12-h Values Research Articles

Comparison of the effects of peficitinib and tofacitinib in the adjuvant-induced arthritis rat model

We investigated and compared the pharmacologic properties of two Janus kinase (JAK) inhibitors, peficitinib and tofacitinib, in an adjuvant-induced arthritis rat model. Repeated administration of peficitinib (3 − 30 mg/kg) or tofacitinib (1 − 10 mg/kg) exhibited a dose-related and significant attenuation of arthritis score, paw swelling, pain threshold, grip strength and histopathologic injuries in the model; peficitinib 10 mg/kg and tofacitinib 3 mg/kg demonstrated comparable efficacy. Equivalent Cmax and AUC0–12h values were observed with peficitinib 10 mg/kg and tofacitinib 3 mg/kg, suggesting that the two drugs may demonstrate comparable efficacy on arthritis-associated symptoms at comparable plasma concentration levels. However, peficitinib 10 mg/kg had greater efficacy than tofacitinib 3 mg/kg on some inflammation- and bone destruction-associated parameters in the paw fluid, including the production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), receptor activator of nuclear factor kappa-B ligand, and matrix metalloproteinase-3, which are associated with arthritis exacerbation. Peficitinib 10 mg/kg also showed significantly greater inhibitory effects than tofacitinib 3 mg/kg on loss of bone mineral density and synovial thickening score, which might be a result of the VEGF and PDGF receptor kinase inhibitory effects of peficitinib, in addition to JAK inhibition. In conclusion, both tofacitinib and peficitinib potently improved arthritis and associated symptoms in adjuvant-induced arthritis rats; moreover, owing to possible differences in the mechanism of action of the two drugs, peficitinib may have exerted its effects through JAK inhibition and additional unique off-target properties.

Impact of dose and duration of therapy on dexamethasone pharmacokinetics in childhood acute lymphoblastic leukaemia—a report from the UKALL 2011 trial

IntroductionThe use of dexamethasone in acute lymphoblastic leukaemia therapy contributes to short- and long-term toxicities. The UKALL 2011 randomised trial investigated whether a more intense dexamethasone dose (10 mg/m2/d x 14d, short vs 6 mg/m2/d x 28d, standard) would lead to a more rapid cytoreduction and reduced adverse effects associated with longer durations of steroids in induction. The impact of dose and duration on dexamethasone pharmacokinetics was investigated. MethodsBlood samples were obtained on one of the first three and last three days of induction dexamethasone dosing at time points up to 8 h after oral administration. Plasma dexamethasone levels were quantified in 1084 plasma samples obtained from 174 children and a population pharmacokinetic model developed. ResultsDrug exposure varied significantly between patients, with a >12-fold variation in AUC0–12h values and a marked overlap in dexamethasone exposures between dose levels. Intuitively, AUC0–12h was significantly higher with short dosing (10 mg/m2/d), but cumulative exposure was significantly higher with standard dosing over 28 days, after a higher cumulative dose. Concomitant rasburicase administration was associated with a 60% higher dexamethasone clearance. Day 8 bone marrow response was comparable between dosing arms, but those with <5% blast count exhibited a greater mean dexamethasone exposure than those with >5%. No statistical differences were observed between arms in terms of steroid-related toxicity or minimal residual disease at the end of induction. ConclusionThe potential significance of dexamethasone AUC0–12h on early response and higher cumulative exposure on the standard arm suggest that duration of therapy and exposure may be more important factors than absolute dose from a clinical pharmacology perspective.

