Pharmacokinetics and bioequivalence of tofacitinib 5 mg in healthy Korean male subjects.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor marketed as an immunomodulator that can effectively treat rheumatoid arthritis. This study aimed to compare the pharmacokinetics and evaluate the bioequivalence of tofacitinib free base (CKD-374) with those of tofacitinib citrate (Xeljanz). MATERIALS AND METHODS: A randomized, open-label, single-dose, 2-sequence, 2-period crossover study was conducted in healthy Korean male subjects. A total of 36 subjects were randomized into two sequence groups. At each period, subjects were administered the test formulation (tofacitinib free base, 5 mg) or the reference formulation (tofacitinib citrate, 8.078 mg; as tofacitinib, 5 mg). The plasma samples were collected up to 12 hours post dose and analyzed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration vs. time curve from dosing to the last measurable concentration (AUC0-t), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) of the geometric mean ratios for Cmax and AUC0-t were calculated to evaluate pharmacokinetic equivalence. RESULTS: The 90% CIs of the geometric mean ratios of Cmax and AUC0-t for tofacitinib free base to tofacitinib citrate were 0.9144 - 1.1230 and 1.0245 - 1.0932, respectively. All reported adverse events were of mild intensity, and there were no serious adverse events. CONCLUSION: In healthy Korean male adult subjects, the pharmacokinetic parameters of tofacitinib free base and tofacitinib citrate were evaluated and met the pharmacokinetic bioequivalent criteria. Both formulations were safe and well-tolerated.

Profiling of endogenous metabolites and changes in intestinal microbiota distribution after GEN-001 (Lactococcus lactis) administration.

This study aimed to identify metabolic biomarkers and investigate changes in intestinal microbiota in the feces of healthy participants following administration of Lactococcus lactis GEN-001. GEN-001 is a single-strain L. lactis strain isolated from the gut of a healthy human volunteer. The study was conducted as a parallel, randomized, phase 1, open design trial. Twenty healthy Korean males were divided into five groups according to the GEN-001 dosage and dietary control. Groups A, B, C, and D1 received 1, 3, 6, and 9 GEN-001 capsules (1 × 1011 colony forming units), respectively, without dietary adjustment, whereas group D2 received 9 GEN-001 capsules with dietary adjustment. All groups received a single dose. Fecal samples were collected 2 days before GEN-001 administration to 7 days after for untargeted metabolomics and gut microbial metagenomic analyses; blood samples were collected simultaneously for immunogenicity analysis. Levels of phenylalanine, tyrosine, cholic acid, deoxycholic acid, and tryptophan were significantly increased at 5-6 days after GEN-001 administration when compared with predose levels. Compared with predose, the relative abundance (%) of Parabacteroides and Alistipes significantly decreased, whereas that of Lactobacillus and Lactococcus increased; Lactobacillus and tryptophan levels were negatively correlated. A single administration of GEN-001 shifted the gut microbiota in healthy volunteers to a more balanced state as evidenced by an increased abundance of beneficial bacteria, including Lactobacillus, and higher levels of the metabolites that have immunogenic properties.

Comparative pharmacokinetics of two formulations of 2.5-mg rivaroxaban in healthy Korean subjects.

OBJECTIVE: Rivaroxaban is a direct factor Xa inhibitor used for the prevention and treatment of thromboembolic disorders. The objective of this study was to compare the pharmacokinetic profiles of two rivaroxaban formulations after a single dose of rivaroxaban (2.5-mg tablet) in healthy Korean subjects. MATERIALS AND METHODS: This study was a randomized, open-label, single-dose, two-period, crossover study that included 34 healthy adult subjects under fasting conditions. The test drug (Yuhan rivaroxaban tablet) or reference drug (Xarelto tablet) was administered in each period. Serial blood samples were collected up to 36 hours post-dose. Plasma concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to the last measurable concentration (AUCt), were determined by non-compartmental analysis. The 90% confidence intervals (CIs) for the ratio of the geometric means of Cmax and AUCt for the test drug/reference drug were calculated to evaluate pharmacokinetic equivalence. RESULTS: A total of 28 subjects were included in the pharmacokinetic analysis. The geometric mean ratios (90% CI) of the test drug/reference drug for rivaroxaban were 1.0140 (0.9794 - 1.0499) for AUCt and 0.9350 (0.8797 - 0.9939) for Cmax. All adverse events (AEs) were mild, and there was no significant difference in the incidence of AEs between the formulations. CONCLUSION: The pharmacokinetic parameters of rivaroxaban were compared between the test and reference drug, and both formulations were bioequivalent. The newly developed rivaroxaban tablet is safe and well tolerated as the reference drug (ClinicalTrials.gov identifiers: NCT05418803).

