, the siRNA knockdown decreased the number of differentiated Neuro2a cells showing long neurites, but increased the total number of cells. Thus, OCTN1 is involved in cellular differentiation, but inhibits their proliferation, possibly via the regulation of cellular oxidative stress. This is the first evidence that OCTN1 plays a role in neuronal differentiation and proliferation, which are required for brain development.

Relationship between the oxygen uptake during cardiopulmonary exercise testing and left ventricular function in patients with acute myocardial infarction.

The relationship between exercise capacity and left ventricular function has been evaluated in 35 patients with acute myocardial infarction (34 males and 1 female; mean age 55.5 ± 7.1 years). Single photon emission computed tomography (SPECT) was used to measure left ventricular function in the acute phase (4.9 ± 2.2 days after onset) and the chronic phase (188.5 ± 22.9 days after onset). More than 10% left ventricular dilatation from the acute phase to the chronic phase was defined as remodeling (RM) and the subjects were divided into 2 groups: RM and non-RM. Cardiopulmonary exercise testing was performed at 1 month (1M), 3 months (3M) and 6 months (6M) after onset. In the RM group, anaerobic threshold (AT) and peak oxygen uptake (Peak ) did not change significantly. In the non-RM group, AT was 15 ± 1 (ml/min/Kg) at 1M, 16 ± 2 at 3M and 18 ± 4 at 6M. Peak was 26 ± 3 (ml/min/Kg) at 1M, 30 ± 2 at 3M and 32 ± 3 at 6M. Both parameters in the chronic phase increased significantly compared with those at 1M (p<0.002 and p<0.0001). Thus, change in exercise capacity would correlate with change in left ventricular function.