AUC 0-24h Research Articles

Effect of short bouts of high intensity activity on glucose among adults with prediabetes: A pilot randomized crossover study

AimFew data exist on the effects of vigorous-intensity activity on blood glucose. The study aim was to determine the effects of 2-min and 4-min bouts of vigorous-intensity stair climbing on glucose levels. MethodsNine overweight/obese adults with prediabetes (40–64 years, HbA1C 5.7%–6.4%) participated in a randomized cross-over design with three conditions on consecutive days: control; 2-min bouts of stair climbing once per hour for 8 h; and 4-min bouts of stair climbing once every 2 h for 8 h, with the two activity days randomized in order. Continuous glucose monitoring estimated five-minute average interstitial glucose values. ResultsTotal physical activity and 12-h AUC did not differ significantly by condition. The 4-min bout caused a significant decrease in glucose after 30 min (Cohen’s d = −0.91) compared to the control condition, while the 2-min bout did not (Cohen’s d = −0.13). Post-exercise change in glucose varied by pre-exercise glucose and by condition. No significant change in post-exercise glucose with stair climbing was found when pre-exercise glucose was <90 mg/dl, but when pre-exercise glucose was ≥90 mg/dl, the 4-min condition caused significant reductions in glucose. ConclusionsThese results suggest short, intermittent bouts of vigorous-intensity exercise can be substituted for an equivalent volume of lower-intensity lifestyle activity when glucose is over 90 mg/dl.Trial Registration: Clinical Trials NCT02827383.

Salidroside shows a particular pharmacokinetic property in model rats of myocardial ischemia

ObjectiveSalidroside showed potential pharmacological effect on plateau hypoxia and cardiovascular disease like myocardial ischemia. However, pharmacokinetic differences have not been assessed between the pathological model and the normal animals. This study focused on evaluating the pharmacokinetic properties of salidroside in animals with myocardial ischemia. MethodsA reproducible and sensitive method was established and optimized based on liquid chromatography tandem mass spectrometry (LC–MS/MS) to determine salidroside in rats plasma. The data showed the AUC0–∞ and Cmax of salidroside proportionally increased along with dose elevation after singly intragastric administration of salidroside at a dose of 20, 50, and 100 mg/kg. ResultsCompared to the single dose, the Cmax, and AUC0–8h of salidroside markedly decreased while CL/F and V/F increased after multiple dosing. However, the Cmax and AUC0–8h of ischemic model rats were 0.35 and 0.39 fold lower than those in normal rats after a single dose at 50 mg/kg, with an increased CL/F and V/F. Surprisingly, after a consecutive administration of salidroside for 7 d, the mean Cmax, AUC0–8h increased 2.89 and 2.61 fold higher than a single dose in model rats, and even 2.28 and 4.03 fold higher than the normal controls after multiple doses. All the above fold values were statistically different (P < 0.01). ConclusionThe particular PK properties of salidroside in ischemic model rats were presented in our study for the first time, suggesting that myocardial ischemia greatly affected pharmacokinetics exposure of the orally administrated salidroside after a single or multiple doses.

Application of liquid chromatography–tandem mass spectrometry to study the effect of docetaxel on pharmacokinetics and tissue distribution of apatinib in mice

Apatinib, a highly selective small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), has attracted many attentions due to its anticancer activity in various malignancies containing non-small-cell lung cancer (NSCLC). Our previous preclinical study confirmed the enhanced anti-tumor efficacy of combined treatment between apatinib and docetaxel for NSCLC. However, the effects of docetaxel on pharmacokinetics and tissue distribution of apatinib are not clear. In present study, a reliable HPLC-MS/MS method was established for determination of apatinib. This method had a good linearity in the range of 1–5000 ng/mL, and the recovery and matrix effect were 100.1–103.5%, 77.6–83.5%, respectively. Plasma exposure level of apatinib and the values of Cmax, AUC0–12h, T1/2, and MRT were not affected by multi-dose of docetaxel. The tissue distributions (kidney, heart, lung, spleen) of apatinib in combined treatment group were lower at 0.25 h but higher at 2 h, and that in intestine and liver were not significantly changed compared with control group. However, pre-treatment with docetaxel had no significant effect on AUC0–4h of apatinib in tissues in mice. In conclusion, plasma and tissues exposure levels of apatinib were not affected by long-termed treatment with docetaxel, indicating that docetaxel is less likely to increase the side effect of apatinib such as hypertension, hand-foot syndrome and so on.