Injury-mechanism directness as a key factor for fracture laterality in pediatric extremity fractures.

BACKGROUND: Associations between certain extremity fracture sites and laterality in pediatric trauma are well known, whereas the rationale for such laterality tendencies are unclear. We hypothesized that the laterality tendency of a specific fracture would be affected by directness of injury mechanism and not by the fracture site itself. METHODS: We retrospectively enrolled 1382 children (aged 2-16 years) who were diagnosed with extremity fractures sustained during loss-of-balance situations and investigated the laterality tendencies (dominant vs. non-dominant extremity) of specific fracture sites. Multivariate analyses were sequentially performed to adjust for potential confounding variables-with and without injury-mechanism directness as a covariate. RESULTS: In the upper extremities, the non-dominant side was more prone to fractures (p < 0.001), especially of the distal supracondylar humerus, radial and/or ulnar shaft, and distal radius. In the lower extremities, the dominant side was more frequently fractured (p < 0.001), especially at the tibial shaft and distal tibia. However, the predisposing effects of specific fracture sites on fracture laterality were not statistically significant when in analysis adjusted for injury-mechanism directness as a covariate. Fracture laterality was affected by whether the injury mechanism was direct or indirect. Indirect injury to the upper extremity was strongly associated with non-dominant arm injury (odds ratio 0.686 [95% CI 0.517-0.991]; p = 0.009), whereas indirect injury to the lower extremity was strongly associated with dominant leg injury (odds ratio 2.138 [95% CI 1.444-3.165]; p < 0.001). CONCLUSIONS: Injury-mechanism directness, rather than fracture site itself, is a key factor that affects fracture laterality in pediatric extremity fractures. These findings are helpful for improving our understanding of which factors may affect fracture laterality among children.

Preoperative incongruent subtalar joint predicts less favorable clinical outcome in total ankle arthroplasty.

BACKGROUND: This study aimed to determine the clinical effect of incongruent subtalar joint space on total ankle arthroplasty (TAA). METHODS: Thirty-four consecutive patients who underwent TAA were grouped according to the status of subtalar joint incongruency. A comparison of clinical and radiographic parameters between groups as well as multiple regression analysis was performed to identify contributing factors to the final functional outcome. RESULTS: The final American Orthopaedic Foot and Ankle Society (AOFAS) score was significantly higher in the congruent group compared to that of the incongruent group (p = 0.007). There were no significant differences between the two groups in measured radiographic angles. In multiple regression analysis, the female sex (p = 0.006) and incongruency of the subtalar joint (p = 0.013) were found to be significant contributing factors to the final AOFAS score. CONCLUSIONS: A thorough preoperative investigation should be taken into the state of the subtalar joint for TAA.

Computer-Aided Diagnosis for Determining Sagittal Spinal Curvatures Using Deep Learning and Radiography.

Analyzing spinal curvatures manually is time-consuming and tedious for clinicians, and intra-observer and inter-observer variability can affect manual measurements. In this study, we developed and evaluated the performance of an automated deep learning-based computer-aided diagnosis (CAD) tool for measuring the sagittal alignment of the spine from X-ray images. The CAD system proposed here performs two functions: deep learning-based lateral spine segmentation and automatic analysis of thoracic kyphosis and lumbar lordosis angles. We utilized 322 datasets with data augmentation for learning and fivefold cross-validation. The segmentation model was based on U-Net, which has multiple applications in medical image processing. Here, we utilized parameter equations and trigonometric functions to design spinal angle measurement algorithms. The kyphosis (T4-T12) and lordosis angle (L1-S1, L1-L5) were automatically measured to help diagnose kyphosis and lordosis. The segmentation model had precision, sensitivity, and dice similarity coefficient values of 90.53 ± 4.61%, 89.53 ± 1.8%, and 90.22 ± 0.62%, respectively. The performance of the CAD algorithm was also verified with the Pearson correlation, Bland-Altman, and intra-class correlation coefficient (ICC) analysis. The proposed angle measurement algorithm exhibited high similarity and reliability during verification. Therefore, CAD can help clinicians in reaching a diagnosis by analyzing the sagittal spinal curvatures while reducing observer-based variability and the required time or effort.

