Using the consolidated framework for implementation research to guide a pilot of implementing an institution level patient informed consent process for clinical research at an outpatient setting.

BACKGROUND: In Singapore, research teams seek informed patient consent on an ad hoc basis for specific clinical studies and there is typically a role separation between operational and research staff. With the enactment of the Human Biomedical Research Act, there is increased emphasis on compliance with consent-taking processes and research documentation. To optimize resource use and facilitate long-term research sustainability at our institution, this study aimed to design and pilot an institution level informed consent workflow (the "intervention") that is integrated with clinic operations. METHODS: We used the Consolidated Framework for Implementation Research (CFIR) as the underpinning theoretical framework and conducted the study in three stages: Stage 1, CFIR constructs were used to systematically identify barriers and facilitators of intervention implementation, and a simple time-and-motion study of the patient journey was used to inform the design of the intervention; Stage 2, implementation strategies were selected and mapped to the Expert Recommendations for Implementing Change (ERIC) taxonomy; Stage 3, we piloted and adapted the implementation process at two outpatient clinics and evaluated implementation effectiveness through patient participation rates. RESULTS: We identified 15 relevant CFIR constructs. Implementation strategies selected to address these constructs were targeted at three groups of stakeholders: institution leadership (develop relationships, involve executive boards, identify and prepare champions), clinic management team (develop relationships, identify and prepare champions, obtain support and commitment, educate stakeholders), and clinic operations staff (develop relationships, assess readiness, conduct training, cyclical tests of change, model and simulate change, capture and share local knowledge, obtain and use feedback). Time-and-motion study in clinics identified the pre-consultation timepoint as the most appropriate for the intervention. The implementation process was adapted according to clinic operations staff and service needs. At the conclusion of the pilot, 78.3% of eligible patients provided institution level informed consent via the integrated workflow implemented. CONCLUSIONS: Our findings support the feasibility of implementing an institution level informed consent workflow that integrates with service operations at the outpatient setting to optimize healthcare resources for research. The CFIR provided a useful framework to identify barriers and facilitators in the design of the intervention and its implementation process.

High-Value, Cost-Conscious Care: Iterative Systems-Based Interventions to Reduce Unnecessary Laboratory Testing.

BACKGROUND: Inappropriate testing contributes to soaring healthcare costs within the United States, and teaching hospitals are vulnerable to providing care largely for academic development. Via its "Choosing Wisely" campaign, the American Board of Internal Medicine recommends avoiding repetitive testing for stable inpatients. We designed systems-based interventions to reduce laboratory orders for patients admitted to the wards at an academic facility. METHODS: We identified the computer-based order entry system as an appropriate target for sustainable intervention. The admission order set had allowed multiple routine tests to be ordered repetitively each day. Our iterative study included interventions on the automated order set and cost displays at order entry. The primary outcome was number of routine tests controlled for inpatient days compared with the preceding year. Secondary outcomes included cost savings, delays in care, and adverse events. RESULTS: Data were collected over a 2-month period following interventions in sequential years and compared with the year prior. The first intervention led to 0.97 fewer laboratory tests per inpatient day (19.4%). The second intervention led to sustained reduction, although by less of a margin than order set modifications alone (15.3%). When extrapolating the results utilizing fees from the Centers for Medicare and Medicaid Services, there was a cost savings of $290,000 over 2 years. Qualitative survey data did not suggest an increase in care delays or near-miss events. CONCLUSIONS: This series of interventions targeting unnecessary testing demonstrated a sustained reduction in the number of routine tests ordered, without adverse effects on clinical care.

The evaluation of a scoring system in airway management after oral cancer surgery.

BACKGROUND: The purpose of this retrospective study was to investigate the usefulness of tracheostomy scoring system in the decision of postoperative airway management in oral cancer patients. MATERIALS AND METHODS: A total of 104 patients were reviewed in this retrospective study, who underwent radical resection with or without neck dissection and free flap reconstruction due to oral cancer. The patients were classified into three groups according to the timing of the extubation; extubated groups (n = 51), overnight intubation group (n = 45), and tracheostomy group (n = 8). Cameron's score was used to evaluate the relation between the state of the patient's airway and the type of the operation. RESULTS: Tracheostomy was performed in eight patients (8/104, 7.7 %). A total of 22 patients (21.2 %) had more than 5 points of which 17 patients (77.3 %) did not have a tracheostomy and any postoperative emergency airway problems. The tracheostomy scores were significantly different among the three groups. Hospital stay showed a significant correlation with the tracheostomy score. CONCLUSIONS: The scoring system did not quite agree with the airway management of the authors' clinic; however, it can be one of the clinical factors predicting the degree of the postoperative airway obstruction and surgical aggressiveness for recovery. The further studies are needed for clinically more reliable scoring systems.