Silymarin loaded nanostructured lipid carrier: From design and dermatokinetic study to mechanistic analysis of epidermal drug deposition enhancement

This investigation aimed to develop nanostructured lipid carrier (NLC) gel of silymarin for epidermal tissue deposition enhancement. Binary mixture of solid lipid and liquid lipid was optimized in term of crystallinity, enthalpy of fusion and width of thermal event using DSC. NLC formulation was optimized using central composite rotatable design (CCRD). Optimized freeze dried NLC dispersion containing Sefsol® 218 (0.5% w/w), Geleol® (1.4% w/w), bile salt (1.3% w/w), Cremophor® RH40 (2.7% w/w) and mannitol (3.0% w/w) was characterized for mean particle size (PS), polydispersability index (PDI), zeta potential (ZP) and entrapment efficiency (EE). PS, PDI, ZP and EE were found to be 126.1±0.4nm, 0.33±0.03, −28.8±0.7mV and 85.0±2.9%, respectively. In vitro (Strat-M™ membrane) and ex vivo (rat skin) permeation studies showed close correlation (r2=0.98). The flux and permeability coefficient of NLC gel in ex vivo permeation studies were found to be 23.6μg/cm2/h and 23.6×10−3cm/h respectively. Dermatokinetic study showed a significant (p<0.001) increase in CSkin max and AUC0–8h in skin treated with NLC gel as compared to skin treated with conventional gel. Confocal microscopic (CLMS) studies depicted maximum silymarin deposition in viable epidermis (30μm). FTIR and DSC analysis indicated lipid bilayer fluidization mechanism of epidermal drug deposition enhancement. Skin irritation studies confirmed the nonirritant behavior of NLC gel to skin. These findings show that NLC gel can be used as a potential carrier for topical delivery of silymarin.

Influence of Enzalutamide on Cabazitaxel Pharmacokinetics: a Drug-Drug Interaction Study in Metastatic Castration-resistant Prostate Cancer (mCRPC) Patients.

Purpose: In ongoing clinical research on metastatic castration-resistant prostate cancer (mCRPC) treatment, the potential enhanced efficacy of the combination of taxanes with AR-targeted agents, that is, enzalutamide and abiraterone, is currently being explored. Because enzalutamide induces the CYP3A4 enzyme and taxanes are metabolized by this enzyme, a potential drug-drug interaction needs to be investigated.Experimental Design: Therefore, we performed a pharmacokinetic cross-over study in mCRPC patients who were scheduled for treatment with cabazitaxel Q3W (25 mg/m2). Patients were studied for three consecutive cabazitaxel cycles. Enzalutamide (160 mg once daily) was administered concomitantly after the first cabazitaxel cycle, during 6 weeks. Primary endpoint was the difference in mean area under the curve (AUC) between the first (cabazitaxel monotherapy) and third cabazitaxel cycle, when enzalutamide was added.Results: A potential clinically relevant 22% (95% CI, 9%-34%; P = 0.005) reduction in cabazitaxel exposure was found with concomitant enzalutamide use. The geometric mean AUC0-24h of cabazitaxel was 181 ng*h/mL (95% CI, 150-219 ng*h/mL) in cycle 3 and 234 ng*h/mL (95% CI, 209-261 ng*h/mL) in cycle 1. This combination did not result in excessive toxicity, whereas PSA response was promising.Conclusions: We found a significant decrease in cabazitaxel exposure when combined with enzalutamide. In an era of clinical trials on combination strategies for mCRPC, it is important to be aware of clinically relevant drug-drug interactions. Because recent study results support the use of a lower standard cabazitaxel dose of 20 mg/m2, the clinical relevance of this interaction may be substantial, because the addition of enzalutamide may result in subtherapeutic cabazitaxel exposure. Clin Cancer Res; 24(3); 541-6. ©2017 AACR.

Canagliflozin loaded SMEDDS: formulation optimization for improved solubility, permeability and pharmacokinetic performance