Physeal Abnormalities in Children With High-risk Neuroblastoma Intensively Treated With/Without 13-Cis-Retinoic Acid.

BACKGROUND: This study aimed to investigate the presence of physeal abnormality and its effect on growth in children with high-risk neuroblastoma treated by intensive multimodal treatment with/without 13-cis-retinoic acid (13-CRA). METHODS: Fifteen patients diagnosed with high-risk neuroblastomas at the age of 1 to 10 years, who received treatment such as high-dose chemotherapy and autologous stem cell transplantation with/without 13-CRA, and with complete data during their >2-year follow-up were retrospectively reviewed. The physeal abnormalities were investigated by whole-body magnetic resonance imaging, serially performed every 3 to 6 months. The patients' height growth was also investigated and compared with that of age-and-sex-matched patients with brain tumors who also underwent high-dose chemotherapy and autologous stem cell transplantation. RESULTS: Six of 15 patients presented multifocal physeal abnormalities during follow-up, and all lesions occurred in patients with 13-CRA use. The lesions in 3 patients completely resolved spontaneously without any adverse effect on growth, but some lesions in the other 3 patients progressed to disturb the bony growth. Height growth of matched patients with brain tumors were not significantly different, and none of the matched controls showed definite bony deformity during the follow-up. CONCLUSIONS: Some children who were treated for high-risk neuroblastomas experienced multifocal physeal insults, probably due to the use of 13-CRA. Most lesions resolved spontaneously, but some led to bony deformity. If the lesions are not followed by premature physeal closure, there seems to be no further adverse effect of 13-CRA on leg length growth. Routine periodic screening for physeal status is needed for the patients with high-risk neuroblastomas using 13-CRA. LEVEL OF EVIDENCE: Level IV-prognostic study.

Automated Vertebral Segmentation and Measurement of Vertebral Compression Ratio Based on Deep Learning in X-Ray Images.

Vertebral compression fracture is a deformity of vertebral bodies found on lateral spine images. To diagnose vertebral compression fracture, accurate measurement of vertebral compression ratio is required. Therefore, rapid and accurate segmentation of vertebra is important for measuring the vertebral compression ratio. In this study, we used 339 data of lateral thoracic and lumbar vertebra images for training and testing a deep learning model for segmentation. The result of segmentation by the model was compared with the manual measurement, which is performed by a specialist. As a result, the average sensitivity of the dataset was 0.937, specificity was 0.995, accuracy was 0.992, and dice similarity coefficient was 0.929, area under the curve of receiver operating characteristic curve was 0.987, and the precision recall curve was 0.916. The result of correlation analysis shows no statistical difference between the manually measured vertebral compression ratio and the vertebral compression ratio using the data segmented by the model in which the correlation coefficient was 0.929. In addition, the Bland-Altman plot shows good equivalence in which VCR values are in the area within average ± 1.96. In conclusion, vertebra segmentation based on deep learning is expected to be helpful for the measurement of vertebral compression ratio.

Relationship between calf muscle cross-sectional area and ankle fracture.

BACKGROUND: Whether calf muscles and peroneal muscles have a role in the occurrence of an ankle fractures remains unclear. This study aimed to quantify the calf muscle mass and peroneal muscle mass in patients with an ankle fracture and in controls, then to analyze them together with demographic factors to identify the effects of the regional muscles on the risk of developing ankle fracture. METHODS: A total of 101 ankles with computed tomography (CT) images were retrospectively reviewed. Of them, 51 ankles showed fractures (all unilateral) and 50 ankles, in controls who underwent CT for screening the other diseases, were clinically diagnosed with simple contusion. The cross-sectional areas (CSA) of the calf muscles and the peroneal muscles were measured at approximately 6 cm above the Achilles myotendinous junction in the axial plane of ankle CT. These parameters were compared between the two groups and analyzed with respect to age, sex, body mass index (BMI), laterality, and bone attenuations of the ankle. RESULTS: The demographic factors, including bone attenuation of the ankle showed no significant association with ankle fracture. The ratio of the CSA of the peroneal muscle group to the CSA of the entire calf muscle group was smaller in patients with an fracture (0.12 ± 0.03) than in controls (0.14 ± 0.02) (p = 0.027). The odds ratio for the effect of the calf muscle CSA on the risk of developing ankle fractures was 1.38 (95% confidence interval 1.12-1.69, p = 0.003), whereas that for the effect of peroneal muscle CSA on the risk of developing ankle fractures was 0.18 (95% confidence interval 0.05 to 0.66, p = 0.010). CONCLUSION: The ratio of the peroneal muscle CSA to the entire calf muscle CSA was negatively related to the occurrence of ankle fractures in this study. Further prospective studies on whether peroneal muscle-strengthening exercise are effective in preventing ankle fractures may be needed. LEVEL OF EVIDENCE: III, case-control study.