Pharmacokinetics of mycophenolate mofetil in juvenile patients with autoimmune diseases

Objectives: This study aimed to determine the association between the dosage and pharmacokinetics of mycophenolate mofetil (MMF) in juvenile patients with autoimmune diseases.Methods: Totally, 29 patients were administered oral MMF. The blood concentrations of mycophenolate acid (MPA) at seven points, the area under the time–concentration curve (MPA–AUC0–12h), the peak concentration (Cmax), and the time to peak concentration (Tmax) were measured. To obtain a dose-normalized MPA–AUC0–12h value, the actual measured MPA–AUC0–12h value was divided by the dose value of the morning administration corrected for body weight (BW) or body surface area (BSA). The patients were classified into three age groups (group 1, ≤10 years; group 2, >10–≤15 years; and group 3, >15 years), and pharmacokinetic parameters were compared among the groups.Results: In total, we obtained 37 measurements. The actual measured MPA–AUC0–12h values and the MPA–AUC0–12h values corrected for dose per BW and Tmax were lower in young patients. The MPA–AUC0–12h values corrected for dose per BSA and Cmax were comparable among all the groups.Conclusion: In patients with juvenile autoimmune diseases, determining MMF administration dosage according to BSA may facilitate MPA–AUC0–12h value prediction.

Measurement duration affects the calculation of whole body protein turnover kinetics but not between-day variability

BackgroundAssessment of whole body protein turnover (WBPT) can provide fundamental information about protein kinetics which underpins the conservation of lean tissue. Reliability and methodology studies on the measurement of WBPT are scarce. This study aimed to assess the effects of urine collection duration (9 versus 12 h) and the reproducibility of WBPT with the end product method calculated from ammonia as the end product. MethodsWBPT was assessed in 21 healthy participants (11M, 10F) on 2 test days. WBPT was assessed using the end product method with a single dose of 15N glycine with ammonia as end product in a postprandial state with 9 and 12-h urine collections. ResultsThe CV for protein flux averaged 10% and 12% for 9 and 12-h urine collections respectively. Protein flux, synthesis and balance were significantly higher and protein breakdown significantly lower with 9-h urine collections compared to 12-h collections (P < 0.01) and there was a trend towards increasingly greater overestimation of 9-h calculated WBPT kinetics with greater overall rates of WBPT. Correlations between the 9 and 12-h values were strong (r > 0.962, P < 0.001 for all variables). ConclusionsThe reproducibility of WBPT with ammonia as the end product was similar to previously reported reproducibility of the gold standard precursor technique. The use of a 12-h urine collection is more effective to achieve full turnover of the ammonia free amino acid (AA) pool.

C-type natriuretic peptide (CNP) signal peptide fragments are present in the human circulation

BackgroundSignal peptides may be novel biomarkers in cardiovascular diseases. MethodsWe developed a novel immunoassay to the signal peptide of preproCNP (CNPsp) and used this to document circulating venous concentrations of CNPsp in normal healthy volunteers (n=109), regional plasma CNPsp concentrations in patients undergoing clinically indicated catheterisation (n=24) and temporal CNPsp concentrations in patients with ST-elevation myocardial infarction (STEMI) <4h after symptom onset (n=8). The structure/sequence of circulating CNPsp was confirmed by tandem mass spectrometry (MS/MS). ResultsIn normal human plasma, CNPsp was detectable at levels higher than NT-proCNP (74±17 vs. 20±5.5pmol/L). There was no correlation between NTproCNP and CNPsp, but plasma concentrations of sibling signal peptides – CNPsp and BNPsp – were strongly correlated (r=0.532, P<0.001). In patients undergoing catheterisation, there were significant arterio-venous step-ups in CNPsp concentrations across the heart (P<0.01) and kidney (P<0.01). Arterial concentrations of CNPsp significantly correlated with heart rate (r=0.446, P<0.05). In STEMI patients, plasma concentrations of CNPsp showed a biphasic elevation pattern between 6 and 12h after symptom onset, with 12h values significantly elevated (∼3-fold) compared with levels at presentation (P<0.05). MS/MS verified circulating CNPsp to be preproCNP(14–23) and preproCNP(16–23) peptides. ConclusionsThis is the first report of a circulating preproCNP derived signal peptide. Given the clear cardiac and renal secretion profiles of CNPsp and its response in STEMI patients, further studies on potential biological functions and biomarker applications of CNPsp in cardiovascular disease are warranted.

