Endovascular Occlusion of Giant Posttraumatic Pseudo-Aneurysm of Superior Mesenteric Artery Connected to Mesenteric Arteriovenous Fistula.

The aim of the study was to show the capabilities of endovascular occlusion of giant posttraumatic pseudo-aneurysm of superior mesenteric artery (SMA) connected to a mesenteric arteriovenous fistula (AVF) under the conditions of portal hypertension and life-threatening esophageal variceal bleeding. MATERIALS AND METHODS: A 27-old male patient underwent endovascular occlusion; the patient being hospitalized with a clinical picture of gastrointestinal bleeding. The examinations: ultrasound, esophagogastroduodenoscopy, multispiral computed tomography with angiography - revealed the source of bleeding to be esophageal varices against the background of portal hypertension caused by massive arteriovenous shunt, its source being AVF with an aneurysmal component (32×35 mm in size) between SMA and superior mesenteric vein (SMV) dilated up to 50 mm in diameter. Patient's past medical history recorded that 4.5 years ago the patient had undergone the resection of a small intestine area due to a penetrating stab wound in the abdominal cavity. Taking into consideration an extremely high operative intervention risk due to the condition severity related to blood loss, portal hypertension, and ascites, it was decided to embolize AVF with a vascular occluder - Amplatzer Vascular Plug II (USA), 14×10 mm in size. RESULTS: A unique endovascular intervention - transcatheter occlusion of pseudo-aneurysm and AVF separation - was performed in life-threatening esophageal variceal bleeding under the condition of a giant post-traumatic aneurysm of SMA and mesenteric AVF. Due to an extremely large-sized SMV and an arterial pseudo-aneurysm, first ever we used the technique applied for transcatheter occlusion of a cardiac septum defect.Occluder implantation enabled to completely close the communication of aneurysmatic AVF with SMV, and occlude the aneurysm cavity. During an immediate postoperative period portal hypertension was arrested. No recurrent bleedings occurred within 4 postoperative months.

[Diagnosis and surgical treatment of symptomic stomach diverticulum]. / Diagnostika i khirurgicheskoe lechenie simptomnogo divertikula zheludka.

Gastric diverticulum is a rather rare disease. This lesion is diagnosed in about 0.01% of cases during contrast-enhanced X-ray examination and in 0.04-0.11% of patients undergoing endoscopic examination. Symptomatic diverticulum is complicated by diverticulitis, bleeding, perforation and malignant transformation. Therefore, surgical resection is indicated. We report surgical treatment of a patient with diverticulum of the cardiac part of the stomach. Endoscopic and X-ray examination was valuable to establish the correct diagnosis. Laparoscopic approach minimized surgical trauma and reduced surgery time.

Changes in anti-müllerian hormone levels as a biomarker for ovarian reserve after ultrasound-guided high-intensity focused ultrasound treatment of adenomyosis and uterine fibroid.

OBJECTIVE: To assess the changes in antimüllerian hormone (AMH) levels after ablation for symptomatic uterine fibroids and adenomyosis using ultrasound-guided high-intensity focused ultrasound (USgHIFU). DESIGN: A prospective study. SETTING: Gynaecological department in multiple hospitals in South Korea. POPULATION: Patients with uterus fibroids and adenomyosis. METHODS: Seventy-nine women with symptomatic uterine fibroids and adenomyosis who met the inclusion criteria were enrolled in our study between January 2014 and December 2014. All patients underwent USgHIFU ablations. Each patient was examined before and after treatment, and at 6 and 12 months after treatment by T2-weighted MRI imaging (T2WI) and T1-weighted MRI imaging (T1WI) with gadolinium injection. Symptom severity scores (SSS), Uterine Fibroid Symptom Quality of Life (UFS-QOL) questionnaire subscales, and reductions of treated volume were assessed. AMH levels before and 6 months after HIFU ablation were compared to determine whether USgHIFU ablation affected ovarian reserve. MAIN OUTCOME MEASURES: HIFU treatment did not affect the ovarian function. RESULTS: HIFU treatment time (mean ± standard deviation), HIFU ablation time, and treatment energy were 73.5 ± 25.6 minutes, 9994.7 ± 386.8 seconds, and 364 713.8 ± 156 350.7 Joules, respectively. AMH levels before and 6 months after HIFU ablation were 2.11 ± 2.66 and 1.84 ± 2.57 µg/l, respectively. There was no significant difference in AMH level between the two time points (P > 0.05). CONCLUSIONS: USgHIFU ablation for uterine fibroid and adenomyosis was effective without affecting ovarian reserve. TWEETABLE ABSTRACT: HIFU ablation is a safe and effective treatment for patients with uterine fibroids and adenomyosis that does not affect ovarian function.