The effect of tube voltage combination on image artefact and radiation dose in dual-source dual-energy CT: comparison between conventional 80/140 kV and 80/150 kV plus tin filter for gout protocol.

OBJECTIVES: In dual-source CT, dual-energy (DE) performance is affected by various X-ray tube voltage combinations with and without tin filter (Sn). The purpose of this study was to assess the utility of the 80/150 Sn kV voltage combination in terms of image artefact and radiation dose for DECT gout protocol, compared with the conventional 80/140 kV. METHODS: Seventy-four patients with suspected gout who underwent dual-source DECT examinations scanned at 80/140 kV (n = 37) and at 80/150 Sn kV (n = 37) were included. Patients' age, sex, and serum uric acid levels were matched between the two groups. The types and incidence of image artefacts and radiation dose were evaluated. RESULTS: The 80/150 Sn kV group had significantly fewer patients with artefacts, compared to the 80/140 kV group [11 (30 %) of 37 vs 35 (94.6 %) of 37, p < 0.001]. Except for the motion artefact, the rest of the artefacts-skin, nail bed, submillimetre, motion, vascular, beam-hardening, clumpy artefact along tendon-were significantly less observed in the 80/150 Sn kV acquisitions. The dose-length product (DLP) and effective dose were significantly lower for the 80/150 Sn kV acquisitions compared with the 8s0/140 kV scans (DLP: 104.46 ± 10.66 mGy·cm vs 344.70 ± 56.39 mGy·cm, p < 0.001; effective dose: 1.04 ± 0.11 mSv vs 3.45 ± 0.56 mSv, p < 0.001). CONCLUSIONS: The 80/150 Sn kV voltage combination in dual-source DECT system could be used as one of the artefact reduction methods while reducing radiation dose for gout protocol when compared to the conventional 80/140 kV. KEY POINTS: • DECT has emerged as the leading modality for non-invasive diagnosis of gout. • Various X-ray tube voltage combinations are now feasible in dual-source DECT. • The 80/150 Sn kV acquisition could facilitate artefact reduction in gout protocol.

Pharmacokinetic and bioequivalence study of a fixed-dose combination of amlodipine besylate and rosuvastatin calcium compared to co-administration of separate tablets in healthy Korean subjects
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CONTEXT: A fixed-dose combination (FDC) tablet of amlodipine and rosuvastatin was recently developed for the treatment of concomitant hypertension and dyslipidemia and is anticipated to improve medication compliance. OBJECTIVE: This study was performed to compare the single-dose pharmacokinetic properties and safety of DP-R212 (FDC of amlodipine and rosuvastatin) to those of each agent co-administered in healthy Korean subjects. MATERIALS AND METHODS: A total of 36 healthy Korean subjects were enrolled in this randomized, open-label, single-dose, two-treatment, two-way crossover study. During each treatment period, subjects received the test drug (FDC tablet containing amlodipine and rosuvastatin) or reference drugs (individual tablets). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 24, 48, and 72 hours post-dose. Safety was assessed by the evaluation of adverse events (AEs), laboratory assessments, 12-lead electrocardiograms (ECGs), physical examinations, and vital sign measurements. RESULTS: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of AUClast and Cmax were 0.9796 - 1.0590 and 1.0135 - 1.0981 for amlodipine, and 0.9156 - 1.0490 and 0.8400 - 1.0306 for rosuvastatin, respectively. All AEs were of mild to moderate intensity, and no significant difference was observed in the incidence of AEs between the treatments. Moreover, the pharmacokinetic properties of the test and reference drugs were bioequivalent to each other, satisfying the regulatory criteria (0.8 - 1.25). DISCUSSION AND CONCLUSION: Both drugs were safe and well tolerated, and the pharmacokinetic profiles were comparable between the treatments.