Pharmacokinetic Interaction Between Amlodipine and Lobeglitazone, a Novel Peroxisome Proliferator-activated Receptor-γ Agonist, in Healthy Subjects.

PURPOSE: Lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, was developed for the treatment of diabetes mellitus. Because the prevalence of hypertension is high among patients with diabetes mellitus, lobeglitazone is likely to be used with the antihypertensive drug amlodipine. We evaluated the pharmacokinetic interactions between lobeglitazone and amlodipine in healthy male Korean subjects. METHODS: The study used a randomized, open-label, multiple-dose, 3-treatment, 3-period, 6-sequence crossover design. A total of 24 healthy subjects were enrolled. Blood samples for pharmacokinetic analysis were collected according to a planned schedule after 0.5 mg of lobeglitazone and 10 mg of amlodipine were administered alone or concomitantly once per day for 10 days. FINDINGS: A total of 24 healthy male subjects participated in the study (mean [SD] age, 26.6 [3.9] years; weight, 67.8 [5.7] kg; and height, 173.6 [6.4] cm). Three participants voluntarily withdrew after the second period, and 1 participant dropped out because of increased creatinine kinase levels caused by strenuous exercise before the start of the third period. Thus, 21 participants completed the study schedule to compare the pharmacokinetic parameters of lobeglitazone, and 22 participants completed the study of amlodipine. The geometric mean ratio (with 90% CIs) of Cmax,ss and AUCτ,ss for lobeglitazone administered concomitantly with amlodipine versus lobeglitazone administered alone was 1.01 (0.93-1.09) and 1.06 (0.92-1.23), respectively. The geometric mean ratio (with 90% CIs) of Cmax,ss and AUCτ,ss for amlodipine administered concomitantly with lobeglitazone versus amlodipine administered alone was 0.98 (0.94-1.02) and 1.00 (0.96-1.05). No serious drug-induced adverse events were reported in the study, and no clinically significant changes in vital signs, physical examination results, clinical laboratory results, or ECGs were noted. IMPLICATIONS: The coadministration of lobeglitazone and amlodipine did not affect the pharmacokinetics of lobeglitazone or amlodipine in these healthy male Korean subjects. ClinicalTrials.gov identifier: NCT01341392.

Dose proportionality and pharmacokinetics of carvedilol sustained-release formulation: a single dose-ascending 10-sequence incomplete block study.

BACKGROUND: Carvedilol is a third-generation ß-blocker indicated for congestive heart failure and high blood pressure. The aim of this study was to investigate the dose proportionality of the carvedilol sustained-release (SR) formulation in healthy male subjects. METHODS: An open-label, single dose-ascending, 10-sequence, 3-period balanced incomplete block study was performed using healthy male subjects. In varying sequences, each subject received three of five carvedilol SR formulations (8, 16, 32, 64, or 128 mg once). The treatment periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 h after dosing. The plasma concentrations of carvedilol were determined by using validated liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters including the area under the plasma concentration-time curve (AUC) from time 0 to the last measurable time (AUClast), AUC extrapolated to infinity (AUCinf), and the measured peak plasma concentration (C max) were obtained by noncompartmental analysis. Dose proportionality was evaluated if the ln-ln plots of AUClast, AUCinf, and C max versus dose were linear and the 90% confidence intervals (CIs) of the slopes were within 0.9195 and 1.0805. Tolerability was assessed by vital signs, electrocardiogram, clinical laboratory tests, and monitoring of adverse events (AEs) throughout the study. RESULTS: A total of 31 subjects were enrolled, and 30 completed the study. The assessment of dose proportionality meets the statistical criteria; the point estimates of slope were 1.0104 (90% CI: 0.9849-1.0359) for AUClast, 1.0003 (90% CI: 0.9748-1.0258) for AUCinf, and 0.9901 (90% CI: 0.9524-1.0277) for C max, respectively. All AEs were mild, and none of the subjects dropped out due to AEs. CONCLUSION: In this study, exposure to carvedilol was proportional over the therapeutic dose range of 8-128 mg. The carvedilol SR formulation was well tolerated.