The aim of the present investigation is to systematically optimize and develop microemulsion preconcentrates to improve the solubility and oral bioavailability profile of canagliflozin employing D-optimal mixture design. Preconcentrate constituents, i.e. oils, surfactants and co-surfactants were selected on the basis of solubility studies and their concentration range capable of influencing the formation of microemulsions was determined. D-optimal mixture design was employed for studying the interaction behavior of desired responses and optimized using desirability approach. The optimized formulation was evaluated for its in vitro, ex vivo and in vivo behavior to determine the dissolution rate, permeation rate and oral bioavailability of the drug. The optimized formulation containing Lauroglycol FCC (80 mg), Tween 80 (300 mg) and Transcutol P (120 mg) showed desired attributes of measured responses with minimum experimental variation and desirability value of 0.751. The morphological behavior showed uniform nano-structured globules with negligible aggregation as confirmed in transmission electron microscopy. Ex vivo permeation rate of the drug across excised intestinal segments (duodenum, jejunum, ileum and colon) was observed to be 3.51, 5.62, 4.52 and 2.98 folds higher, respectively, as compared to drug powder and marketed tablets Compared with the pure drug and commercial tablets, enhanced in vitro dissolution rate of optimized formulation was observed, resulting in 2.56 fold enhancement in Cmax and AUC0–24h following oral administration in fasting wistar rats. Establishment of level A IVIVC for the developed SMEDDS indicated excellent goodness of fit between the in vitro drug release and in vivo drug absorbed. Accelerated stability studies indicated stability of the optimized formulation over 3 months storage.

Activity of Simulated Human Dosage Regimens of Meropenem and Vaborbactam against Carbapenem-Resistant Enterobacteriaceae in an In Vitro Hollow-Fiber Model.

The objective of these studies was to evaluate the exposures of meropenem and vaborbactam that would produce antibacterial activity and prevent resistance development in carbapenem-resistant Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains when tested at an inoculum of 108 CFU/ml. Thirteen K. pneumoniae isolates, three Enterobacter cloacae isolates, and one Escherichia coli isolate were examined in an in vitro hollow-fiber model over 32 h. Simulated dosage regimens of 1 to 2 g of meropenem with 1 to 2 g of vaborbactam, with meropenem administered every 8 h by a 3-h infusion based on phase 1 or phase 3 patient pharmacokinetic data, were studied in the model. A dosage of 2 g of meropenem in combination with 2 g of vaborbactam was bactericidal against K. pneumoniae, E. cloacae, and E. coli strains, with meropenem-vaborbactam MICs of up to 8 mg/liter. When the vaborbactam exposure was adjusted to the levels observed in patients enrolled in phase 3 trials (24-h free AUC, ∼550 mg · h/liter, versus 320 mg · h/liter in the phase 1 studies), 2 g of meropenem with 2 g of vaborbactam was also bactericidal against strains with meropenem-vaborbactam MICs of 16 mg/liter. In addition, this level of vaborbactam also suppressed the development of resistance observed using phase 1 exposures. In this pharmacodynamic model, exposures similar to 2 g of meropenem in combination with 2 g of vaborbactam administered every 8 h by a 3-h infusion in phase 3 trials produced antibacterial activity and suppressed the development of resistance against carbapenem-resistant KPC-producing strains of Enterobacteriaceae.

Carcinogenicity assessment of the Hedgehog pathway inhibitor, vismodegib in Tg.rasH2 mice and Sprague-Dawley rats

Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0.1-fold and ≥0.6-fold, respectively, of the steady-state exposure (AUC0–24h) of the recommended human dose. No malignant tumors were identified in either species. Overall, the totality of pharmacology and nonclinical safety data (lack of genotoxicity, in vitro secondary pharmacological binding, and immunoregulatory effects, and limited effects on the endocrine system) suggests that the development of the benign hair follicle tumors may be related to pharmacologically-mediated disruption of hair follicle morphogenesis, although the exact mechanism of tumorigenesis is unclear. Hair follicle tumors have not been reported in vismodegib-treated patients. The relevance of this finding in rats to patients is uncertain.

Isoniazid and rifampicin concentrations in children with tuberculosis with either a daily or intermittent regimen: implications for the revised RNTCP 2012 doses in India

Suboptimal plasma drug concentrations in antitubercular therapy (ATT) may lead to delayed treatment response and the emergence of acquired drug resistance. This study aimed (i) to determine and compare plasma concentrations of isoniazid (INH) and rifampicin (RIF) in children treated for tuberculosis receiving a daily or intermittent ATT regimen and (ii) to study the effect of INH and RIF exposure on clinical outcome at the end of therapy (EOT). A total of 41 children aged 2–16 years initiated on either a daily or three-times weekly (intermittent) ATT regimen were recruited into the study. Towards the end of the intensive phase, blood specimens were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 4 and 6 h post-dose. Concentrations of INH and RIF were analysed using validated liquid chromatography–tandem mass spectrometry and high-performance liquid chromatography assays, respectively. The maximum plasma concentration (Cmax), the area under the concentration–time curve from 0–6 h (AUC0–6h) and treatment outcome were determined. Ninety-two percent of patients had an INH Cmax > 3 µg/mL. Seventy-seven percent of patients had a RIF Cmax < 8 µg/mL and 28% of patients had a RIF AUC0–24h < 13 mg ⋅ h/L. INH and RIF exposure did not differ between daily and intermittent ATT regimens on the day of administration. All children had a favourable outcome at EOT. Since 77% of children had low RIF exposure, we recommend routine use of therapeutic drug monitoring to prevent relapse and to support implementation of the revised RNTCP 2012 doses.