Lateral epicondylitis: Associations of MR imaging and clinical assessments with treatment options in patients receiving conservative and arthroscopic managements.

OBJECTIVES: We assessed the implications of MR imaging with clinical history in lateral epicondylitis management by evaluating imaging and clinical features in patients with lateral epicondylitis treated conservatively or operatively. METHODS: Sixty patients with lateral epicondylitis treated conservatively (n = 38) or operatively (n = 22) from 2011-2015 were included. MR imaging findings of common extensor tendon (CET), lateral collateral ligament (LCL) complex, muscle oedema, ulnar nerve and elbow joint were reviewed. Clinical data recorded were frequency, duration and intensity of pain, history of trauma and injection therapy, range of motion. RESULTS: MRI-assessed CET and LCL complex abnormalities, muscle oedema, radiocapitellar joint widening, joint effusion/synovitis, pain frequency and intensity differed significantly between the two groups (p < .05) with increased severity in operative group. Persistent pain (OR 12.2, p < .01), CET abnormality on longitudinal plane (OR 7.5, p = .03 for grade 2; OR 22.4, p < .01 for grade 3) and muscle oedema (OR 6.7, p = .03) were major factors associated with operative treatment. Area under the ROC curve of predicted probabilities for combination of these factors was 0.83. CONCLUSION: MR imaging, combined with clinical assessment, could facilitate appropriate management planning for patients with lateral epicondylitis. KEY POINTS: • MRI can reflect different disease severity between patients treated conservatively/operatively. • CET abnormality, muscle oedema were major MRI findings with operative treatment. • Patients in operative group were more likely to experience persistent pain. • MRI plus clinical symptoms could facilitate appropriate management for lateral epicondylitis.

Pharmacokinetics and bioequivalence of 0.5 mg lobeglitazone tablets in healthy male subjects
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OBJECTIVE: This study was conducted to evaluate the pharmacokinetics and bioequivalence of two formulations of -DuvieTM (0.5-mg lobeglitazone sulfate). MATERIALS AND METHODS: This study was designed as an open-label, randomized, single-dose, crossover bioequivalence study in healthy male subjects. A total of 28 subjects were randomized into two groups: one group received the test drug, 0.5-mg DuvieTM tablets, which have formulations available on the global market; and the other group received the reference drug, the initially-approved 0.5-mg DuvieTM tablets. Plasma samples were collected for up to 48 hours after drug treatment and were analyzed for lobeglitazone using validated liquid chromatography-tandem mass spectrometry. Individual pharmacokinetic properties were determined by noncompartmental methods. Safety assessments were performed. RESULTS: 28 subjects completed the study and were included in the pharmacokinetic analysis. The mean (standard deviation) values of -AUClast for the test and reference formulations were 367.49 (157.92) and 362.40 (140.05) ng×h/mL, respectively. The mean (standard deviation) values of Cmax for the test and reference formulations were 50.35 (6.94) and 49.29 (6.71) ng/mL, respectively. The 90% confidence intervals for AUClast and Cmax were 0.9150 - 1.1088 and 0.9879 - 1.0561, respectively. All adverse events were mild, and there were no serious adverse events. CONCLUSION: This study suggests that the two lobeglitazone tablet formulations have similar exposure and absorption rates. Therefore, the newly-developed formulation of the 0.5-mg DuvieTM tablet is expected to contribute to the treatment of patients with type 2 diabetes.
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CT arthrography visualizes tissue growth of osteochondral defects of the talus after microfracture.

