Population pharmacokinetic, pharmacodynamic and efficacy modeling of SB12 (proposed eculizumab biosimilar) and reference eculizumab.

PURPOSE: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. METHODS: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). RESULTS: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. CONCLUSION: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.

Co-Administration of Vonoprazan, Not Tegoprazan, Affects the Pharmacokinetics of Atorvastatin in Healthy Male Subjects.

Potassium-competitive acid blocker is a new class of drugs inhibiting gastric acid. It is controversial that vonoprazan showed the inhibitory activities of cytochrome P450 3A4. This study aimed to evaluate the pharmacokinetics (PK) of atorvastatin and safety when atorvastatin was administered alone and co-administered with vonoprazan or tegoprazan. An open-label, multiple-dose, 3-intervention, 4-sequence, 4-period, partial replicate crossover study was conducted, and three interventions were; one is orally administered atorvastatin 40 mg alone once daily for 7 days, another is atorvastatin co-administered with vonoprazan 20 mg, and the other is atorvastatin co-administered with tegoprazan 50 mg. PK blood samples were collected up to 24 h after the last dose, and PK parameters for atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were estimated by a non-compartmental method. Safety was evaluated, including adverse events and clinical laboratory tests. A total of 28 subjects completed the study. When atorvastatin was co-administered with vonoprazan, the systemic exposures of atorvastatin and atorvastatin lactone significantly increased, and the metabolic ratio of 2-hydroxyatorvastatin significantly decreased. Hypergastrinemia only occurred when atorvastatin was co-administered with vonoprazan. However, the plasma concentration profiles of atorvastatin, 2-hydroxyatorvastatin and atorvastatin lactone were similar when atorvastatin was administered alone or co-administered with tegoprazan. In conclusion, after multiple doses of atorvastatin co-administered with vonoprazan in healthy subjects, the systemic exposure of atorvastatin and the incidence of hypergastrinemia increased. With tegoprazan, however, those interactions were not observed.

Locking Multi-Laser Frequencies to a Precision Wavelength Meter: Application to Cold Atoms.

We herein report a simultaneous frequency stabilization of two 780-nm external cavity diode lasers using a precision wavelength meter (WLM). The laser lock performance is characterized by the Allan deviation measurement in which we find σy=10-12 at an averaging time of 1000 s. We also obtain spectral profiles through a heterodyne spectroscopy, identifying the contribution of white and flicker noises to the laser linewidth. The frequency drift of the WLM is measured to be about 2.0(4) MHz over 36 h. Utilizing the two lasers as a cooling and repumping field, we demonstrate a magneto-optical trap of 87Rb atoms near a high-finesse optical cavity. Our laser stabilization technique operates at broad wavelength range without a radio frequency element.

A first-in-human study of KMRC011, a potential treatment for acute radiation syndrome, to explore tolerability, pharmacokinetics, and pharmacodynamics.

KMRC011 is a novel Toll-like receptor 5 agonist under development as a treatment for acute radiation syndrome (ARS). The aim of this first-in-human study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of a single intramuscular dose of KMRC011 in healthy subjects. A randomized, single-blind, placebo-controlled, single dose-escalation study was conducted with the starting dose of 5 µg. Eight (4 only for 5 µg cohort) subjects per cohort were randomly assigned to KMRC011 or placebo in a 3:1 ratio. Dose-limiting toxicity (DLT) was assessed throughout the study. Serum concentrations of KMRC011, granulocyte colony-stimulating factor (G-CSF), and interleukin-6 (IL-6) were measured up to 48 h postdose. Based on safety review, the dose of KMRC011 escalated up to 20 µg, and consequently, a total of 4 dose levels (5, 10, 15, and 20 µg) were explored. The most common adverse event was injection site reaction, showing no dose-related trend. Three DLTs (2 cases of hepatic enzyme increased and 1 of pyrexia) were observed; 1 in the 15 µg cohort and 2 in the 20 µg cohort. A developed method could not detect any KMRC011 in serum. KMRC011 15 µg and 20 µg showed significant increases of G-CSF, IL-6, and absolute neutrophil counts, compared with the placebo. A single intramuscular administration of KMRC011 ranging from 5 to 15 µg was tolerated in healthy subjects. Doses of KMRC011 equal to or greater than 15 µg exerted TLR5 agonist-like activities by increasing serum G-CSF and IL-6. It suggests that KMRC011 has the potential for a treatment for ARS.

