Prediction of osteoporosis and osteopenia by routine computed tomography of the lumbar spine in different regions of interest.

BACKGROUND: We aimed to investigate the utility of Hounsfield units (HU) obtained from different regions of interest in opportunistic lumbar computed tomography (CT) to predict osteoporosis coupling with data of dual-energy X-ray absorptiometry (DXA). METHODS: A total of 100 patients who attended a university hospital in Shanghai, China, and had undergone CT and DXA tests of the lumbar spine within 3 months were included in this retrospective review. Images were reviewed on axial sections, and regions of interest (ROI) markers were placed on the round, oval, anterior, left, and right of the L1-L4 vertebra to measure the HU. The mean values of CT HU were then compared to the bone mineral density (BMD) measured by DXA. Receiver operator characteristic curves were generated to determine the threshold for diagnosis and its sensitivity and specificity values. RESULTS: The differences in CT HU of different ROI based on DXA definitions of osteoporosis, osteopenia, and normal individuals were statistically significant (p < 0.01). The HU values of the different ROI correlated well with the BMD values (Spearman coefficient all > 0.75, p < 0.01). The threshold for diagnosing osteoporosis varies from 87 to 111 HU in different ROIs, and the threshold for excluding osteoporosis or osteopenia is 99-125 HU. CONCLUSION: This is the first study on osteoporosis diagnosis of different ROI with routine CT lumbar scans. There is a strong correlation between CT HU of different ROI in the lumbar spine and BMD, and HU measurements can be used to predict osteoporosis.

Safety, tolerability, and pharmacokinetics/pharmacodynamics of JMT103 in patients with bone metastases from solid tumors.

Bone metastases are common complications of solid tumors. The outcome is poor despite major progress in cancer therapies. We describe a multicenter, open-label, phase 1, dose escalation and expansion trial of JMT103, a novel fully humanized receptor activator of nuclear factor kappa-B ligand (RANKL)-targeting monoclonal antibody, in adults with bone metastases from solid tumors. The study assessed the safety, tolerability, and pharmacokinetics/pharmacodynamics of JMT103. Patients received JMT103 at doses of 0.5, 1.0, 2.0, and 3.0 mg/kg every 4 weeks for 3 cycles. Among 59 patients enrolled, 20 and 39 patients participated in the dose-escalation and dose-expansion phases, respectively. One dose-limiting toxicity was observed at 2.0 mg/kg. The maximum tolerated dose was not determined. Treatment-related adverse events were reported in 29 (49.2%) patients, most commonly hypophosphatemia (30.5%), hypocalcemia (23.7%), and hypermagnesemia (10.2%). No treatment-related serious adverse events were reported. Two patients died due to disease progression, which were attributed to gastric cancer and lung neoplasm malignant respectively. Dose proportionality occurred between exposure levels and administered dose was within a dose range of 0.5 to 3.0 mg/kg. The suppression of urinary N-telopeptide corrected for creatinine was rapid, significant, and sustained across all doses of JMT103, with the median change from baseline ranging from -61.4% to -92.2% at day 141. JMT103 was well tolerated in patients with bone metastases from solid tumors, with a manageable safety profile. Bone antiresorptive activity shows the potential of JMT103 for treatment of bone metastases from solid tumors. Registration No.: NCT03550508; URL: https://www.clinicaltrials.gov/.

Reduced antioxidant and anti-inflammatory effects of propofol at high-dose on morbidly obese patients.