Comparative clinical trial of the variability factors of the exposure indices used for the drug monitoring of two tacrolimus formulations in kidney transplant recipients

BackgroundSeveral studies found differences in tacrolimus whole blood trough levels (C0) or area-under-the curve (AUC) between the twice-daily (Tac-BID) and once-daily (Tac-OD) formulations given to kidney transplant recipients at equal doses. As C0 is widely used as a surrogate of the AUC for individual dose adjustment, this study investigated the correlation and proportionality between C0 and the 24h-AUC, depending on the formulation, time post-transplantation, pharmacogenetics traits and other individual characteristics. Methods45 adult kidney transplant recipients were randomized to receive either Tac OD or Tac BID. On days 8±1 (D8) and 90±3 (month 3, M3), blood samples were collected over 24h in both groups. Tacrolimus concentrations were determined using HPLC–MS/MS and common CYP3A5, CYP3A4 and ABCB1 genotypes characterized using allelic discrimination assays. Tacrolimus population pharmacokinetics was studied in the two patient groups using the Iterative Two Stage (ITS) technique, considering a one-compartment model with two gamma laws to describe the absorption phase. Bayesian estimation based on the C0, C1h and C3h concentrations was employed to estimate individual Tac AUC0-12h and AUC12-24h (for Tac BID), or AUC0–24h (for Tac OD). Multiple linear regression was used to evaluate the influence of Tac formulation, post-transplantation period, recipient gender, existing glucose metabolism disorders, and CYP3A5, CYP3A4 and ABCB1 genotypes on C0, AUC0–24h and the AUC-to-trough concentration ratios. ResultsThe Full Analysis Set comprised 22 patients on Tac OD and 20 on Tac BID. Tac exposure indices as well as their time evolution were similar in the two groups. Multi-linear modeling analysis showed that the Tac dose was higher with Tac-OD than Tac-BID, on D8 than at M3 and in CYP3A5 expressors (p<0.0001 for all). No such influence was found on C0 or C24h, while the AUC0–24h was significantly higher on D8 than at M3. The AUC0–24h/C0 ratio was not affected by the drug formulation and the polymorphisms studied, but it was significantly lower on D8 than at M3 (p=7.8×10−5). In contrast, both the post-transplantation period (p=1.53×10−4), and CYP3A5 expression (p=0.003) had a significant influence on the AUC0–24h/C24h ratio, explaining 19% and 12% of its variability, respectively. Consistently, for both Tac formulations, the AUC0–24h was better correlated with C24h than C0, and for Tac-BID the AUC0-12h was better correlated with C12h than C0. ConclusionsThis study confirms that the precisely timed 12h- or 24h-post-dose blood concentration (as opposed to the vaguely defined ‘trough level’) is a convenient surrogate of the 24h-AUC of tacrolimus for the two TAC formulations over the first 3 months post-transplantation. Still, for a given C24h value, AUC0–24h was higher on D8 and in CYP3A5 expressors. Bayesian estimation of AUC0-12h for TAC BID and AUC0–24h for TAC OD is feasible using only 3 time points within the first 3h, thus giving access to the actual overall exposure.

Application of hot melt extrusion for improving bioavailability of artemisinin a thermolabile drug

Hot melt extrusion has been used to produce a solid dispersion of the thermolabile drug artemisinin. Formulation and process conditions were optimized prior to evaluation of dissolution and biopharmaceutical performance. Soluplus®, a low Tg amphiphilic polymer especially designed for solid dispersions enabled melt extrusion at 110 °C although some drug-polymer incompatibility was observed. Addition of 5% citric acid as a pH modifier was found to suppress the degradation. The area under plasma concentration time curve (AUC0–24h) and peak plasma concentration (Cmax) were four times higher for the modified solid dispersion compared to that of pure artemisinin.