Poly (ADP-Ribose) Polymerase Inhibitor Treatment as a Novel Therapy Attenuating Renal Ischemia-Reperfusion Injury.

Intrarenal robust inflammatory response following ischemia-reperfusion injury (IRI) is a major factor in the pathogenesis of renal injury in ischemic acute kidney injury (AKI). Although numerous studies have investigated various agents of immune modulation or suppression for ischemic AKI, few showed reproducible effects. We hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitor may favorably change post-ischemic intrarenal immunologic micromilieu by reducing damage-associated molecular pattern (DAMP) signals and improve renal outcome in ischemic AKI. The effects of JPI-289 (a PARP inhibitor) on early renal injury in a murine IRI model and hypoxic HK-2 cell model were investigated. Bilateral IRI surgery was performed in three groups of 9-week-old male C57BL/6 mice (control, JPI-289 50 mg/kg, and JPI-289 100 mg/kg; n = 9-10 in each group). Saline or JPI-289 was intraperitoneally injected. Renal function deterioration was significantly attenuated in the JPI-289 treatment groups in a dose-dependent manner. Inflammatory cell infiltration and proinflammatory cytokine/chemokine expressions in the post-ischemic kidneys were also attenuated by JPI-289 treatment. JPI-289 treatment at 0.5 and 0.75 µg/ml facilitated the proliferation of hypoxic HK-2 cells. PARP inhibition with JPI-289 treatment showed favorable effects in ischemic AKI by attenuating intrarenal inflammatory cascade in a murine model and facilitating proliferation of hypoxic HK-2 cells.

Phase I clinical trial of KML001 monotherapy in patients with advanced solid tumors.

BACKGROUND: We evaluated the tolerability, pharmacokinetics (PK) and preliminary efficacy of KML001, an oral trivalent arsenical, as a monotherapy in patients with advanced solid tumors. RESEARCH DESIGN AND METHODS: With a standard 3 + 3 design for dose-escalation stage, the planned dose levels of KML001 were 5, 7.5, 10, 12.5, and 15 mg/day for 28 days. Once the maximum tolerated dose was determined, 22 subjects were additionally enrolled for dose-expansion stage. PK analysis was performed in the 5, 10, and 15 mg/day cohort at the dose-escalation stage and also at the dose-expansion stage. Moreover, response was assessed using the standard RECIST 1.1. RESULTS: A total of 45 Korean subjects were enrolled. No DLT was reported at the dose-escalation stage. Three DLTs, two cases of prolonged QTc interval and one of neutropenia, were reported in the 12.5 mg/day cohort at the dose-expansion stage. Higher total daily doses up to 12.5 mg/day of KML001 resulted in higher trough plasma concentrations. Among the 18 subjects who completed 2 cycles of therapy, 15 had progressive disease and 3 had stable disease. CONCLUSIONS: Doses equal to or greater than 10 mg/day KML001 alone were tolerable and produced plasma concentrations higher than biologically relevant targets.

Photocatalytic degradation of dissolved organic matter under ZnO-catalyzed artificial sunlight irradiation system.

This study investigates the photocatalytic degradation of dissolved organic matter (DOM) under ZnO-assisted artificial sunlight system at various conditions (ZnO dosage, pH, and the presence of Cl-, SO42-, and HCO3-). The results show that the degradation of DOM follows a pseudo-first-order kinetics. Fluorescence excitation-emission matrices coupled with parallel factor (EEM-PARAFAC) analysis decomposes DOM into two fluorophores (C1 and C2). The total removals and photodegradation rates calculated with DOC, UV254, and the Fmax of C1 are similar, increasing with higher ZnO dosages and being highest in pH 7 and lowest in pH 4. ZnO dosage has a similar effect on DOM degradation when assessed using C2, as with C1, but pH effect is not consistent. As for the anions, HCO3- shows the strongest inhibition for DOC, UV254 and C1 while Cl- has the strongest facilitation effect for C2. The total removal and photodegradation rates calculated with the Fmax of C1 and C2 are higher than those calculated using DOC and UV254. This study demonstrates that the successful application of EEM-PARAFAC analysis in addition to traditional parameters can provide further insight into the photocatalytic degradation mechanisms associated with DOM in conjunction with a ZnO catalyst under artificial sunlight.