Lack of the effect of lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, on the pharmacokinetics and pharmacodynamics of warfarin.

AIMS: Lobeglitazone has been developed for the treatment of type 2 diabetes mellitus. This study was conducted to evaluate potential drug-drug interactions between lobeglitazone and warfarin, an anticoagulant with a narrow therapeutic index. METHODS: In this open-label, three-treatment, crossover study, 24 healthy male subjects were administered lobeglitazone (0.5 mg) for 1-12 days with warfarin (25 mg) on day 5 in one period. After a washout interval, subjects were administered warfarin (25 mg) alone in the other period. Pharmacokinetics of R- and S-warfarin and lobeglitazone, as well as pharmacodynamics of warfarin, as measured by international normalized ratio (INR) and factor VII activity, were assessed. RESULTS: The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for area under the curve from time zero to the time of the last quantifiable concentration (AUClast) for warfarin + lobeglitazone: warfarin alone were 1.0076 (90% CI: 0.9771, 1.0391) for R-warfarin and 0.9880 (90% CI: 0.9537, 1.0235) for S-warfarin. The maximum observed plasma concentration (C max) values were 1.0167 (90% CI: 0.9507, 1.0872) for R-warfarin and 1.0028 (90% CI: 0.9518, 1.0992) for S-warfarin, both of which were contained in the interval 0.80-1.25. Lobeglitazone had no effect on the area under the effect-time curve from time 0 to 168 hours (AUEC) of INR and factor VII activity, as demonstrated by the GMRs of 1.0091 (90% CI: 0.9872, 1.0314) and 0.9355 (90% CI: 0.9028, 0.9695), respectively. In addition, the pharmacokinetics of lobeglitazone was also unaffected by warfarin. CONCLUSION: Concomitant administration of lobeglitazone and warfarin was well tolerated. Lobeglitazone had no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin. These findings indicate that lobeglitazone and warfarin can be coadministered without dosage adjustments for either drug.

Effect of ketoconazole on lobeglitazone pharmacokinetics in Korean volunteers.

PURPOSE: Lobeglitazone, a peroxisome proliferator-activated receptor-γ agonist, is metabolized primarily by the cytochrome P450 (CYP) 3A4 isoenzyme. Individuals concomitantly taking lobeglitazone and a CYP3A4 inhibitor may experience some adverse effects secondary to increased systemic exposure to lobeglitazone. To address such potential concern, we evaluated the effects of ketoconazole, a prototypic CYP3A4 inhibitor, on the pharmacokinetic (PK) properties and associated adverse effects of lobeglitazone. METHODS: A PK drug-drug interaction study was conducted in healthy individuals between 20 and 45 years old in a randomized, open-label, 2-way crossover design. Even though the PK study was performed on a single dose of lobeglitazone, multiple ketoconazole doses were given to ensure that the full extent of inhibition of CYP3A4 was maintained during the PK sampling. All study participants received a single oral dose of lobeglitazone 0.5 mg with or without 9 oral 200-mg doses of ketoconazole pretreatment twice daily. The primary PK parameter end points (AUC and Cmax) were estimated using noncompartmental analysis, and the 90% CIs for the geometric mean ratios (ratio of lobeglitazone and ketoconazole to lobeglitazone alone) were investigated. Tolerability (adverse events, vital signs, ECG, and laboratory tests) was also assessed. FINDINGS: A total of 24 Korean men (mean age, 26 years; age range, 20-32 years; mean weight, 68 kg; weight range, 59-81 kg) completed the study and were evaluable for lobeglitazone PK properties and tolerability. The mean (SD) Cmax values of lobeglitazone with and without ketoconazole were 49 (7) ng/mL and 48 (6) ng/mL at 1.5 and 1.0 hours after dosing, respectively. The mean (SD) AUC∞ values were 532 (117) ng·h/mL and 405 (110) ng·h/mL, respectively. Although the Cmax was not significantly affected, the geometric mean ratio for AUC∞ was increased by a point estimate of 1.33 (90% CI, 1.23-1.44). A single oral administration of lobeglitazone 0.5 mg with or without ketoconazole pretreatment did not produce any clinically significant adverse effects on vital signs, 12-lead ECG profiles, or laboratory tests. IMPLICATIONS: The administration of lobeglitazone, 0.5 mg alone or in combination with multiple doses of ketoconazole, was generally well tolerated. The systemic exposure of lobeglitazone was increased to a modest extent by pretreatment with 9 twice-daily doses of ketoconazole. Clinicaltrials.gov identifier: NCT01330563.