Loss of Functional Connectivity in Patients with Parkinson Disease and Visual Hallucinations.

Purpose To gain more insight into the pathophysiological mechanisms of visual hallucinations (VHs) in patients with Parkinson disease (PD) by analyzing whole-brain resting-state functional connectivity in PD patients with VH (hereafter, referred to as PD + VH patients) and without VH (hereafter, referred to as PD - VH patients) and control participants. Materials and Methods For this retrospective study, 15 PD + VH patients, 40 PD - VH patients, and 15 control participants from a prospective cohort study were included, which was approved by the local ethics board and written informed consent was obtained from all participants. Functional connectivity was calculated between 47 regions of interests, of which whole-brain and region-specific means were compared by using a general linear model with false discovery rate control for multiple comparisons. Results Whole-brain mean functional connectivity was significantly lower in PD patients compared with control participants, with regional decreases involving paracentral and occipital regions in both PD + VH and PD - VH patients (mean whole-brain functional connectivity in PD + VH vs PD - VH, 0.12 ± 0.01 [standard deviation] vs 0.14 ± 0.03, respectively; control participants, 0.15 ± 0.04; P < .05, corrected). In PD + VH patients, nine additional frontal, temporal, occipital, and striatal regions showed decreased functional connectivity compared with control participants (mean of these nine regions in PD + VH, PD - VH, and control participants: 0.12 ± 0.02, 0.14 ± 0.03, and 0.16 ± 0.04, respectively; P < .05, corrected). Resting-state functional connectivity was unrelated to motor performance (r = 0.182; P = .184) and related to cognitive deficits such as attention and perception (ρ, -0.555 and -0.558, respectively; P < .05). Conclusion The findings show a PD-related effect on resting-state functional connectivity of posterior and paracentral brain regions, whereas the presence of VH is associated with a more global loss of connectivity, related to attention and perception. These findings suggest that the pathophysiological mechanisms of VH in PD may include a global loss of network efficiency, which could drive disturbed attentional and visual processing. © RSNA, 2017 Online supplemental material is available for this article.

Damaged fiber tracts of the nucleus basalis of Meynert in Parkinson's disease patients with visual hallucinations.

Damage to fiber tracts connecting the nucleus basalis of Meynert (NBM) to the cerebral cortex may underlie the development of visual hallucinations (VH) in Parkinson's disease (PD), possibly due to a loss of cholinergic innervation. This was investigated by comparing structural connectivity of the NBM using diffusion tensor imaging in 15 PD patients with VH (PD + VH), 40 PD patients without VH (PD - VH), and 15 age- and gender-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) of pathways connecting the NBM to the whole cerebral cortex and of regional NBM fiber tracts were compared between groups. In PD + VH patients, compared to controls, higher MD values were observed in the pathways connecting the NBM to the cerebral cortex, while FA values were normal. Regional analysis demonstrated a higher MD of parietal (p = 0.011) and occipital tracts (p = 0.027) in PD + VH, compared to PD - VH patients. We suggest that loss of structural connectivity between the NBM and posterior brain regions may contribute to the etiology of VH in PD. Future studies are needed to determine whether these findings could represent a sensitive marker for the hypothesized cholinergic deficit in PD + VH patients.

Changes in resting-state directed connectivity in cortico-subcortical networks correlate with cognitive function in Parkinson's disease.