Pharmacokinetic and Safety Profiles of a Fixed-Dose Combination of Amlodipine, Valsartan, and Atorvastatin: A 3-Period Replicate Crossover Study.

The objective of study was to compare the pharmacokinetic and safety profiles of a fixed-dose combination (FDC) formulation of 5/160/20 mg amlodipine/valsartan/atorvastatin with those of separate formulations of a 5/160-mg amlodipine/valsartan tablet and a 20-mg atorvastatin tablet. This was a randomized, open-label, single-dose, 3-sequence, 3-period replicate crossover study with 42 subjects. Serial blood samples for pharmacokinetic assessment were collected up to 72 hours postdose. For establishing bioequivalence (BE) for amlodipine, valsartan, and atorvastatin, a reference-scaled average BE approach was used if applicable, as well as the conventional limit of 0.80-1.25. The 90% confidence intervals (CIs) for the geometric mean ratios (GMRs) for the maximum plasma concentration (Cmax ) and the area under the curve to the last measurable concentration (AUCt ) between the FDC and separate formulations were within the 0.80-1.25 limit for all analytes but atorvastatin. The estimated within-subject standard deviation of the log-transformed values of the separate formulations, the reference intervention, was 0.3804 for the Cmax of atorvastatin, being set at 0.7489-1.3352 for the BE acceptance limit. For both the Cmax and AUCt for atorvastatin, the GMRs lay within 0.80-1.25, and the 90%CIs for the GMRs were within the BE acceptance limit. This 3-period replicate crossover study demonstrated the BE of the FDC formulation of amlodipine, valsartan, and atorvastatin and the separate formulations of an amlodipine/valsartan tablet and an atorvastatin tablet. A similar incidence of treatment-emergent adverse events (TEAEs) was observed in both interventions, and headache was the most common TEAE.

Do All ASPECT Score Regions have the Same Predictive Power for Functional Outcomes?

BACKGROUND AND PURPOSE: ASPECTS (Alberta Stroke Program Early CT Score) is a 10-point topographic CT scan score that has been shown to be a strong prognostic factor in acute ischemic stroke. We investigated whether all ASPECTS regions have the same prognostic value. METHODS: Clinical characteristics, ASPECTS, and 3-month modified Rankin Scale (mRS) data were retrospectively collected in 350 patients who were diagnosed with middle cerebral artery (MCA) territory stroke. To describe the 3-month mRS data, an ordered categorical approach was applied using a proportional odds model. Furthermore, external validation was performed using additional data from 30 patients. RESULTS: As expected, ASPECTS was an independently important predictor. However, when 10 regions were analyzed separately, the M1, M2, and M3 regions, related to MCA cortex, were not found to predict 3-month mRS scores in the final model. The odds ratios for ischemic change in other regions (except M1, M2, and M3) ranged from 2.6 to 3.8. Moreover, among clinical characteristics, only age was identified as a significant predictor. The sensitivity and specificity of the final model in the external validation were 91% and 88%, respectively. CONCLUSIONS: All ASPECTS regions did not have the same predictive power for functional outcomes, defined as the 3-month mRS. The implementation of a proportional odds model allowed a proper description of the ordered categorical nature of the mRS and the identification of relevant predictors.

Effects of Celecoxib on the QTc Interval: A Thorough QT/QTc Study.