Tolerability and pharmacokinetics of lobeglitazone, a novel peroxisome proliferator-activated receptor-γ agonist, after a single oral administration in healthy female subjects.

BACKGROUND AND OBJECTIVES: Lobeglitazone is a recently approved peroxisome proliferator-activated receptor-γ agonist for the treatment of type 2 diabetes mellitus in Korea. The purpose of this study was to investigate the pharmaco kinetic properties of lobeglitazone in healthy females and to compare these with historical data in healthy males. METHODS: This study was designed as a block-randomized, double-blind, placebo-controlled, parallel-group study. A single 2 or 4 mg oral dose of lobeglitazone or a placebo was randomly administered to 22 female subjects, and pharmacokinetic blood samples were obtained after dosing. Pharmacokinetic parameters were calculated by a non-compartmental method, and the results were compared with those previously obtained from male subjects. Tolerability was assessed by clinical and laboratory parameters. RESULTS: During the study, a total of 28 adverse events (AEs) were observed in the lobeglitazone group (n = 16) and nine AEs in the placebo group (n = 6). Serious AEs or significant clinical changes were not observed. After oral administration, lobeglitazone was rapidly absorbed with the time to maximum plasma concentration (t(max)) ranging from 0.5 to 4.0 h. The mean (standard deviation) maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to infinity (AUC(∞)) for the 2 mg dose were 214.8 (56.4) µg/L and 2,251.3 (721.2) µg·h/L, respectively, and the corresponding values for the 4 mg dose were 310.0 (47.8) µg/L and 6,942.6 (1,778.9) µg·h/L, respectively. The ratios (95 % CIs) for the geometric means (female/male) of the C(max) and AUC∞ were 1.23 (0.89-1.69) and 1.11 (0.73-1.68), respectively (2 mg), and 1.28 (1.01-1.63) and 2.36 (1.60-3.47), respectively (4 mg). CONCLUSION: Lobeglitazone was well-tolerated in healthy females. There was no sex difference for systemic lobeglitazone exposure at a 2 mg dose; however, female subjects showed greater systemic exposure than males after the administration of 4 mg of lobeglitazone. In spite of the pharmacokinetic difference, dose adjustment based on sex alone is not needed in clinical use because therapy should be individualized for each patient to achieve glycemic control.

Stability of mandibular setback surgery with and without presurgical orthodontics.

PURPOSE: The purpose of this study was to compare stability after mandibular setback surgery in patients with skeletal Class III malocclusion with and without presurgical orthodontics. MATERIALS AND METHODS: This retrospective cohort study included consecutive patients with skeletal Class III malocclusion who underwent only mandibular surgery. Patients treated with the surgery-first approach without presurgical orthodontics (SF group) were compared with a control group (conventional surgery with presurgical orthodontics; CS group) using lateral cephalograms taken preoperatively, immediately postoperatively, and at the time of debonding. Predictor variables (group and timing), outcome variables (cephalometric measurements over time), and other variables, such as baseline characteristics, were evaluated to determine the difference in stability of mandibular positions such as the B point. RESULTS: Sixty-one patients were enrolled in this study (CS group, n = 38; SF group, n = 23). Baseline demographic variables were similar in the 2 groups except for orthodontic treatment period. The mean setback of the mandible at the B point was similar (CS group, 8.7 mm; SF group, 9.1 mm; difference, P > .05), but the horizontal relapse in the SF group (2.4 mm) was significantly greater than in the CS group (1.6 mm; P < .05). Patients with a horizontal relapse greater than 3 mm comprised 39.1% of the SF group compared with 15.8% of the CS group (P < .05). CONCLUSION: Mandibular sagittal split ramus osteotomy without presurgical orthodontic treatment was less stable than conventional orthognathic surgery for mandibular prognathism. Before performing a surgery-first approach, skeletal stability needs to be considered.

Single-dose, randomized crossover comparisons of different-strength imatinib mesylate formulations in healthy Korean male subjects.