PURPOSE: Little is known about the arthroscopic or radiographic outcomes after arthroscopic microfracture of osteochondral lesions of the talus (OLTs). The purpose of this study was to investigate tissue growth after arthroscopic microfracture of OLTs using computed tomography arthrography (CTA) and to identify the relationship between CTA findings and clinical outcomes. We hypothesized that the morphology of the repaired tissue would be similar to that of normal anatomy and correlate with the clinical outcomes. METHODS: Forty-two ankles treated using arthroscopic microfracture of OLTs between 2009 and 2014 were monitored. CTA was performed post-operatively at 6 months and at 1 and 2 years after surgery. The post-operative thickness of the repaired tissue associated with OLT (grade) and the volume of the subchondral cystic lesions were evaluated using CTA. Clinical outcomes, including the pain visual analog scale (VAS) and American Orthopaedic Foot and Ankle Society (AOFAS) ankle functional scores, were evaluated and correlated with CTA. RESULTS: The proportion of fully grown tissue (grade 3) increased over time; specifically, the rates were 12/40 (33.3%) at 6 months, 11/18 (61.1%) at 1 year, and 8/10 (80%) at 2 years after surgery (p = 0.005). The VAS pain (p < 0.001) and AOFAS scores (p < 0.001) were also improved at the final follow-up; however, they were not associated with repaired tissue thickness as shown by CTA (n.s.). CONCLUSIONS: After microfracture of OLTs, tissue growth in the osteochondral defects was well visualized using CT arthrography and was observed in most cases. However, the CTA findings were not related to the clinical outcomes. LEVEL OF EVIDENCE: IV.

Sonographic diagnosis of neuritis ossificans of the median nerve.

We report the sonographic appearance of a rare case of neuritis ossificans of the median nerve at the wrist, which appeared as a hyperechoic lesion around the nerve. Diagnosis was confirmed with magnetic resonance imaging (MRI).

Comparison of 3D magnetic resonance imaging and digital subtraction angiography for intracranial artery stenosis.

OBJECTIVES: To compare three-dimensional high-resolution magnetic resonance imaging (3D HR-MRI) and digital subtraction angiography (DSA) for diagnosing and evaluating stenosis in the entire circle of Willis. METHODS: The study included 516 intracranial arteries from 43 patients with intracranial artery stenosis (ICAS) who underwent both 3D HR-MRI and DSA within 1 month. Two readers independently diagnosed atherosclerosis, dissection, moyamoya disease and vasculitis, rated their diagnostic confidence for each vessel and measured the luminal diameters. Reference standard was made from clinico-radiologic diagnosis. Diagnostic accuracy, diagnostic confidence, the degree of stenosis and luminal diameter were assessed and compared between both modalities. RESULTS: For atherosclerosis, 3D HR-MRI showed better diagnostic accuracy (P = .03-.003), sensitivity (P = .006-.01) and positive predictive value (P ≤ .001-.006) compared to DSA. Overall, the readers were more confident of their diagnosis of ICAS when using 3D HR-MRI (reader 1, P ≤ .001-.007; reader 2, P ≤ .001-.015). 3D HR-MRI showed similar degree of stenosis (P > .05) and higher luminal diameter (P < .05) compared to DSA. CONCLUSIONS: 3D HR-MRI might be useful to evaluate atherosclerosis, with better diagnostic confidence and comparable stenosis measurement compared to DSA in the entire circle of Willis. KEY POINTS: • 3D HR-MRI showed better diagnostic accuracy for atherosclerosiscompared to DSA • 3D HR-MRI showed better overall diagnostic confidence for stenosiscompared to DSA • 3D HR-MRI and DSA showed similar degree of stenosis.

Diagnostic Efficacy of Structural MRI in Patients With Mild-to-Moderate Alzheimer Disease: Automated Volumetric Assessment Versus Visual Assessment.

OBJECTIVE: The purpose of this study was to compare the diagnostic efficacies of an automated volumetric assessment tool and visual assessment in the evaluation of medial temporal lobar atrophy in mild-to-moderate Alzheimer disease (AD). MATERIALS AND METHODS: This retrospective study included 30 patients with mild-to-moderate AD and 25 age-matched healthy control subjects undergoing MRI with a 3D fast spoiled gradient recalled-echo sequence at 3 T. The images were processed with fully automated volumetric analysis software. To assess medial temporal lobe (MTL) atrophy, two MTL indexes, which took into account the volumes of the hippocampus and the inferior lateral ventricle, were calculated with the automated volumetric assessment software. In addition, two neuroradiologists assessed MTL atrophy visually using the Scheltens scale. ROC curve analysis was used to compare the diagnostic performances of the two methods. The weighted kappa statistic was used to assess the intrarater and interrater reliability of visual inspection. RESULTS: The automated volumetric assessment tool had moderate sensitivity (63.3%) and high specificity (100%) in differentiating patients with mild-to-moderate AD from control subjects. Visual inspection showed sensitivity of 63.3% and specificity of 92.0%. The diagnostic performance was not significantly different between the two methods (p = 0.536-0.906). Intraobserver reliability for visual inspection was 0.858 and 0.902 for the two reviewers, and interobserver reliability was 0.692-0.780. CONCLUSION: Both the automated volumetric assessment tool and visual inspection can be used to evaluate MTL atrophy and differentiate patients with AD from healthy individuals with good diagnostic accuracy. Thus, the automated tool can be a useful and efficient adjunct in clinical practice for evaluating MTL atrophy in the diagnosis of AD.