PURPOSE: Celecoxib is a selective cyclooxygenase-2 inhibitor widely used in patients with osteoarthritis and rheumatoid arthritis. Recently, nonclinical data on the inhibition of human ether-à-go-go-related gene potassium channels by celecoxib were reported, but there is no compelling evidence for this finding in humans. The aim of this study was to assess the potential effects of celecoxib on cardiac repolarization by conducting a thorough QT study, which was designed in compliance with the related guidelines. METHODS: This randomized, open-label, positive- and negative-controlled, crossover clinical study was conducted in healthy male and female subjects. Each subject received, in 1 of 4 randomly assigned sequences, all of the following 3 interventions: celecoxib 400 mg once daily for 6 days; a single dose of moxifloxacin 400 mg, which served as a positive control to assess the assay sensitivity; and water without any drug, which served as a negative control. Serial 12-lead ECG and blood samples for pharmacokinetic analysis were collected periodically over 24 h. Individually RR-corrected QT intervals (QTcI) and Fridericia method-corrected QT intervals (QTcF) were calculated and evaluated. FINDINGS: Twenty-eight subjects were allocated to 1 of the 4 intervention sequences. The largest time-matched mean effects of celecoxib on the QTcI and QTcF were <5 ms, and the upper bounds of the 1-sided 95% CIs of those values did not exceed 10 ms. Moreover, none of the subjects had an absolute QTcI value of >450 ms or a change from baseline in QTcI of >60 ms after multiple administrations of celecoxib. The QTcI did not show a positive correlation with celecoxib concentrations in the range up to ~2700 µg/L. The overall effects of moxifloxacin on the QTcI and QTcF were enough to establish assay sensitivity. No serious adverse events were reported, with a total of 11 AEs reported in 8 subjects. IMPLICATIONS: Celecoxib caused no clinically relevant increase in the QT/QTc interval at the maximum dose level used in current practice settings. ClinicalTrials.gov identifier: NCT03822520.

Effect of Cilostazol on the Pharmacokinetics of Simvastatin in Healthy Subjects.

PURPOSE: We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. METHODS: An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. RESULTS: The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. CONCLUSIONS: Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.

Effect of surgical approach for contralateral side hip arthroplasty in below knee amputees: a retrospective cohort study.

BACKGROUND: The gluteus medius muscle plays a very important role in the stability of the gait, especially in patients with amputation of the lower limbs. Therefore, choosing the appropriate type of approach for hip arthroplasty is very important. Hence, this study aimed to compare the outcomes and complications between the anterolateral approach (ALA) and posterior approach (PA) for hip arthroplasty in patients with contralateral below knee amputation. METHODS: From January 1999 to November 2014, 67 patients who underwent hip arthroplasty with contralateral below knee amputation were retrospectively analyzed. The study subjects were divided into two groups: the PA group (33 cases) and the ALA group (34 cases). The results of the clinical functional recovery with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Harris Hip Score, and activity of daily living scale were compared between the two groups. During the follow-up period, complications related to gait such as fall, dislocation, and periprosthetic fractures (PPFs) were investigated. RESULTS: The Harris Hip Score (p = 0.024) and the activity of the daily living scale (p = 0.043) of the ALA group were significantly lower at 3 months compared to the PA group, but no significant difference was observed between the two groups from 6 months postoperatively to the last follow-up. The WOMAC score was not significantly different between the two groups. Within 3 months after surgery, falls occurred in 3 cases in the PA group and in 11 cases in the ALA group (p = 0.019) Dislocation and PPF were caused by prosthesis-related trauma. Two dislocations and 1 PPF occurred 8 years postoperatively in the PA group. PPF occurred in 3 patients in the ALA group, of which 2 occurred within 3 months after surgery. CONCLUSION: Orthopedic surgeons should pay particular attention in patients with hip arthroplasty on the contralateral side hip who had below knee amputation because functional recovery is delayed until 3 months after ALA compared with PA.

Non-compartmental data analysis using SimBiology and MATLAB.

MATLAB® is widely used for numerical analysis, modeling, and simulation. One of MATLAB's tools, SimBiology®, is often used for pharmacokinetic, pharmacodynamic model and dynamic systems; however, SimBiology seems to be rarely used for non-compartmental analysis (NCA), and the published official documentation provides a poor description of the analysis algorithm for NCA. Therefore, we conducted NCAs with a hypothetical dataset and some scenarios and compared the results. According to the results of this study, SimBiology estimates parameters using the unweighted linear regression for the terminal slope and linear interpolation method. Moreover, although the documentation describing the actual analysis algorithm used to process non-numeric data is not easily accessible to users, users may introduce numeric data at time zero to perform NCA properly. Using the command window, users can perform analyses more quickly and effectively. If the NCA official documentation were improved, SimBiology might be more widely adopted to perform NCA in clinical pharmacology.