BACKGROUND: Imatinib mesylate is used to treat chronic myeloid leukemia and advanced gastrointestinal stromal tumors. OBJECTIVE: The purpose of this study was to compare the pharmacokinetics of 2 different strengths of the imatinib formulation containing 100 mg (reference) and 400 mg (test) to satisfy the regulatory requirement for marketing. METHODS: A single-center, randomized, single-dose, open-label, 2-period, 2-sequence, comparative crossover study with a 14-day washout period was conducted in 30 healthy male volunteers. Plasma samples for the drug analysis were collected up to 72 hours after drug treatment. Participants received either the reference (4 tablets of 100-mg imatinib) or the test (1 tablet of 400-mg imatinib) formulation during the first period and the alternative formulation during the second period. The safety profiles and tolerability of the 2 formulations were also assessed based on physical examinations, laboratory tests, a 12-lead ECG, and vital signs. RESULTS: Thirty participants were initially enrolled; their mean (SD) age, height, weight, and body mass index were 24.9 (2.0) years (range, 23-30 years), 174 (5) cm (range, 164-185 cm), 69.9 (2.0) kg (range, 54.1-87.4 kg), and 23.0 (2.0) kg/m(2) (range, 18.5-26.9 kg/m(2)); 28 healthy participants completed both treatment periods. Two subjects did not complete the study because they withdrew consent for personal reasons. The observed mean (SD) Cmax, AUC0-last, and AUC0-∞ values for the reference formulation were 1792 (357) ng/mL, 28,485 (6274) ng · h/mL, and 29,079 (6371) ng · h/mL, respectively. Corresponding values for the test formulation were 1710 (312) ng/mL, 27,222 (4624) ng · h/mL , and 27,872 (4751) ng · h/mL. The geometric mean ratios (90% CIs) between the 2 formulations at the 400-mg dose of imatinib were 0.9579 (0.9054-1.0136) for Cmax, 0.9652 (0.9174-1.0155) for AUC0-last, and 0.9679 (0.9203-1.0179) for AUC0-∞, respectively. During the study period, 6 adverse events (3 for the reference and 3 for the test formulation) were reported; all were transient, mild, and resolved completely during the treatment period. There were 4 cases of nausea and 1 case each of dizziness and oropharyngeal pain. Four adverse events were considered related to the study drugs. CONCLUSIONS: The results showed that despite the different strengths of the 2 imatinib formations, the test and reference formulations both met the regulatory criteria for pharmacokinetic equivalence at a dose of imatinib 400 mg in these healthy Korean male subjects. Both imatinib formulations seemed to be generally well tolerated. ClinicalTrials.gov identifier: NCT01270984.

Vascular disrupting effect of CKD-516: preclinical study using DCE-MRI.

Vascular disrupting agents (VDAs) are new class of anti-cancer drugs targeting pre-existing tumor vasculature which lead to tumor ischemia and necrosis. An innovative tubulin polymerization inhibitor, CKD-516, was recently developed as a VDA. We attempted to evaluate its tubulin destabilizing effect using immunofluorescence staining on human endothelial cells (HUVECs) and to ascertain its antivascular effect in a rabbit VX2 tumor model using dynamic contrast-enhanced (DCE) MRI by measuring the changes in kinetic parameters such as K-trans and IAUGC. Immunofluorescence staining using anti-tubulin and anti-actin antibodies on HUVECs showed that CKD-516 selectively disrupted tubulin component of the endothelial cytoskeleton. Serial DCE-MRI showed a significant decrease in K-trans and IAUGC parameters from baseline at 4 h (39.9 % in K-trans; -45.0 % in IAUGC) and at 24 h (-32.2 % in K-trans; -36.5 % in IAUGC), and a significant recovery at 48 h (22.9 % in K-trans; 34.8 % in IAUGC) following administration of CKD-516 at a 0.7-mg/kg dose. When the tumors were stratified according to the initial K-trans value of 0.1, tumors with a high K-trans > 0.1 which was indicative of having well-developed pre-existing vessels, showed greater reduction in K-trans and IAUGC values. On histologic examination, the degree of necrosis of treated tumors was significantly greater than that of untreated tumors. In summary, CKD-516 is an effective VDA which results in rapid vascular shutdown by targeting the tubulin component of tumor vessels and thus leads to necrosis.

Free-breathing dynamic contrast-enhanced MRI of the abdomen and chest using a radial gradient echo sequence with K-space weighted image contrast (KWIC).