This study was aimed to investigate differences in antioxidant and anti-inflammatory effects of propofol at two commonly used dosing schedules on morbidly obese patients. Twenty-two morbidly obese patients were randomly divided into two groups, namely, TBW (dosing based on total body weight) and LBW (dosing based on lean body weight) groups. Three biomarkers, i.e. superoxide dismutase (SOD), malondialdehyde (MDA) and nitric oxide (NO) were measured as indicators of the level of oxidation stress reaction. Pro-inflammatory cytokines including Interleukin-6 (IL-6) and Interleukin-8 (IL-8) were used to describe the degree of inflammation. Plasma levels of SOD, MDA and NO were increased and reached a peak value 0.5h after anesthesia induction, but the increase was smaller in the LBW group compared with the TBW group. Besides, plasma concentrations of IL-6 and IL-8 were also increased and attained a peak level 0.5h after anesthesia induction, but the increase was higher in the TBW group compared with the LBW group. The LBW-based dosing of propofol had more potent antioxidant and anti-inflammatory effects than the TBW-based dosing during anesthesia induction period on morbidly obese patients. This study provided a dosing recommendation of propofol for morbidly obese patients.

Impact of epidural analgesia during labor on breastfeeding initiation and continuation: a retrospective study.

Objective: Although epidural analgesia is widely used during labor, its impact on breastfeeding has not yet reached a consensus. This retrospective cohort study was to investigate the association of patient-controlled epidural analgesia (PCEA) during labor with breastfeeding initiation and continuation.Methods: Medical records from 1 February, 2016 to 31 December, 2016 at Guangzhou Women and Children's Medical Center, China were reviewed for women received PCEA or not. Breastfeeding continuation was assessed by a questionnaire at 6 months after hospital discharge.Results: Nine hundred twenty-two women were enrolled in the study, with 527 of these women received PCEA for labor analgesia. The proportion of timely initiation of breastfeeding (within 1 h after birth), and exclusive or partial breastfeeding at any of the evaluation time points (1, 3, and 6 months) between two groups showed no statistically significant difference.Conclusion: Our data do not support an association between the PCEA and discontinuation of breastfeeding within 6 months postpartum.

The impact of proton pump inhibitors on the pharmacokinetics of voriconazole in vitro and in vivo.

Voriconazole (VRC) and proton pump inhibitors (PPIs) have similar metabolic pathways. The objectives of the study are to evaluate the impact of PPIs on the pharmacokinetics of VRC. Human liver microsomes model was applied to assess the inhibitory effects of PPIs on the metabolism of VRC in vitro. A retrospective study was also carried out to explore the relationship between the plasma VRC trough concentrations and PPIs uses. Patients were divided into six groups: control (n = 166), lansoprazole (LAN, n = 38), esomeprazole (ESO, n = 19), omeprazole (OME, n = 45), pantoprazole (PAN, n = 43), and ilaprazole (ILA, n = 38) groups. All five PPIs showed concentration-dependent inhibitory effects on the VRC metabolism in human liver microsomes, among which LAN, OME and ESO were three of the most potent inhibitors. Consistently, co-administered with LAN, OME and ESO significantly increased the plasma VRC trough levels (p < 0.05), whereas there was no significant association between VRC concentrations and PAN or ILA use. Interestingly, patients in the PPIs groups were more likely to reach the therapeutic VRC range of 1-5.5 µg/mL in steady state when compared with control patients (75-81% VS 69%). In conclusion, although all PPIs showed inhibitory effects on the VRC metabolism in vitro, only LAN, OME and ESO significantly increased VRC plasma concentrations. This study should be helpful for choice of the type of PPIs for patients administered with VRC.

Characterization of cardiovascular depression effect for propofol during anesthesia induction period on morbidly obese patients.

This study aims to determine the pharmacodynamics (PD) effect (measured by cardiovascular depression) of propofol during anesthesia induction period on morbidly obese (MO) patients. Four hemodynamics indexes [i.e., three indexes about blood pressure and cardiac output (CO)] representing cardiovascular function were measured. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was performed by population analysis to obtain PD parameters. Two propofol dosing scalars, namely, dosing based on total body weight (TBW) or lean body weight (LBW), were used for MO subjects. The PD data were well described by a PK/PD model. Blood pressure and CO were rapidly decreased within one minute after intravenous injection of propofol (2 mg/kg). TBW group showed significantly lower blood pressure and CO values at and 1 min after propofol administration compared with the control group, whereas the control and LBW groups had similar PD profiles. In addition, the propofol EC50 value was significantly decreased in MO patients, whereas all other PD parameters were similar between control and MO subjects. This change indicated that propofol potency and/or sensitivity was increased in MO subjects. For MO patients, dosing of propofol based on LBW rather than TBW would be a safer choice due to a less cardiovascular depression effect.