Comparison of the Pharmacokinetic-Pharmacodynamic Relationships of Two Darbepoetin Alfa Formulations in Healthy Male Volunteers.

OBJECTIVE: This study compared the pharmacokinetic (PK), pharmacodynamic (PD), and safety properties of the test (CJ-40001) and reference (NESP®) versions of darbepoetin alfa following a single subcutaneous (SC) or intravenous (IV) administration in healthy male subjects. METHODS: A single-blind, randomized, single-dose, two-period, two-intervention crossover study was conducted, with two separate parts consisting of SC or IV administration. In each period, either a test or reference product was administered via the SC or IV route. Serial blood samples for PK analysis and the reticulocyte, hematocrit, hemoglobin, and red blood cell counts for PD analysis were collected for up to 360 or 264 h after SC or IV administration, respectively. The PK and PD parameters were calculated using non-compartmental methods. The 90% confidence intervals of the geometric mean ratios for the PK and PD parameters between the two interventions were estimated. Safety and anti-drug antibody profile assessments were performed. RESULTS: The mean darbepoetin alfa concentration-time profiles were comparable between the two products for SC and IV administration. Additionally, the PD and safety profiles were similar between the two products. Anti-drug antibody reactivity was negative for all samples from both intervention groups for SC and IV administration. The time-matched serum darbepoetin alfa concentration and the PD markers presented a counter-clockwise hysteresis, which suggests a time delay between the exposure and response. CONCLUSION: The test and reference darbepoetin alfa formulations had similar PK, PD, and safety profiles. Thus, it is expected that the two formulations are able to be used interchangeably in clinical settings. ClinicalTrials.gov Identifier: NCT03542916.

No pharmacokinetic interactions between candesartan and amlodipine following multiple oral administrations in healthy subjects.

PURPOSE: To evaluate the pharmacokinetics and pharmacodynamics of candesartan and amlodipine in the absence and presence of each other in healthy subjects. METHODS: This study consisted of two parts: part 1, the effect of amlodipine on candesartan; part 2, the effect of candesartan on amlodipine. Each part was designed as a randomized, open-label, two-sequence, two-period, two-intervention crossover study with 20 subjects and performed separately in different populations. Pharmacokinetic assessments were performed over 48 hours for candesartan in part 1 and 72 hours for amlodipine in part 2 after drug administration on Day 10. Safety data included the results of physical examinations, clinical laboratory tests, vital signs, an electrocardiogram, and adverse events. RESULTS: For both candesartan and amlodipine, the 90% confidence intervals for the geometric mean ratios of area under the concentration-time curve from time zero to the time of dosing interval of 24 hours and maximum concentration after drug administration fell within the bioequivalence acceptance criteria. Although this study was conducted in normotensive subjects, blood pressure lowering effects were observed in all intervention groups and co-administration of candesartan and amlodipine reduced blood pressure more than amlodipine alone, but similar to candesartan alone. No serious adverse event was reported throughout the study, and all treatment emergent adverse events were mild to moderate in severity and were recovered without sequelae. CONCLUSION: Co-administration of candesartan and amlodipine did not change the systemic exposure of each drug alone in healthy subjects. The administration of candesartan 32 mg alone, amlodipine 10 mg alone, and co-administration of candesartan and amlodipine were well tolerated during the study.

Mid-to long-term results of total hip arthroplasty after contralateral lower extremity amputation.