Pharmacokinetics of dabigatran etexilate and rivaroxaban in patients with short bowel syndrome requiring parenteral nutrition: The PDER PAN study

Background and aimsPatients on parenteral nutrition for short bowel syndrome (SBS) have a high risk of thrombotic complications and are often treated with parenteral anticoagulation. Direct oral anticoagulants are absorbed proximally in the digestive tract and may represent alternative regimens in selected SBS patients. In our pilot study, we provided pharmacokinetics parameters of dabigatran etexilate and rivaroxaban in this setting and compared peak (Cmax), trough (Ctrough) concentrations, and areas-under-the-concentration-time-curve (AUC0−t) to reference values retrieved from phase I-III studies. MethodsWe enrolled 6 adults with a remaining small bowel length≤200cm, normal renal/hepatic function, and intact stomach. In our crossover study, patients were exposed to twice-daily dabigatran etexilate 150mg and once-daily rivaroxaban 20mg. ResultsAfter 5days of dabigatran dosing, Ctrough and Cmax geometric means were 39μg/L (90% CI: 23–66) and 88μg/L (90% CI: 56–137), respectively; AUC0–12h was 958μg∗h/L (90% CI: 635–1445). After 5days of rivaroxaban dosing, Ctrough and Cmax geometric means were 9μg/L (90% CI: 1–71) and 167μg/L (90% CI: 102–276), respectively; AUC0–24h was 1720μg∗h/L (90% CI: 899–3300). Absorption was negligible in one patient with ultra-short (~15cm) bowel. For dabigatran, Cmax ratio was 0.57 (SD 0.33) and Ctrough ratio was 0.35 (SD 0.44). For rivaroxaban, the mean observed-to-reference ratios AUC0–24h and Cmax ratios were 0.73 (SD 0.32) and 0.76 (SD 0.34), respectively. ConclusionsWhile in SBS patients there is some absorption of the oral anticoagulants dabigatran etexilate and rivaroxaban, it appears to be lower than reference values. Plasma drug levels showed significant inter-individual variability.

Non-ionic surfactant based vesicular drug delivery system for topical delivery of caffeine for treatment of cellulite: design, formulation, characterization, histological anti-cellulite activity, and pharmacokinetic evaluation

Cellulite is a common topographical alteration where skin acquires an orange peel or mattress appearance with alterations in adipose tissue and microcirculation. This work aims to develop and evaluate a topical niosomal gel formulae with good permeation to reach the subcutaneous fat layer. Several caffeine niosomal dispersions were prepared and incorporated into gel formulae using Carbopol 940 polymer, chemical penetration enhancers, and iontophoresis, then the prepared gels were applied onto the skin of rats and anticellulite activity of caffeine from the prepared gels compared to that of the commercial product Cellu Destock® was evaluated by histological study of the skin and measurement of plasma level of caffeine passing through the skin using liquid chromatography (LC/MS–MS). Results of histology revealed reduction of size and thickness of fatty layer of rat skin in the following order: FVII > FXIV > Cellu Destock® > FVII + Iontophoresis > FXIV + Iontophoresis. Pharmacokinetic results of caffeine in plasma revealed that Cmax, Tmax, and AUC0–12h decreased in the following order: FXIV > FVII > Cellu Destock®. These results conclude that incorporation of caffeine niosomal dispersion into gel matrix with penetration enhancers and iontophoresis resulted in improvement in penetration of caffeine through the skin into the underlying fatty layer in treatment of cellulite.

Plasma anti-FXa concentration after continuous intravenous infusion and subcutaneous dosing of enoxaparin for thromboprophylaxis in critically ill patients. A randomized clinical trial

IntroductionIn intensive care unit (ICU) patients, subcutaneous low-molecular weight heparin thromboprophylaxis results in lower plasma anti-factor Xa (anti-FXa) levels compared to general ward patients. The aim of this study was to examine whether enoxaparin thromboprophylaxis given as a continuous intravenous infusion (CII) results in more constant and predictable anti-FXa concentration than standard subcutaneous bolus (SCB) administration. Materials and methodsThis was a prospective, single-blind, multicenter, randomized controlled trial where ICU patients requiring thromboprophylaxis received enoxaparin either 40mg as a SCB once daily or 40mg as a CII over 24h for three consecutive days.The primary outcome was maximum serum anti-FXa concentration (Cmax24h) within the first 24h; the secondary outcome was anti-FXa area under the curve (AUC)(0–24h). Trough level was measured at 72h. ResultsThirty-nine patients were included in the intention to treat analysis. The median anti-FXa Cmax24h was 0.05 (interquartile range, IQR, 0.05–0.18) IU/ml in the CII group and 0.18 (IQR, 0.12–0.33) IU/ml in the SCB group (p=0.05). Median anti-FXa AUC(0–24h) was 1.20 (IQR, 0.98–2.88) in the CII and 1.54 (IQR, 1.22–4.12) in the SCB group (p=0.095). After 72h, 66.7% of patients in the CII group had a detectable anti-FXa concentration of >0.1IU/ml, compared with 16.7% in the SCB group (p=0.019). ConclusionsContinuous infusion of enoxaparin led to lower anti-FXa Cmax24h than standard SCB administration. No difference in anti-FXa AUC0–24h was detected.