A validated ultra-performance liquid chromatography-tandem mass spectrometry method to identify the pharmacokinetics of SR8278 in normal and streptozotocin-induced diabetic rats.

There is a relationship between circadian rhythm and metabolic disorders. The active agent, SR8278, could competitively bind to and inhibit the nuclear receptor, Rev-erb (a major modulator of mammalian circadian clock system), to regulate the metabolism in organisms. However, we had limited knowledge of the pharmacokinetic (PK) characteristics of SR8278. Here, we describe a sensitive and reproducible ultra-performance liquid chromatography-tandem mass spectrometric (UPLC-MS/MS) method to quantify SR8278 in vivo. The linearity range and the limit of quantification (LOQ) for SR8278 were 30-3000 ng/mL and 6 ng/mL, respectively. The inter-day and intra-day variability were within 10%. This UPLC-MS/MS method was successfully used to characterize the PK behaviors of SR8278 in normal and diabetic rats after intravenous (i.v.) injection at a dosage of 2mg/kg. No significant differences were observed in the PK parameters of SR8278 in normal and diabetic rats. Specifically, the values of areas under plasma concentration time curves (AUC), initial plasma concentrations (C0), elimination half-lives (t1/2), and clearances (CL) were 608.33 ± 295.25 vs. 598.59 ± 276.92 ng·h/mL, 2410.25 ± 202.36 vs. 3742.11 ± 1300.21 ng/mL, 0.17 ± 0.08 vs. 0.11 ± 0.04 h, 3330.83 ± 1609.48 vs. 3364.81 ± 1111.38 mL/kg·h for SR8278 in normal rats vs. diabetic rats, respectively. In conclusion, a UPLC-MS/MS method was successfully developed and validated for the first time, with a wide linearity range, low LOQ, small sample volume (10 µL), rapid analysis (4 min) and excellent recoveries (>80%). It was also used to clarify the PK characteristics of SR8378 in rats. The same PK behaviors of SR8278 in normal and diabetic rats showed that diabetes may have little or no effect on the disposition, metabolism and/or elimination in vivo, which may be of great importance for future clinical studies.

Altered Cisatracurium Pharmacokinetics and Pharmacodynamics in Patients with Congenital Heart Defects.

The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. We aimed to determine the pharmacokinetics (PK)/pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHDs), such as ventricular septal defects and atrial septal defects, and to assess the effects of CHDs on the PK/PD profiles of cisatracurium. A modified two-compartment model with drug clearance from both compartments was best fitted to the PK data to determine the PK parameters. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from the central to peripheral compartment. The intercompartment rate constants k12 and k21 were significantly reduced (35%-60%, P < 0.05) in patients with ventricular septal defects and in patients with atrial septal defects compared with control patients. Consistently, septal defects caused a marked increase (160%-175%, P < 0.001) in the distribution half-life. Furthermore, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block) was prolonged from 2.2 minutes to 5.0 minutes. PK/PD modeling suggested that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause of lagged pharmacodynamic responses. In conclusion, cisatracurium PK/PD were significantly altered in patients with septal defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHDs.

Establishment of pharmacophore and VolSurf models to predict the substrates of UDP-glucuronosyltransferase1A3.