OBJECTIVES: To evaluate the feasibility of free-breathing, dynamic contrast-enhanced (DCE) MRI of the abdomen and thorax using the radial-gradient-echo sequence with k-space weighted image contrast (KWIC) reconstruction. METHODS: Institutional review board approval was obtained. Fourteen patients underwent free-breathing radial DCE-MRI. Radial MRI yielded full-frame images by gridding all k-space data and time-resolved subframe images by using KWIC reconstruction technique. Using subframe KWIC images, voxel-wise perfusion maps were created. For comparison, the breath-hold conventional Cartesian 3D-gradient-echo sequence (VIBE) was also performed during the equilibrium phase. The image qualities of radial and conventional VIBE images were compared quantitatively and qualitatively. RESULTS: Radial DCE-MRI provided high spatial resolution (1.4 × 1.4 mm) and temporal resolution (4.1 s for subframe images) allowing voxel-wise perfusion mapping with negligible motion or streaking artefacts. There were no significant differences in SNR between full-frame radial images and conventional VIBE images (79.08 vs 74.80, P > 0.05). Overall image quality score of full-frame radial images was slightly lower than that of conventional VIBE images (3.88 ± 0.59 vs. 4.31 ± 0.97, P < 0.05), but provided clinically useful images. CONCLUSIONS: The free-breathing radial DCE-MRI can provide high spatial and temporal resolution while maintaining reasonably high image quality and thus is a feasible technique for DCE-MRI in the abdomen and thorax. KEY POINTS: • Dynamic contrast-enhanced magnetic resonance imaging (DCE) MRI is important in oncological imaging • Radial MRI with k-space weighted image contrast (KWIC) reconstruction offers potential improvements • Radial DCE-MRI provides good image quality, reduced artefacts and high spatial/temporal resolution.

Scalp free flap reconstruction using anterolateral thigh flap pedicle for interposition artery and vein grafts.

We experienced satisfactory outcomes by synchronously transplanting an artery and vein using an anterolateral thigh flap pedicle between the vascular pedicle and recipient vessel of a flap for scalp reconstruction. A 45-year-old man developed a subdural hemorrhage due to a fall injury. In this patient, the right temporal cranium was missing and the patient had 4×3 cm and 6×5 cm scalp defects. We planned a scalp reconstruction using a latissimus dorsi free flap. Intraoperatively, there was a severe injury to the right superficial temporal vessel because of previous neurosurgical operations. A 15 cm long pedicle defect was needed to reach the recipient facial vessels. For the vascular graft, the descending branch of the lateral circumflex femoral artery and two venae comitantes were harvested.The flap survived well and the skin graft was successful with no notable complications. When an interposition graft is needed in the reconstruction of the head and neck region for which mobility is mandatory to a greater extent, a sufficient length of graft from an anterolateral flap pedicle could easily be harvested. Thus, this could contribute to not only resolving the disadvantages of a venous graft but also to successfully performing a vascular anastomosis.

Expression of transient receptor potential ankyrin 1 in human dental pulp.

INTRODUCTION: Transient receptor potential ankyrin 1 (TRPA1) is activated by noxious cold (<17°C) and contributes to cold and mechanical hypersensitivity after inflammation and nerve injury. METHODS: To investigate whether TRPA1 is involved in the mediation of nociception, including noxious cold and cold hypersensitivity in teeth, we examined the expression of TRPA1 and sodium channel Nav1.8 in human dental pulp using fluorescent and electron microscopic immunocytochemistry. RESULTS: TRPA1 was expressed in a large number of axons branching extensively in the peripheral pulp and in a few axons within the nerve bundles in the core of the coronal pulp and in the radicular pulp. Under electron microscopy, TRPA1 immunoreactivity was typically localized near the plasma membrane of unmyelinated axons in the peripheral pulp, suggesting that in these axons it may act as a functional receptor. The proportion of axons expressing TRPA1 in neurofilament 200-positive axons significantly increased in the painful pulp compared with the normal pulp. TRPA1 was also densely expressed in the processes and the cell body of odontoblasts. A large number of axons coexpressed TRPA1 and Nav1.8. CONCLUSIONS: These findings support the notion that TRPA1 is involved in the perception of noxious cold and cold hypersensitivity in human dental pulp and that TRPA1-mediated nociception is primarily mediated by axons and odontoblasts in the peripheral pulp.

A Phase Ib pharmacokinetic study of the anti-angiogenic agent CKD-732 used in combination with capecitabine and oxaliplatin (XELOX) in metastatic colorectal cancer patients who progressed on irinotecan-based chemotherapy.