OBJECTIVE: There is limited literature concerning the outcomes and role of THA as a surgical option for amputee patients. The aim of this study is to determine the mid-to long-term survival and complication rates of cementless total hip arthroplasty (THA) in patients with contralateral below knee amputations. METHODS: A retrospective review of 54 patients with below knee amputation were perfomed who underwent THA for osteoarthritis of the contralateral hip over a 5-year period between 1999 and 2014. Patients were monitored for at least 5 years and assessed with the Harris Hip Score and activities of daily living scale and by evaluating migration or osteolysis around the acetabular cup and femoral stems (amputee group). The amputee group was compared with a control group (non-amputee group) with the same number of patients. RESULTS: Differences in the Harris Hip Score (p = 0.021) and activities of daily living scale (p = 0.043) between the two groups were statistically significant lower in the amputee group at 3 months after surgery. However, no differences were found between the groups from 6 months postoperatively to the last follow-up (Harris Hip Score p = 0.812, activities of daily living scale p = 0.885). Radiologically, any cups or stems showed no signs of migration or osteolysis. In the amputee group, dislocation was found in 1 patient 2 months after arthroplasty (p = 0.315) and long stem revision surgery were performed on two patients due to periprosthetic fracture (p = 0.153). CONCLUSIONS: THA performed on the contralateral side of patients with below knee amputation is considered to be an effective treatment with good clinical and radiological results at mid-to long-term follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Comparison of the pharmacokinetics and tolerability of montelukast/levocetirizine administered as a fixed-dose combination and as separate tablets.

OBJECTIVE: A novel fixed-dose combination (FDC) capsule of 10/5 mg of montelukast/levocetirizine may lead to better compliance than two separate tablets taken together. The aim of this study was to evaluate the pharmacokinetics (PK) and tolerability of an FDC of montelukast and levocetirizine compared to separate tablets. MATERIALS AND METHODS: A randomized, open-label, single-dose, two-sequence, two-period, crossover study was conducted with healthy male subjects. In each period, either an FDC or separate tablets were administered orally, and serial blood samples were collected for PK analysis for up to 34 hours after dosing. PK parameters were calculated using noncompartmental methods. The 90% confidence intervals (CIs) of the geometric mean ratios (GMRs) of the maximum plasma concentration (Cmax) and the area under the curve to the last measurable concentration (AUClast) for the two interventions were estimated. Tolerability assessments were performed for all the subjects who received the drug at least once. RESULTS: The PK profiles of the two interventions were comparable. For montelukast, the GMRs and 90% CIs for the Cmax and AUClast were 0.9800 (0.8903 - 1.0787) and 1.0706 (0.9968 - 1.1498), respectively. The corresponding values for levocetirizine were 0.9195 (0.8660 - 0.9763) and 1.0375 (1.0123 - 1.0634), respectively. Both interventions were well tolerated. CONCLUSION: The PK and tolerability profiles of montelukast and levocetirizine after a single oral administration were comparable between the FDC and separate tablets. For patients with allergic rhinitis who require a combination treatment, the FDC of montelukast and levocetirizine will be a convenient therapeutic option.
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Biomechanical Evaluation of Glenoid Version and Dislocation Direction on the Influence of Anterior Shoulder Instability and Development of Hill-Sachs Lesions.

BACKGROUND: Abnormal glenoid version is a risk factor for shoulder instability. However, the degree to which the variance in version (both anteversion and retroversion) affects one's predisposition for instability is not well understood. PURPOSE: To determine the influence of glenoid version on anterior shoulder joint stability and to determine if the direction of the humeral head dislocation is a stimulus for the development of Hill-Sachs lesions. STUDY DESIGN: Controlled laboratory study. METHODS: Ten human cadaveric shoulders (mean age, 59.4 ± 4.3 years) were tested using a custom shoulder dislocation device placed in a position of apprehension (90° of abduction with 90° of external rotation). Glenoid version was adjusted in 5° increments for a total of 6 version angles tested: +10°, +5°, 0°, -5°, -10°, and -15° (anteversion angles are positive, and retroversion angles are negative). Two humeral dislocation directions were tested. The first direction was true anterior through the anterior-posterior glenoid axis. The second dislocation direction was 35° inferior from the anterior-posterior glenoid axis based on the deforming force role of the pectoralis major. The force and energy to dislocate were recorded. RESULTS: Changes in glenoid version manifested a linear effect on the dislocation force. The energy to dislocate increased as a second-order polynomial as a function of increasing glenoid retroversion. Glenoid version of +10° anteversion and -15° retroversion was highly unstable, resulting in spontaneous dislocation in one-quarter (10/40) and one-half (25/40) of the specimens anteriorly and posteriorly, respectively, in the absence of an applied dislocation force. The greater tuberosity was observed to engage with the anterior glenoid rim, consistent with Hill-Sachs lesions, 40% more frequently when the dislocation direction was true anterior compared with 35° inferior from the anterior-posterior glenoid axis. The engagement of the greater tuberosity caused an increase in the energy required to dislocate. CONCLUSION: Glenoid version has a direct effect on the force required for a dislocation. An anterior-inferior dislocation direction requires less energy for a dislocation and results in a lower risk of the development of a Hill-Sachs lesion than a direct anterior dislocation direction. CLINICAL RELEVANCE: Consideration should be given to glenoid version when choosing a surgical treatment option for anterior shoulder instability.