1.UDP-glucuronosyltransferase1A3 (UGT1A3) catalyzes glucuronidation of numerous xenobiotics/drugs. Here, we aimed to establish substrate selectivity models for UGT1A3 using the pharmacophore and VolSurf approaches. 2.Fifty structurally diverse substrates of UGT1A3 were collated from the literature. These substrates were divided into training (n=34) and test sets (n=16). The pharmacophore model was developed using the Discovery Studio 2.5 software. A user-defined feature (i.e. the glucuronidation site) was included in the program for model generation. The VolSurf model was derived using the VolSurf program implemented in SYBYL 8.0 software. 3.The pharmacophore model consisted of three features (i.e. one glucuronidation site and two hydrogen-bond acceptors). The activities of 81% of test set substrates were adequately predicted (deviated by less than one-log unit) by the model, suggestive of a satisfactory predictive power. The refined VolSurf model based on 22 molecular descriptors was statistically significant (r(2)=0.793, q(2)=0.606). It also processed a good predictability as the activities of 14 test set compounds were well predicted. The VolSurf model highlighted the chemical features (including large molecule size, hydrophilic regions and hydrogen-bonding groups) contributing to favored glucuronidation by UGT1A3. 4.In conclusion, two predictive 3D-QSAR models (i.e. the pharmacophore and VolSurf models) for UGT1A3 were successfully established. These models contributed to an improved understanding of the substrate preference of UGT1A3 and a more comprehensive prediction of UGT-mediated metabolism.

Warfarin is an effective modifier of multiple UDP-glucuronosyltransferase enzymes: evaluation of its potential to alter the pharmacokinetics of zidovudine.

In this study, we aimed to determine the modulatory effects of warfarin (an extensively used anticoagulant drug) and its metabolites on UDP-glucuronosyltransferase (UGT) activity and to assess the potential of warfarin to alter the pharmacokinetics of zidovudine (AZT). The effects of warfarin and its metabolites on glucuronidation were determined using human and rat liver microsomes (HLM and RLM) as well as expressed UGTs. The mechanisms of warfarin-UGT interactions were explored through kinetic characterization and modeling. Pharmacokinetic studies with rats were performed to evaluate the potential of warfarin to alter the pharmacokinetics of AZT. We found that warfarin was an effective modifier of a panel of UGT enzymes. The effects of warfarin on glucuronidation were inhibitory for UGT1A1, 2B7, and 2B17, but activating for UGT1A3. Mixed effects were observed for UGT1A7 and 1A9. Consistent with its inhibitory effects on UGT2B7 activity, warfarin inhibited AZT glucuronidation in HLM (Ki = 74.9-96.3 µM) and RLM (Ki = 190-230 µM). Inhibition of AZT glucuronidation by UGT2B7, HLM, and RLM was also observed with several hydroxylated metabolites of warfarin. Moreover, the systemic exposure (AUC) of AZT in rats was increased by a 1.5- to 2.1-fold upon warfarin coadministration. The elevated AUC was associated with suppressed glucuronidation that was probably attained through a combined action of warfarin and its hydroxylated metabolites. In conclusion, the activities of multiple UGT enzymes can be modulated by warfarin and the nature of modulation was isoform dependent. Also, pharmacokinetic interactions of zidovudine with warfarin were highly possible through inhibition of UGT metabolism.

Regioselective glucuronidation of gingerols by human liver microsomes and expressed UDP-glucuronosyltransferase enzymes: reaction kinetics and activity correlation analyses for UGT1A9 and UGT2B7.