OBJECTIVE: The pathophysiological mechanisms underlying Parkinson's disease (PD)-related cognitive decline and conversion to PD dementia are poorly understood. In the healthy human brain, stable patterns of posterior-to-anterior cortical information flow have recently been demonstrated in the higher frequency bands using magnetoencephalography (MEG). In this study we estimated PD-related changes in information flow patterns, as well as the contribution of subcortical regions. METHODS: Resting-state MEG recordings were acquired in moderately advanced PD patients (n=34; mean Hoehn and Yahr-stage 2.5) and healthy controls (n=12). MEG signals were projected to both cortical and subcortical brain regions, following which we estimated the balance between incoming and outgoing information flow per region. RESULTS: In PD patients, compared to controls, preferential beta band information outflow was significantly higher for the basal ganglia and frontotemporal cortical regions, and significantly lower for parieto-occipital regions. In addition, in patients, low preferential information outflow from occipital regions correlated with poor global cognitive performance. CONCLUSION: In the PD brain, a shift in balance towards more anterior-to-posterior beta band information flow takes place and is associated with poorer cognitive performance. SIGNIFICANCE: Our results indicate that a reversal of the physiological posterior-to-anterior information flow may be an important mechanism in PD-related cognitive decline.

Functional connectivity and cognitive decline over 3 years in Parkinson disease.

OBJECTIVE: To evaluate fMRI whole-brain resting-state functional connectivity changes in relation to cognitive decline in Parkinson disease (PD) over a 3-year period. METHODS: Resting-state fMRI scans were acquired in 55 patients with PD (mean age 65.8 years, SD 6.37; average disease duration 9.24 years, SD 3.96) and 15 matched controls (mean age 64.4 years, SD 8.65). We first performed overall (i.e., 1 whole-brain mean) as well as regional (i.e., for all individual regions of interest) functional connectivity analyses, in which we compared subject groups cross-sectionally. After a 3-year follow-up period, 36 patients with PD and 12 controls were rescanned to study functional connectivity changes over time and correlate the changes in functional connectivity with deteriorating cognitive and motor function in the PD sample. RESULTS: In the cross-sectional analysis, we found widespread decreases of resting-state functional connectivity in patients with PD in comparison to controls. Subsequent comparison between the 2 timepoints revealed that patients with PD displayed further decreases in functional connectivity independent of aging effects. These functional connectivity changes were most prominent for posterior parts of the brain and correlated across time with clinical measures of disease progression, especially cognitive decline. CONCLUSIONS: In this fMRI study in PD, we demonstrated a progressive loss of resting-state functional connectivity over a period of 3 years for multiple brain regions, especially in posterior parts of the brain. The strong correlation with decreasing cognitive performance supports the pathophysiologic role of reduced functional connectivity in cognitive decline and the development of dementia in PD.

Bioequivalence study of two imatinib formulations after single-dose administration in healthy Korean male volunteers.

Imatinib mesylate is effective for chronic myeloid leukaemia and gastrointestinal tumours. We aimed to evaluate the pharmacokinetics of a 200-mg imatinib tablet compared to 2×100-mg imatinib tablets in order to meet the regulatory requirements for marketing in Korea.An open-label, randomized, single-dose, 2-period, 2-treatment cross-over study was conducted in 28 healthy Korean male volunteers. Subjects were administered a 200-mg imatinib tablet and 2×100-mg imatinib tablets under a fasting state according to a randomly assigned order with a 2-week wash-out period. Serial blood samples were collected up to 72 h post-dose. The pharmacokinetic parameters were calculated using non-compartmental methods.A total of 28 subjects were enrolled and 23 subjects completed the study. There were no serious adverse events during the study. 23 mild to moderate adverse events were reported (11 events with 200-mg imatinib vs. 12 events with 2×100-mg imatinib) and subjects recovered without sequelae. The Cmax value was 922.8±318.8 µg/L at 3.15 h for 200-mg imatinib tablet, and 986.3±266.0 µg/L at 2.91 h for the 2×100-mg imatinib tablet. The AUClast of 200-mg and 2×100-mg tablets were 13 084.3±39.1 and 14 131.7±3 826.2 h · µg/L, respectively. The geometric mean ratios (90% confidence intervals) for Cmax and AUClast were 0.9121 (0.8188, 1.0161) and 0.9558 (0.8685, 1.0519), respectively.A newly developed 200-mg imatinib tablet was bioequivalent to 2×100-mg imatinib tablets in healthy Korean subjects. A single-dose of either of the 2 formulations was generally well tolerated.