RhBMP-2 Activates Hippo Signaling through RASSF1 in Esophageal Cancer Cells.

Despite that recombinant human bone morphogenetic protein-2 (rhBMP-2) has been reported as a stimulatory effecter of cancer cell growth because of its characteristic like morphogen, the biological functions of rhBMP-2 in human esophageal cancer cells are unknown. The purpose of this study was to investigate whether rhBMP-2 has an inhibitory effect on the growth of human esophageal squamous carcinoma cells (ESCC). RhBMP-2 significantly inhibited proliferation of ESCC cells in a dose-dependent manner in the MTT assay. Cell cycle arrest at the G1 phase was induced 24 h after rhBMP2 treatment. RhBMP-2 also reduced cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK 6 activities, and stimulated p-Smad1/5/8, p53, and p21 levels at 12 h. In contrast, rhBMP-2 diminished poly (ADP-ribose) polymerase (PARP) protein expression levels and activated cleaved PARP, cleaved caspase-7, and cleaved-caspase 9 levels in ESCC cells. In addition, rhBMP-2 increased MST1, MOB1, and p-YAP protein levels and the RASSF1 binds Mst1 more upon treatment with rhBMP2. The induced p-YAP expression in TE-8 and TE-12 cells by rhBMP-2 was reversed by the RASSF1 knockdown. In vivo study, rhBMP-2 decreased tumor volume following subcutaneous implantation and showed higher radiologic score (less bony destruction) after femoral implantation compared to those in a control group. These results suggest that rhBMP-2 inhibits rather than activates proliferation of human esophageal cancer cells which is mediated through activating the hippo signaling pathway.

Evaluation of Titanium-Coated Pedicle Screws: In Vivo Porcine Lumbar Spine Model.

OBJECTIVE: Many studies have addressed the problem of loosening pedicle screws in spinal surgery, which is a serious concern. Titanium coating of medical implants (arthroplasty) is common, but few studies involving in vivo spine models have been reported. We evaluated the radiological, mechanical, and histological characteristics of titanium-coated pedicle screws compared with uncoated or hydroxyapatite-coated pedicle screws. METHODS: Three different types of pedicle screws, i.e., uncoated, hydroxyapatite-coated, and titanium-coated, were implanted into the lumbar 3-4-5 levels of 9 mature miniature pigs. Radiological evaluation of loosening of pedicle screws was performed. Peak torsional extraction torque was tested in the 42 screws from 7 miniature pigs at 12 weeks postoperatively. The implant-bone interface of the remaining 12 pedicle screws from 2 miniature pigs in each group was assessed by micro-computed tomography and histologic studies. RESULTS: The incidence of loosening at 12 weeks postoperatively was not significantly different between the titanium-coated pedicle screw group and the other groups. The titanium-coated pedicle screw group exhibited the greatest mean extraction torsional peak torque at 12 weeks postoperatively (P < 0.05). Quantitative micro-computed tomography data were greatest in the titanium-coated pedicle screw group (P < 0.05). Histologic findings showed osteointegration with densely packed new bone formation at the screw coating-bone interface in the titanium-coated pedicle screw group. CONCLUSIONS: Fixation strength was greatest in the titanium-coated pedicle screw group. Osteointegration at the interface between the titanium-coated implant and bone produced prominent and firm bonding. The titanium-coated pedicle screw is a promising device for application in spinal surgery.