Schisandra chinensis extract decreases chloroacetaldehyde production in rats and attenuates cyclophosphamide toxicity in liver, kidney and brain

Ethnopharmacological relevanceSchisandra chinensis (Turcz.) Baill (S. chinensis) has been used for thousands years in China, and is usually applied in treatment of urinary tract disorders and liver injury. S. chinensis extract (SCE) has board protective effects on liver, kidney and nervous system. Schisandra lignans are generally considered as the bioactive components of SCE. Aim of the studyTo investigate the pharmacokinetic herb-drug interactions (HDIs) between SCE and cyclophosphamide (CTX). To evaluate the protective effects of SCE against CTX induced damage in rat liver, kidney and brain. Materials and methodsThe pharmacokinetic HDIs between SCE and CTX were investigated by determining plasma concentrations of CTX and three metabolites, namely 4-ketocyclophosphamide (4-Keto), 2-dechloroethylcyclophosphamide (DCCTX) and carboxyphosphamide (CPM) using a previously developed UPLC-MS/MS method. To evaluate the protective effects of SCE pretreatment, toxicity and oxidation stress assessments along with histology investigations were carried out in rat liver, kidney and brain. ResultsThe equimolar produced metabolite DCCTX was chosen to reflect chloroacetaldehyde (CAA, a toxic metabolite of CTX) production in rats. Single-dose pretreatment of SCE significantly reduced CAA production and decreased the Cmax and AUC0–24h of DCCTX by 69% and 49% respectively (P < 0.05). After pretreated with SCE for 7 consecutive days, the Cmax and AUC0–24h of DCCTX were still decreased (−25% and −37%, P < 0.05) when compared with CTX alone group. Parallel toxicity and oxidation stress investigations showed that single-dose SCE pretreatment significantly decreased plasma BUN and Cr levels (−12% and −46%, respectively) and reduced liver AST activity (−32%). Moreover, SCE pretreatment potently increased the brain GSH content by 7.8-fold, and reduced MDA levels in rat liver, kidney and brain by 39%, 28% and 31%, respectively (compared with CTX alone group). The protective effects of SCE were also supported by histological observations. ConclusionOur experiment results suggest that S. chinensis may find use as a complementary medicine in CTX treatment.

Clinical activity, safety and tolerability of ASN002, a dual SYK/JAK inhibitor, in patients non-Hodgkin lymphoma (NHL) and solid tumors.

7545 Background: ASN002 is a novel, potent inhibitor of Spleen Tyrosine Kinase (SYK) and Janus Kinases (JAK). Pre-clinical studies indicate that ASN002 has low nM IC50s against SYK and JAK, decreases proliferation in ibrutinib-resistant cell lines, and suppresses tumor growth in rodent xenograft models of NHL and other hematologic malignancies. Methods: This Phase 1/2 clinical trial in patients with solid tumors and hematologic malignancies evaluates escalating ASN002 oral doses of 10, 20, 30, 40, 50 and’ 75 mg BID and 80 and 120 mg QD mg (NCT02440685). Phase 1 allows patients with solid tumors or hematologic malignancies; Phase 2 allows only patients with diffuse large B-Cell lymphoma (DLBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL). Endpoints include safety, tolerability, pharmacokinetics, serum markers of inflammation, and response using RECIST or Lugano Classification System. Results: Twenty-eight patients have enrolled in the DLT phase at doses of 10 mg – 75 mg BID and at 80 mg QD. All patients had multiple prior lines of treatment (range: 2 – 8). ASN002 was well tolerated. No dose limiting adverse events have been reported at these dose levels. Most drug-related adverse events were Gr 1/2 (e.g. headache, fatigue). Steady-state systemic exposure was high (Cmax, AUC (0-12h) and T1/2 at 40 mg BID were 0.7 µM, 6.3 µM.h and 18 h, respectively). High systemic exposure was also observed at 80 mg QD. Robust reduction of CRP, IL-18, MIP1β, VCAM-1, TNFR2 was observed at all doses. Stable disease (RECIST, 9+ months) in a patient with primary peritoneal cancer, about 50% reduction in target lesions at 3 months in a FL patient (Lugano, 6 prior lines) and stable disease and reduction of pruritus in a peripheral T-Cell lymphoma patient after 2 months (Lugano, 2 prior lines) of treatment were observed. ASN002 treatment continues in both lymphoma patients. Accrual of patients continues. Conclusions: ASN002 was safe and well tolerated. Encouraging preliminary evidence of efficacy in NHL patients was observed. MTD has not been reached and dose escalation continues. Updated and detailed results will be presented. Clinical trial information: NCT02440685.