OBJECTIVES: To determine the reaction kinetics for regioselective glucuronidation of gingerols (i.e. 6-, 8- and 10-gingerol) by human liver microsomes and expressed UDP-glucuronosyltransferase (UGT) enzymes, and to identify the main UGT enzymes involved in regioselective glucuronidation of gingerols. METHODS: The rates of glucuronidation were determined by incubating the gingerols with uridine diphosphoglucuronic acid-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Activity correlation analyses were performed to identify the main UGT enzymes contributing to hepatic metabolism of gingerols. KEY FINDINGS: Glucuronidation at the 4'-OH group was much more favoured than that at 5-OH. The degree of position preference was compound-dependent; the catalytic efficiency ratios of 4'-O- to 5-O-glucuronidation were 9.1, 19.7 and 2.9 for 6-, 8- and 10-gingerol, respectively. UGT1A8 (an intestinal enzyme), UGT1A9 and UGT2B7 were the enzymes showing the highest activity towards gingerols. Formation of 5-O-glucuronide was mainly catalysed by UGT1A9. UGT2B7 was the only enzyme that generated glucuronides at both 4'-OH and 5-OH sites, although a strong position preference was observed with 4'-OH (≥80.2%). Further, activity correlation analyses indicated that UGT2B7 and UGT1A9 were primarily responsible for 4'-O-glucuronidation and 5-O-glucuronidation of gingerols in the liver, respectively. CONCLUSIONS: Gingerols were metabolized by multiple hepatic and gastrointestinal UGT enzymes. Also, UGT1A9 and 2B7 were the main contributors to regioselective glucuronidation of gingerols in the liver.

Glucuronidation of macelignan by human liver microsomes and expressed UGT enzymes: identification of UGT1A1 and 2B7 as the main contributing enzymes.

Macelignan is a natural phenolic compound that possesses many types of health benefits such as antiinflammation. This study aimed to characterize the metabolism of macelignan via the glucuronidation pathway and to identify the main UGT enzymes involved in macelignan glucuronidation. The rates of glucuronidation were determined by incubating macelignan with UDPGA-supplemented microsomes. Kinetic parameters were derived by fitting an appropriate model to the data. Reaction phenotyping, the relative activity factor (RAF) approach and activity correlation analysis were employed to identify the main UGT enzymes contributing to the hepatic metabolism of macelignan. Glucuronidation of macelignan in pooled human liver microsomes (pHLM) was rather efficient with a high CLint (the intrinsic clearance) value of 13.90 ml/min/mg. All UGT enzymes, except UGT1A4, 1A6 and 2B10, showed metabolic activities toward macelignan. UGT1A1 and 2B7 were the enzymes with the highest activities; the CLint values were 4.92 and 2.13 ml/min/mg, respectively. Further, macelignan glucuronidation was significantly correlated with 3-O-glucuronidation of ß-estradiol (r = 0.69; p < 0.01) and glucuronidation of zidovudine (r = 0.60; p < 0.05) in a bank of individual HLMs (n = 14). Based on the RAF approach, UGT1A1 and 2B7, respectively, contributed 55.40% and 32.20% of macelignan glucuronidation in pHLM. In conclusion, macelignan was efficiently metabolized via the glucuronidation pathway. It was also shown that UGT1A1 and 2B7 were probably the main contributors to the hepatic glucuronidation of macelignan.

P-glycoprotein (P-gp)-mediated efflux limits intestinal absorption of the Hsp90 inhibitor SNX-2112 in rats.

1. The promising anticancer agent SNX-2112 (a novel Hsp90 inhibitor) is poorly bioavailable after oral administration. Here, we aim to determine the role of P-glycoprotein (P-gp) in the intestinal absorption of SNX-2112. 2. We found that SNX-2112 significantly stimulated P-gp ATPase activity in in vitro ATPase assay with a small EC50 (the half-maximal effective concentration) value of 0.32 µM. 3. In the single-pass perfused rat intestine model, absorption of SNX-2112 was not favored in the small intestine with a [Formula: see text] (the wall permeability) value of 0.38-0.64. By contrast, the compound was well absorbed in the colon with a [Formula: see text] value of 1.19. The P-gp inhibitors cyclosporine and elacridar (i.e. GF120918A) markedly enhanced SNX-2112 absorption in all four intestinal segments (i.e. duodenum, jejunum, ileum and colon) and the fold change ranged from 3.1 to 14.1. Pharmacokinetic study revealed that cyclosporine increased the systemic exposure of SNX-2112 by a 2.5-fold after oral administration. 4. This is the first report that P-gp-mediated efflux is a limiting factor for intestinal absorption of SNX-2112 in rats.