A stable and practical etoposide-containing intravenous long-/medium-chain triglycerides-based lipid emulsion formulation: pharmacokinetics, biodistribution, toxicity, and antitumor efficacy

Objectives: This work aimed to evaluate pharmacokinetics, biodistribution, toxicity, and antitumor activities of a highly stable long-/medium-chain triglycerides (LCT/MCT)-based etoposide parenteral emulsion (EPE) in comparison to etoposide parenteral solution (EPS).Methods: Using high-pressure homogenization method, EPE was prepared and sterilized at 121°C for 10 min by autoclaving. The biological samples were analyzed using the UPLC-ESI-MS/MS method.Results: Superior stability of EPE was verified with no significant changes in physicochemical properties in the accelerating and long-term stability tests. Similar pharmacokinetic behavior in beagle dogs was obtained and the AUC0 – 12h values were 1196.73 ± 320.85 and 1505.56 ± 617.93 µg·h/L for EPE and EPS (p > 0.5), respectively. Likewise, no remarkable difference in biodistribution profiles in mice was found for both formulations. Safety assessment studies including hemolysis test, rabbit ear vein test and injection anaphylaxis were undertaken and the EPE was proven to be safe for intravenous administration. Specifically, after consecutive 12 weeks administration in rats, systematic and local toxicity induced by EPE were alleviated relative to that of EPS. Furthermore, significant and comparable antitumor activities to EPS were also demonstrated by EPE with tumor suppression rate (TSR) of 66.63, 55.94, and 60.16% against H460, Hep G2, and BCAP-37 human cancer cell lines in nude mice at the dose of 15 mg/kg, respectively.Conclusion: These results suggest that this LCT/MCT-based lipid emulsion is a promising alternative intravenous carrier for etoposide with high stability, improved convenience, alleviated toxicity, and noncompromised antitumor efficacy.

A Novel In-Situ-Gelling Liquid Suppository for Site-Targeting Delivery of Anti-Colorectal Cancer Drugs

In order to avoid anti-cancer drugs undergoing a first-pass effect and reduce their toxicity, and to solve conventional suppositories defects, we developed an in-situ-gelling and injectable Pluronic–poly(acrylic acid) (Pluronic–PAA) liquid suppository, which could gel fast in the physiological state and had suitable gel strength and bioadhesive force. The liquid suppositories were inserted into the rectum of rabbits without difficulty and leakage, and retained in the rectum for at least 6 h and while releasing the drug. The toxicity and cytotoxic tests indicated that Pluronic and PAA were non-toxic materials and could inhibit colon cancer cells when oxaliplatin was incorporated. C max and AUC0→12h values of oxaliplatin after rectal administration of a oxaliplatin suppository were higher than those for an oxaliplatin solution administered orally. These results suggest that an in-situ-gelling and injectable liquid suppository for humans can be further developed as a more convenient and effective rectal dosage form.

Limited Sampling Strategy for the Estimation of Mycophenolic Acid Area under the Curve in Adult Renal Transplant Patients Treated with Concomitant Tacrolimus

Significant relationships between the mycophenolic acid (MPA) area under the concentration-time curve (AUC(0-12h)) and the risks for acute rejection and side effects have been reported. We developed a practical method for estimation of MPA AUCs. Regression equations were developed using repeated cross-validation for randomly chosen subsets, characterized statistically, and verified for acceptable performance. Twenty-one renal transplant patients receiving 0.5 or 1.0 g of mycophenolate mofetil twice daily and concomitant tacrolimus provided a total of 50 pharmacokinetic profiles. MPA concentrations were measured by a validated HPLC method in 12 plasma samples collected at predose and at 30 and 60 min; 2, 3, 4, 6, 8, 9, 10, 11, and 12 h; 1 and 2 weeks; and 3 months after transplantation. Twenty-six 1-, 2-, or 3-sample estimation models were fit (r(2) = 0.341-0.862) to a randomly selected subset of the profiles using linear regression and were used to estimate AUC(0-12h) for the profiles not included in the regression fit, comparing those estimates with the corresponding AUC(0-12h) values, calculated with the linear trapezoidal rule, including all 12 timed MPA concentrations. The 3-sample models were constrained to include no samples past 2 h. The model using c(0h), c(0.5h), and c(2h) was superior to all other models tested (r(2) = 0.862), minimizing prediction error for the AUC(0-12h) values not included in the fit (i.e., the cross-validation error). The regression equation for AUC estimation that gave the best performance for this model was: 7.75 + 6.49c(0h) + 0.76c(0.5h) + 2.43c(2h). When we applied this model to the full data set, 41 of the 50 (82%) estimated AUC values were within 15% of the value of AUC(0-12h) calculated using all 12 concentrations. This limited sampling strategy provides an effective approach for estimation of the full MPA AUC(0-12h) in renal transplant patients receiving concomitant tacrolimus therapy.