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial

Aims/hypothesisSemaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed.MethodsIn this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18–64 years) participants with type 2 diabetes (eligibility: HbA1c of 6.5–9.0% (47.5–74.9 mmol/mol); BMI 20.0–35.0 kg/m2; and treatment with diet and exercise and/or metformin monotherapy with a dose unchanged in the 30 days prior to screening) were randomised (1:1) to once-weekly s.c. semaglutide 1.0 mg (0.25, 0.5, 1.0 mg escalated) or placebo for 12 weeks. Co-primary endpoints were changes from baseline to end of treatment in the first (AUC0–10 min) and second (AUC10–120 min) insulin secretion phases, as measured by the IVGTT. An arginine stimulation test (AST) and a 24 h meal stimulation test were also conducted. A graded glucose infusion test (GGIT) assessed insulin secretion rate (ISR) in treated participants and a group of untreated healthy participants. Safety endpoints were also assessed.ResultsIn total, 37 participants received semaglutide and 38 received placebo. Following IVGTT, for insulin, both AUC0−10min and AUC10−120min were significantly increased with semaglutide (estimated treatment ratio [95% CI] 3.02 [2.53, 3.60] and 2.10 [1.86, 2.37], respectively; p < 0.0001). The 24 h meal test showed reduced fasting, postprandial and overall (AUC0–24h) glucose and glucagon responses with semaglutide (p < 0.0001). The AST showed that maximal insulin capacity increased following semaglutide treatment. During GGIT, semaglutide significantly increased ISR to levels similar to those in healthy participants. Semaglutide was well tolerated.Conclusions/interpretationTwelve weeks of once-weekly treatment with semaglutide significantly improved beta cell function and glycaemic control in participants with type 2 diabetes.Trial registration:ClinicalTrials.gov NCT02212067Funding:The study was funded by Novo Nordisk A/S.

Oral fast-dissolving films containing lutein nanocrystals for improved bioavailability: formulation development, in vitro and in vivo evaluation

Lutein is widely used as diet supplement for prevention of age-related macular degeneration. However, the application and efficacy of lutein in food and nutritional products has been hampered due to its poor solubility and low oral bioavailability. This study aimed to develop and evaluate the formulation of oral fast-dissolving film (OFDF) containing lutein nanocrystals for enhanced bioavailability and compliance. Lutein nanocrystals were prepared by anti-solvent precipitation method and then encapsulated into the films by solvent casting method. The formulation of OFDF was optimized by Box-Behnken Design (BBD) as follows: HPMC 2.05% (w/v), PEG 400 1.03% (w/v), Cremophor EL 0.43% (w/v). The obtained films exhibited uniform thickness of 35.64±1.64μm and drug content of 0.230±0.003mg/cm2 and disintegrated rapidly in 29±8s. The nanocrystal-loaded films with reconstituted particle size of 377.9nm showed better folding endurance and faster release rate in vitro than the conventional OFDFs with raw lutein. The microscope images, thermograms, and diffractograms indicated that lutein nanocrystals were highly dispersed into the films. After administrated to SD rats, t max was decreased from 3h for oral solution formulation to less than 0.8h for OFDF formulations, and C max increased from 150ng/mL for solution to 350ng/mL for conventional OFDF or 830ng/mL for nanocrystal OFDF. The AUC 0-24h of conventional or nanocrystal OFDF was 1.37 or 2.08-fold higher than that of the oral solution, respectively. These results suggested that drug nanocrystal-loaded OFDF can be applied as a promising approach for enhanced bioavailability of poor soluble drugs like lutein.