BACKGROUND: We conducted a Phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics (PK) of CKD-732 [6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate] in combination with capecitabine and oxaliplatin (XELOX) in nine metastatic colorectal cancer patients who had progressed on irinotecan-based chemotherapy. METHODS: Using a dose-escalation schedule, CKD-732 doses of 2, 5, or 10 mg/m(2)/d were administered twice weekly for 2 weeks, followed by a 1-week rest. Oxaliplatin (130 mg/m(2)) was administered on day 1, and capecitabine (1,000 mg/m(2) twice a day) was orally administered for 14 days of a 3-week cycle. RESULTS: In the group given the 10 mg/m(2)/d dose, two patients experienced dose limiting toxicities (one had grade 3 nausea, insomnia, and fatigue; the other had grade 3 insomnia). The maximum tolerated dose was 10 mg/m(2)/d, and the clinically recommended dose was 5 mg/m(2)/d for CKD-732 in combination with XELOX. Frequently encountered non-hematological grade 3/4 adverse events included insomnia (22.2%), fatigue (11.1%), sensory neuropathy (11.1%), hyperbilirubinemia (11.1%), and dyspnea (11.1%). The area under the concentration-time curve and maximum concentration of CKD-732 increased in a dose-dependent manner. There were no notable effects of CKD-732 on the PK of capecitabine and oxaliplatin-derived platinum. CONCLUSION: The Phase II recommended dose of CKD-732 was determined to be 5 mg/m(2)/d, and this dose was safely combined with a conventional dose of capecitabine and oxaliplatin in this patient population. Further studies on the effects of CKD-732 in combination with XELOX and other chemotherapies using a larger study population are warranted.

Pharmacokinetic comparison of orally disintegrating and conventional donepezil formulations in healthy Korean male subjects: a single-dose, randomized, open-label, 2-sequence, 2-period crossover study.

BACKGROUND: Donepezil is a potent inhibitor of acetylcholinesterase, an enzyme that is targeted in the treatment of Alzheimer's disease. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic characteristics of orally disintegrating (test) and conventional (reference) donepezil formulations to satisfy the regulatory requirement for marketing. METHODS: A single-center randomized, single-dose, open-label, 2-way crossover study with a 21-day washout period was conducted in 22 healthy volunteers. Plasma samples for the analysis of donepezil were collected up to 240 hours after drug administration. Participants received either reference or test drug formulation of 10 mg donepezil in the first period and the alternative formulation in the second period. Plasma concentrations of donepezil were determined by validated high-performance liquid chromatography coupled to tandem mass spectrometry detection. Pharmacokinetic parameters, including C(max) and AUC, were determined by noncompartmental analysis. ANOVA was carried out using log-transformed C(max) and AUC, and the mean ratios and their 90% CIs were calculated. The safety profiles and tolerabilities of the 2 formulations were also assessed based on laboratory tests, 12-lead ECGs, vital signs, and physical examinations. RESULTS: Of the 22 participants initially enrolled, 18 healthy Korean participants completed both treatment periods. Four subjects did not complete both treatments: 3 subjects withdrew consent for personal reasons, and 1 subject experienced adverse events. No significant differences in pharmacokinetic parameters between the 2 formulations were observed. The mean (SD) age, height, and weight of the participants were 25.8 (4.1) years, 173.6 (5.7) cm, and 68.9 (7.8) kg, respectively. The mean (SD) C(max), AUC(last), and AUC(inf) for the reference formulation were 33.26 (6.58) ng/mL, 1521.69 (344.04) ng × h/mL, and 1691.46 (443.05) ng × h/mL, respectively. Corresponding values for the test formulation were 34.23 (6.79) ng/mL, 1554.33 (390.23) ng × h/mL, and 1718.27 (447.03) ng × h/mL, respectively. The median T(max) was 2 hours (range, 1-3 hours) for the reference and test formulations. The geometric mean ratios (90% CI) between the 2 formulations of donepezil were 102.9 (96.8-109.5) for C(max), 102.3 (96.1-108.9) for AUC(last), and 101.6 (95.4-108.2) for AUC(0-∞), respectively. During the study, 15 and 14 adverse events were reported for the reference and test formulations, respectively, and all were transient, mild, and resolved during the treatment period. These adverse events included 7 cases of nausea, 3 cases of headache, and 1 case each of dizziness, vomiting, chills, and sweating. All adverse events were considered related to the study drugs. CONCLUSION: This study found that the test and reference formulations met the regulatory criteria for pharmacokinetic equivalence in these fasting healthy Korean male subjects. Both donepezil formulations appeared to be generally well tolerated.

Study of an experimental microthreaded scalloped implant design: proximal bone healing at different interimplant distances in a canine model.