Prognostic factors for stereotactic radiosurgery-treated patients with cerebral metastasis: implications on randomised control trial design and inter-institutional collaboration.

INTRODUCTION: Defining key prognostic factors for patients with cerebral metastases who underwent stereotactic radiosurgery (SRS) treatment will greatly facilitate future clinical trial designs. METHODS: We adopted a two-phase study design where results from one cohort were validated in a second independent cohort. The exploratory analysis reviewed the survival outcomes of 1017 consecutive patients (with 3610 metastases) who underwent Gamma radiosurgery at the University of California, San Diego (UCSD)/San Diego Gamma Knife Center (SDGKC). Multivariate analysis was performed to identify prognostic factors. Results were validated using data derived from 2519 consecutive patients (with 17,498 metastases) treated with SRS at the Katsuta Hospital. RESULTS: For the SDGKC cohort, the median overall survival of patients following SRS was 7 months. Two year follow-up data were available for 85% of the patients. Multivariate analysis found that patient age, Karnofsky Performance Status, systemic cancer status, tumour histology, number of metastasis and cumulative tumour volume independently associated with overall survival (p<0.001). All statistical associations were validated by multivariate analysis of data derived from the Katsuta Hospital cohort. CONCLUSIONS: This is the first integrated study that defined prognostic factors for SRS-treated patients with cerebral metastases using an inter-institutional validation study design. The work establishes a model for collaborative interactions between large volume centers and provides prognostic variables that should be incorporated into future clinical trial design.

Disrupted brain network topology in Parkinson's disease: a longitudinal magnetoencephalography study.

Although alterations in resting-state functional connectivity between brain regions have previously been reported in Parkinson's disease, the spatial organization of these changes remains largely unknown. Here, we longitudinally studied brain network topology in Parkinson's disease in relation to clinical measures of disease progression, using magnetoencephalography and concepts from graph theory. We characterized whole-brain functional networks by means of a standard graph analysis approach, measuring clustering coefficient and shortest path length, as well as the construction of a minimum spanning tree, a novel approach that allows a unique and unbiased characterization of brain networks. We observed that brain networks in early stage untreated patients displayed lower local clustering with preserved path length in the delta frequency band in comparison to controls. Longitudinal analysis over a 4-year period in a larger group of patients showed a progressive decrease in local clustering in multiple frequency bands together with a decrease in path length in the alpha2 frequency band. In addition, minimum spanning tree analysis revealed a decentralized and less integrated network configuration in early stage, untreated Parkinson's disease that also progressed over time. Moreover, the longitudinal changes in network topology identified with both techniques were associated with deteriorating motor function and cognitive performance. Our results indicate that impaired local efficiency and network decentralization are very early features of Parkinson's disease that continue to progress over time, together with reductions in global efficiency. As these network changes appear to reflect clinically relevant phenomena, they hold promise as markers of disease progression.

Pharmacokinetics of a new once-daily controlled-release sarpogrelate hydrochloride compared with immediate-release formulation and the effect of food.