In Vitro Anaerobic Pharmacokinetic/Pharmacodynamic Model to Simulate the Bactericidal Activity of Levornidazole Against Bacteroides fragilis

PurposeThis study was designed to correlate the pharmacokinetic/pharmacodynamic (PK/PD) parameters with PD indices of levornidazole against Bacteroides fragilis and to calculate the PK/PD target value for levornidazole to attain its expected maximal bactericidal effect using an in vitro anaerobic dynamic PK/PD model. MethodsAn anaerobic dynamic PK/PD model was developed in vitro. The scheme for PK modeling was designed according to the PK parameters of levornidazole in the human body. The device of 2-compartment PK/PD model was constructed by using digital control of flow rate to simulate 4 regimens of single-dose intravenous infusion of levornidazole to determine the bactericidal activity of levornidazole against the 3 strains of B fragilis within 72 hours. PD parameters such as reduction of colony count within 24 hours (∆Log24h), area under bactericidal curve (AUBC), and 2-hour initial killing rate (IKR) were calculated and correlated with PK/PD parameters. Sigmoid Emax model of levornidazole was established to calculate PK/PD target values to attain corresponding PD effect. FindingsPK and PD validation proved the stability of the model in simulating levornidazole against B fragilis and the precision and accuracy in the results of PK modeling. Cmax and AUC0–24h found only –1.46% and –6.72% differences from the values in vivo. Our study found that ∆Log24h, AUBC, and IKR were more correlated with AUC0–24h/MIC and Cmax/MIC than with %T>MIC. According to ∆Log24h, the PK/PD target values of AUC0–24h/MIC, Cmax/MIC, and %T>MIC of levornidazole against B fragilis were 157.6%, 14.1%, and 56.4%, respectively. ImplicationsOur findings are useful for optimizing the clinical dosing regimen of levornidazole sodium chloride injection to attain maximal bactericidal effect.

A simple passive equilibration method for loading carboplatin into pre-formed liposomes incubated with ethanol as a temperature dependent permeability enhancer

A passive equilibration method which relies on addition of candidate drugs to pre-formed liposomes is described as an alternative method for preparing liposome encapsulated drugs. The method is simple, rapid and applicable to liposomes prepared with high (45mol%) or low (<20mol%) levels of cholesterol. Passive equilibration is performed in 4-steps: (i) formation of liposomes, (ii) addition of the candidate drug to the liposomes in combination with a permeability enhancing agent, (iii) incubation at a temperature that facilitates diffusion of the added compound across the lipid bilayer, and (iv) quenching the enhanced membrane permeability by reduction in temperature and/or removal of the permeabilization enhancer. The method is fully exemplified here using ethanol as the permeabilization enhancer and carboplatin (CBDCA) as the drug candidate. It is demonstrated that ethanol can be added to liposomes prepared with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and Cholesterol (Chol) (55:45mol ratio) in amounts up to 30% (v/v) with no change in liposome size, even when incubated at temperatures>60°C. Super-saturated solutions of CBDCA (40mg/mL) can be prepared at 70°C and these are stable in the presence of ethanol even when the temperature is reduced to <30°C. maximum CBDCA encapsulation is achieved within 1h after the CBDCA solution is added to pre-formed DSPC/Chol liposomes in the presence of 30% (v/v) ethanol at 60°C. When the pre-formed liposomes are mixed with ethanol (30% v/v) at or below 40°C, the encapsulation efficiency is reduced by an order of magnitude. The method was also applied to liposomes prepared from other compositions include a cholesterol free formulations (containing 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[carboxy(polyethylene glycol)-2000] (DSPE-PEG2000)) and a low Chol (<20mol%) formulations prepared with the distearoyl-sn-glycero-3-phospho-(1′-rac-glycerol) DSPG)). The cytotoxic activity of CBDCA was unaffected when prepared in this manner and two of the resultant formulations exhibited good stability in vitro and in vivo. The cytotoxic activity of CBDCA was unaffected when prepared in this manner and the resultant formulations exhibited good stability in vitro and in vivo. Pharmacokinetics studies in CD-1 mice indicated that the resulting formulations increased the circulation half life of the associated CBDCA significantly (AUC0–24h of CBDCA=0.016μg·hr/mL; AUC0-24h of the DSPC/Chol CBDCA formulation=1014.0μg·hr/mL and AUC0-24h of the DSPC/DSPG/Chol CBDCA formulation=583.96μg·hr/mL). Preliminary efficacy studies in Rag-2M mice with established subcutaneous H1975 and U-251 tumors suggest that the therapeutic activity of CBDCA is improved when administered in liposomal formulations. The encapsulation method described here has not been disclosed previously and will have broad applications to drugs that would normally be encapsulated during liposome manufacturing.