RELATIONSHIP BETWEEN AIR FLOW INDICES AND LOCAL RAINFALL IN KYUSHU, JAPAN

Downscaling of large-scale atmospheric circulation characteristics to estimate local hydrometeorological processes is important, e. g., for assessing the local impact of a possible future climate change. In the present study, this possibility was investigated for Kyushu Island, Japan. Six months of 12-h values of two large-scale air flow indices, wind flow f and vorticity z, estimated using different spatial resolutions, were correlated with rainfall observed at 128 stations on Kyushu. For both f and z, the correlations increased with increasing resolution. For the highest resolution, the mean correlation for f; was 0.198 and the maximum correlation 0.306. Forz, the corresponding values were 0.482 and 0.764. Firstly, the results show that vorticity has a potential to be used as a predictor in downscaling of GCM output to hydrologically relevant scales, as well as a variable in rainfall time series modeling. Secondly, they indicate that the output of GCM models need to have a spatial resolution of at least 2.5°×2.5° in order for meaningful statistical downscaling to be feasible.

Six-hour and four-hour nocturnal sampling for growth hormone.

Overnight sampling for growth hormone (GH) is a research tool for quantifying characteristics of spontaneous GH secretion. However, the study is costly in assays and blood volume, particularly that required from a small child. Existing overnight GH data from 126 normal children and from 227 children with GH deficiency or short stature were reanalyzed, examining 6-h and 4-h segments of this data for accuracy in representing each child's 12-h GH secretion. The goal was to see whether the test could be made shorter and more practical without losing accuracy. The 6-h segment 2200-0400 h consistently contained the majority of GH peaks. Correlation was high between GH values from 2200-0400 h and from the 12-h period. Normal 95% confidence limits (CL) for GH during 2200-0400 h were derived from data in normal children for gender and each pubertal stage. Data from short children were compared with the normal 6-h 95% CL. In short children, GH values low for 12-h were also low for 6-h. Only a few children with normal 12-h values (1.5% of normals, 0.5% with short stature) had GH values outside 95% CL for 6-h. Six-hour GH sampling (2200-0400 h) is accurate and cost-efficient compared to the 12-h overnight GH study. These studies are primarily useful in research settings.

Evaluation of the levels of free and total amitriptyline and metabolites in the plasma and brain of the rat after long-term administration of doses used in receptor studies.

This study was conducted in order to investigate the level of amitriptyline (AT) and its metabolites. Three separate experiments were carried out. In two of these experiments, rats were treated over 7 days with IP doses of AT (10 mg/kg in experiment A and 2 X 20 mg/kg in experiment C). The rats were sacrificed either 2 (experiment C) or 12 h (experiments A and C) after the last dose. In experiment B, rats were sacrificed 2 or 12 h after a single dose of 20 mg/kg AT. The results of these experiments showed the following: in experiment A only AT was measurable in the brain and in the plasma, in contrast to experiments B and C, where NT and the hydroxylated metabolites AT-OH and NT-OH reached significant levels in the plasma and in the brain. The concentrations of AT-OH, NT-OH, and NT (12-h values) that were found in the brain are probably not pharmacologically relevant. The 12-h plasma values of all compounds tested were, even with the highest dose, lower than those expected to be clinically effective in man. Our results suggest that AT, at higher doses, may induce its own metabolism. The free plasma levels of this drug and its metabolites are higher in man than in the rat. The possible implications of these results in the use of antidepressants in the treatment of depression are discussed.