WHAT IS KNOWN AND OBJECTIVE: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A antagonist that inhibits platelet aggregation and vasoconstriction. The aim of this study was to compare the pharmacokinetics of a sarpogrelate controlled-release formulation (CR) with those of the immediate-release formulation (IR). The effect of food on the pharmacokinetics of CR sarpogrelate was also evaluated. METHODS: A randomized, open-label, 3-period, 3-treatment crossover study was conducted in 50 healthy male subjects. Subjects were allocated into one of six sequence groups. In one period, a 100-mg IR formulation was administered three times at 6-h intervals, and in the other two periods, a 300-mg CR formulation was administered once to fasting and once to fed subjects. Each period was separated by a 7-day washout period. Serial blood samples were collected up to 24 h after the first drug administration in each period. The plasma concentrations of sarpogrelate were analysed by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS AND DISCUSSION: After the administration of the IR formulation, the plasma concentration reached a peak at 0·48 h and the drug was eliminated with a half-life (t1/2 ) of 0·7 h. After administration of the CR formulation, the plasma concentration reached a peak at 0·5 h and the drug was eliminated with a t1/2 of 3·23 h. The geometric mean ratios (CR/IR) for sarpogrelate area under the plasma concentration-time curve (AUC) and the maximum plasma drug concentration (Cmax) were 1·2040 (90% confidence interval (CI): 1·0992-1·3188) and 0·9462 (90% CI: 0·8504-1·0529). When CR was administered to fed subjects, the time to peak concentration was prolonged to 3·97 h and t1/2 was shortened to 1·45 h. The geometric mean ratios (fasting/fed) for sarpogrelate AUC and Cmax were 0·8573 (90% CI: 0·7687-0·9561) and 0·6452 (90% CI: 0·5671-0·7341). WHAT IS NEW AND CONCLUSION: After the administration of CR and IR formulations of the same daily dose of sarpogrelate hydrochloride, the overall systemic exposure was slightly higher for the CR than for the IR formulation, whereas peak concentration was comparable between the two formulations. Food reduced the bioavailability of sarpogrelate CR.

Predicting dementia in Parkinson disease by combining neurophysiologic and cognitive markers.

OBJECTIVE: To assess the ability of neurophysiologic markers in conjunction with cognitive assessment to improve prediction of progression to dementia in Parkinson disease (PD). METHODS: Baseline cognitive assessments and magnetoencephalographic recordings from 63 prospectively included PD patients without dementia were analyzed in relation to PD-related dementia (PDD) conversion over a 7-year period. We computed Cox proportional hazard models to assess the risk of converting to dementia conveyed by cognitive and neurophysiologic markers in individual as well as combined risk factor analyses. RESULTS: Nineteen patients (30.2%) developed dementia. Baseline cognitive performance and neurophysiologic markers each individually predicted conversion to PDD. Of the cognitive test battery, performance on a posterior (pattern recognition memory score < median; hazard ratio (HR) 6.80; p = 0.001) and a fronto-executive (spatial span score < median; HR 4.41; p = 0.006) task most strongly predicted dementia conversion. Of the neurophysiologic markers, beta power < median was the strongest PDD predictor (HR 5.21; p = 0.004), followed by peak frequency < median (HR 3.97; p = 0.016) and theta power > median (HR 2.82; p = 0.037). In combination, baseline cognitive performance and neurophysiologic measures had even stronger predictive value, with the combination of impaired fronto-executive task performance and low beta power being associated with the highest dementia risk (both risk factors vs none: HR 27.3; p < 0.001). CONCLUSIONS: Combining neurophysiologic markers with cognitive assessment can substantially improve dementia risk profiling in PD, providing potential benefits for clinical care as well as for the future development of therapeutic strategies.

Resting-state functional connectivity as a marker of disease progression in Parkinson's disease: A longitudinal MEG study.

The assessment of resting-state functional connectivity has become an important tool in studying brain disease mechanisms. Here we use magnetoencephalography to longitudinally evaluate functional connectivity changes in relation to clinical measures of disease progression in Parkinson's disease (PD). Using a source-space based approach with detailed anatomical mapping, functional connectivity was assessed for temporal, prefrontal and high order sensory association areas known to show neuropathological changes in early clinical disease stages. At baseline, early stage, untreated PD patients (n = 12) had lower parahippocampal and temporal delta band connectivity and higher temporal alpha1 band connectivity compared to controls. Longitudinal analyses over a 4-year period in a larger patient group (n = 43) revealed decreases in alpha1 and alpha2 band connectivity for multiple seed regions that were associated with motor or cognitive deterioration. In the earliest clinical stages of PD, delta and alpha1 band resting-state functional connectivity is altered in temporal cortical regions. With disease progression, a reversal of the initial changes in alpha1 and additional decreases in alpha2 band connectivity evolving in a more widespread cortical pattern. These changes in functional connectivity appear to reflect clinically relevant phenomena and therefore hold promise as a marker of disease progression, with potential predictive value for clinical outcome.