PURPOSE: The aim of the present study was to evaluate the validity of a new experimental microthreaded scalloped (MTS) implant design in comparison to a conventional flat-top (FT) implant by measuring the proximal bone loss at different interimplant distances in a canine model. MATERIALS AND METHODS: MTS implants were placed in one side of the posterior mandible and conventional flat-top (FT) implants were placed in the other side of the mandible in 10 beagle dogs. In five dogs, four each of the MTS and FT implants were placed with an interimplant distance of 2 mm. In another five dogs, three each of the MTS and FT implants were placed at an interimplant distance of 5 mm. All 70 implants (35 MTS and 35 FT implants) were placed in a nonsubmerged (one-stage) manner. The animals were sacrificed 4 months after implant placement, and the crestal bone levels around the MTS and FT implants were measured and compared on radiographs and histologic sections. RESULTS: The experimental MTS implants showed significantly less crestal bone loss (0.81 ± 0.34 mm) than the FT implants (1.60 ± 0.42 mm) on radiographs (P < .001). Histologic measurement also demonstrated that there was significantly less (P < .001) marginal bone loss around the MTS implants (0.74 ± 0.41 mm) than around the FT implants (1.53 ± 0.52 mm). There was no statistically significant difference in bone loss between the 2-mm and 5-mm interimplant distances for either MTS or FT implants (P > .05). CONCLUSION: The experimental MTS implant was more effective in preserving the proximal bone than the conventional FT external-hex implant with the same surface. In this canine model, placement of the implants at either a 2-mm and or a 5-mm interimplant distance did not result in significant differences in marginal bone loss for both MTS and FT implants. This experiment demonstrated a potential benefit of the microthread design on a scalloped implant.

Aspirin induces apoptosis in YD-8 human oral squamous carcinoma cells through activation of caspases, down-regulation of Mcl-1, and inactivation of ERK-1/2 and AKT.

NSAIDs and COX-2 inhibitors show anti-cancer activities in many cancer cells. In this study, we investigated the effects of NSAIDs (aspirin or indomethacin) and COX-2 inhibitor (NS-398) on growth of YD-8 human oral squamous carcinoma cells. Interestingly, among drugs tested, aspirin showed strongest inhibitory effects on viability and survival of YD-8 cells. Profoundly, aspirin treatment resulted in severe cell shrinkage and nuclear DNA fragmentation in YD-8 cells, suggesting the aspirin-induced apoptosis in YD-8 cells. Data of Western blot further demonstrated that aspirin treatment caused activation of caspases, down-regulation of Mcl-1 protein, dephosphorylation of ERK-1/2 and AKT, and also IkappaB-alpha proteolysis-dependent NF-kappaB activation in YD-8 cells. Aspirin, however, had no effect on expressions of Bcl-2, XIAP, and HIAP-1 in YD-8 cells. Importantly, pretreatment with z-VAD-fmk, a pan-caspase inhibitor blocked the aspirin-induced apoptosis and Mcl-1 down-regulation in YD-8 cells. These findings collectively suggest that aspirin induces apoptosis in YD-8 cells and the induction may be correlated to activation of caspases, caspase-dependent Mcl-1 proteolysis, inactivation of ERK-1/2 and AKT, and activation of NF-kappaB. It is suggested that aspirin may be applied a potential anti-cancer drug against human oral squamous carcinoma.

A phase I pharmacokinetic and pharmacodynamic study of CKD-732, an antiangiogenic agent, in patients with refractory solid cancer.

We conducted a phase I trial of the antiangiogenic agent 6-O-(4-dimethylaminoethoxy) cinnamoyl fumagillol hemioxalate (CKD-732). Our aims were to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and safety profiles as well as identify the biologically active dose (BAD) from ex vivo pharmacodynamics (PD) and biomarkers of CKD-732. Using a dose escalation schedule, 19 patients with refractory solid tumors were enrolled at dose levels of CKD-732 ranging from 1 to 15 mg/m(2) given twice weekly for 2 weeks followed by a 1-week rest. No treatment-related deaths occurred in this study. Confusion and insomnia were dose-limiting toxicities (DLTs), and MTD was 15 mg/m(2). The area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased dose dependently with increasing doses. The BAD was 5 mg/m(2) according to ex vivo PD. A decrement in soluble vascular endothelial growth factor receptor-3 (sVEGF-3) level was correlated with a reduction in tumor size (r = 0.54, P = 0.045). The results from this study showed an MTD of 15 mg/m(2) and a BAD of 5 mg/m(2).