Pharmacokinetic and bioequivalence study comparing a candesartan cilexetil/rosuvastatin calcium fixed-dose combination with the concomitant administration of candesartan cilexetil and rosuvastatin calcium in healthy Korean subjects
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CONTEXT: A fixed-dose combination (FDC) of candesartan and rosuvastatin was recently developed for the treatment of cardiovascular disease and expected to enhance patient compliance. OBJECTIVE: This study was performed to compare the single-dose pharmacokinetic properties and tolerability of DP-R208 (candesartan and rosuvastatin FDC) to those of each component administered alone in healthy Korean male volunteers. MATERIALS AND METHODS: A total of 40 healthy Korean volunteers were enrolled in this randomized, open-label, single-dose, two-treatment, two-way crossover study. During each treatment period, subjects received the test formulation (FDC tablet containing candesartan and rosuvastatin) or reference formulation (co-administration of candesartan and rosuvastatin). Plasma samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, and 48 hours post-dose. Safety and tolerability were assessed by the evaluation of adverse events (AEs), physical examinations, laboratory assessments, 12-lead electrocardiograms (ECGs), and vital sign measurements. RESULTS: The 90% confidence intervals (CIs) of the geometric least-square mean ratios of Cmax, AUClast, and AUCinf were 0.86 - 1.00, 0.92 - 1.04, and 0.92 - 1.03 for candesartan, and 0.88 - 1.06, 0.91 - 1.08, and 0.91 - 1.03 for rosuvastatin, respectively. All of the AEs were mild, and there was no significant difference in the incidence of AEs between the formulations. Furthermore, the pharmacokinetic properties of the test and reference formulations met the regulatory criteria for bioequivalence. Discussion and conclusion: Both formulations were safe and well tolerated, and no significant difference was observed in the safety assessments of the treatments.
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Effect of fermented red ginseng on cytochrome P450 and P-glycoprotein activity in healthy subjects, as evaluated using the cocktail approach.

AIMS: We assessed the drug interaction profile of fermented red ginseng with respect to the activity of major cytochrome (CYP) P450 enzymes and of a drug transporter protein, P-glycoprotein (P-gp), in healthy volunteers. METHODS: This study was an open-label crossover study. The CYP probe cocktail drugs caffeine, losartan, dextromethorphan, omeprazole, midazolam and fexofenadine were administered before and after 2 weeks of fermented red ginseng administration. Plasma samples were collected, and tolerability was assessed. Pharmacokinetic parameters were calculated, and the 90% confidence intervals (CIs) of the geometric mean ratios of the parameters were determined from logarithmically transformed data. Values were compared between before and after fermented red ginseng administration using analysis of variance (anova). RESULTS: Fifteen healthy male subjects were evaluated, none of whom were genetically defined as a poor CYP2C9, CYP2C19 or CYP2D6 metabolizer based on genotyping. Before and after fermented red ginseng administration, the geometric least-square mean metabolic ratio (90% CI) was 0.901 (0.830-0.979) for caffeine (CYP1A2) to paraxanthine, 0.774 (0.720-0.831) for losartan (CYP2C9) to EXP3174, 1.052 (0.925-1.197) for omeprazole (CYP2C19) to 5-hydroxyomeprazole, 1.150 (0.860-1.538) for dextromethorphan (CYP2D6) to dextrorphan, and 0.816 (0.673-0.990) for midazolam (CYP3A4) to 1-hydroxymidazolam. The geometric mean ratio of the area under the curve of the last sampling time (AUClast ) for fexofenadine (P-gp) was 1.322 (1.112-1.571). CONCLUSION: No significantly different drug interactions were observed between fermented red ginseng and the CYP probe substrates following the two-week administration of concentrated fermented red ginseng. However, the inhibition of P-gp was significantly different between fermented red ginseng and the CYP probe substrates. The use of fermented red ginseng requires close attention due to the potential for increased systemic exposure when it is used in combination with P-gp substrate drugs.