Cognitive decline in Parkinson's disease is associated with slowing of resting-state brain activity: a longitudinal study.

The pathophysiological mechanisms of Parkinson's disease (PD)-related dementia (PDD) are still poorly understood. Previous studies using electroencephalography (EEG) and magnetoencephalography (MEG) have demonstrated widespread slowing of oscillatory brain activity as a neurophysiological characteristic of PD-related dementia. Here, we use MEG to longitudinally study early changes in oscillatory brain activity in initially nondemented PD patients that may be associated with cognitive decline. Using a longitudinal design, resting-state MEG recordings were performed twice at an approximate 4-year interval in 14 healthy controls and 49 PD patients. Changes in peak frequency and in relative spectral power for 10 brain regions were analyzed in relation to clinical measures of cognitive and motor function. In contrast to healthy controls, PD patients showed a slowing of the dominant peak frequency. Furthermore, analysis per frequency band revealed an increase in theta power over time, along with decreases in alpha1 and alpha2 power. In PD patients, decreasing cognitive performance was associated with increases in delta and theta power, as well as decreases in alpha1, alpha2, and gamma power, whereas increasing motor impairment was associated with a theta power increase only. The present longitudinal study revealed widespread progressive slowing of oscillatory brain activity in initially nondemented PD patients, independent of aging effects. The slowing of oscillatory brain activity strongly correlated with cognitive decline and therefore holds promise as an early marker for the development of dementia in PD.

A novel HLA-B*35 allele, B*35:188, identified by sequence-based typing.

The novel allele B*35:188 allele showed a single nucleotide difference with B*35:96 at nt 347 T>C in exon 3.

Complexity analysis of resting-state MEG activity in early-stage Parkinson's disease patients.

The aim of the present study was to analyze resting-state brain activity in patients with Parkinson's disease (PD), a degenerative disorder of the nervous system. Magnetoencephalography (MEG) signals were recorded with a 151-channel whole-head radial gradiometer MEG system in 18 early-stage untreated PD patients and 20 age-matched control subjects. Artifact-free epochs of 4 s (1250 samples) were analyzed with Lempel-Ziv complexity (LZC), applying two- and three-symbol sequence conversion methods. The results showed that MEG signals from PD patients are less complex than control subjects' recordings. We found significant group differences (p-values <0.01) for the 10 major cortical areas analyzed (e.g., bilateral frontal, central, temporal, parietal, and occipital regions). In addition, using receiver-operating characteristic curves with a leave-one-out cross-validation procedure, a classification accuracy of 81.58% was obtained. In order to investigate the best combination of LZC results for classification purposes, a forward stepwise linear discriminant analysis with leave-one out cross-validation was employed. LZC results (three-symbol sequence conversion) from right parietal and temporal brain regions were automatically selected by the model. With this procedure, an accuracy of 84.21% (77.78% sensitivity, 90.0% specificity) was achieved. Our findings demonstrate the usefulness of LZC to detect an abnormal type of dynamics associated with PD.

Open label, three period, single sequence, study of 5, 25, 50 mg sertraline pharmacokinetics in healthy male Korean volunteers.

BACKGROUND: Sertraline is a naphthalenamine derivative which has the effect of selective serotonin reuptake inhibition. It has been used for major depression, and obsessive compulsive disorder. This study was performed to evaluate the pharmacokinetic (PK) characteristics after the administration of low dose sertraline for the purpose of exploring an application of microdosing methods in PK studies. METHODS: An open-label, three-period, single-sequence, dose-escalation study was performed in 6 healthy Korean male volunteers. Subjects were administered a single dose of 5 mg, 25 mg and 50 mg sertraline orally in each period, with 1 week washouts between periods. Blood samples were obtained up to 96 h after drug administration. Plasma concentrations were determined using high performance liquid chromatography-tandem mass spectrometry. PK parameters of sertraline were analyzed using non-compartmental methods. RESULTS: A total of 6 subjects completed the study. After the administration of sertraline at 5 mg, 25 mg and 50 mg, the median tmax were 6.0, 6.0 and 4.0 h and the mean (SD) elimination half-lives were 31.9 (6.5), 27.2 (6.7) and 28.0 (6.6) h, respectively. The AUC and Cmax increased dose-dependently. The dose-normalized mean (SD) AUC and Cmax were different in each dosing group (p < 0.01) with 2.0 (0.8), 5.3 (1.2) and 6.0 (1.9) mg × hr/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized AUC, and 0.07 (0.01), 0.18 (0.05) and 0.21 (0.08) mg/l/mg in the 5 mg, 25 mg and 50 mg groups for dose-normalized Cmax, respectively, which indicates a lack of dose proportionality. CONCLUSION: A lack of dose proportional properties was shown in the 5 mg dose relative to the 25 mg and 50 mg doses of sertraline. This shows that the PK parameters for low-dose sertraline could be different from those in clinical concentrations.

Pharmacokinetics and tolerability of probucol after multiple oral administrations in healthy volunteers.

BACKGROUND: Probucol is indicated for primary hyperlipidemia and for hypercholesterolemia with hypertriglyceridemia. The objective of this study was to evaluate the tolerability and pharmacokinetics of probucol by multiple oral administration in healthy Korean male subjects. METHODS: This study was conducted by a randomized, openlabel, three-treatment, parallel-group design. A total of 30 subjects were randomly assigned to 1 of the 3 treatment groups were administered probucol orally at 250 mg once daily (QD) after breakfast (250 mg/d), at 500 mg once daily after breakfast (500 mg/d), or at 250 mg twice a day (b.i.d) after breakfast and dinner (500 mg/d) for 14 days. Serial samples of blood were collected and plasma drug concentrations were determined using liquid chromatography-tandem mass spectrometry (LC/MS/MS). For tolerability assessment, measurement of vital signs and electrocardiograms (ECG), clinical laboratory tests and physical examinations were performed. RESULTS: At Day 13, the mean of the AUC(24h) of probucol was 123,800 µg × h/l in the 250 mg QD group, 198,500 µg × h/l in the 500 mg QD group, and 244,700 µg × h/l in the 250 mg BID group. The mean accumulation index for AUC(24h) (ratio of AUC(24h) for Day 13 to that for Day 1) was 2.5 in the 250 mg QD group, 2.85 in the 500 mg QD group, and 4.21 in the 250 mg b.i.d. group. No clinically significant changes in ECG, including QTc prolongation were observed during the study period. All adverse events were mild and no clinically significant changes were observed in any other tolerability assessment, thus confirming tolerability for all regimens tested. CONCLUSIONS: This study provided data on the pharmacokinetics and tolerability of probucol by multiple oral administrations in healthy male volunteers.

Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers.

UNLABELLED: Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. OBJECTIVE: This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. METHODS: An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. RESULTS: The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of digoxin (with/without fimasartan) were 1.307 (1.123 - 1.520) and 1.087 (1.015 - 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. CONCLUSIONS: Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects.

Concomitant reconstruction of the medial collateral and posterior oblique ligaments for medial instability of the knee.

We present the operative technique and clinical results of concomitant reconstruction of the medial collateral ligament (MCL) and the posterior oblique ligament for medial instability of the knee using autogenous semitendinosus tendon with preservation of the tibial attachment. The semitendinosus tendon graft between the screw on the medial epicondyle and the tibial attachment of the graft was overlapped by the MCL, while the graft between the screw and the insertion of the direct head of the semimembranosus tendon was overlapped by the central arm of the posterior oblique ligament. Assessment was by stress radiograph and the Lysholm knee scoring scale. After a mean follow-up of 52.6 months (25 to 92), the medial joint opening of the knee was within 2 mm in 22 of 24 patients. The mean Lysholm score was 91.9 (80 to 100). Concomitant reconstruction of the MCL and posterior oblique ligament using autogenous semitendinosus tendon provides a good solution to medial instability.