Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions.Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz ® ) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultraperformance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ) for the test formulation were 52.67 ng/mL and 133.86 ng·h/mL, respectively, and 50.61 ng/mL and 133.49 h·ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944–1.148) and 1.003 (0.968–1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.Trial Registration: ClinicalTrials.gov Identifier: NCT04278391

Bioequivalence of the pharmacokinetics between tofacitinib aspartate and tofacitinib citrate in healthy subjects

Tofacitinib is an oral disease-modifying anti-rheumatic drug to selectively inhibit Janus kinases. Tofacitinib is a representative small molecule inhibitor that is used to treat many diseases including rheumatoid arthritis and various autoimmune conditions.Unlike biological agents, tofacitinib has several advantages, including the ability to be administered orally and a short half-life. This study aimed to evaluate the bioequivalence of the pharmacokinetics (PK) between tofacitinib aspartate 7.13 mg (test formulation) and tofacitinib citrate 8.08 mg (reference formulation; Xeljanz ® ) in healthy subjects. A randomized, open-label, single-dose, 2-sequence, 2-period, 2-treatment crossover trial was conducted in 41 healthy volunteers. A total of 5 mg of tofacitinib as the test or the reference formulation was administered, and serial blood samples were collected up to 14 hours after dosing for PK analyses. The plasma concentration of tofacitinib was determined by ultraperformance liquid chromatography-tandem mass spectrometry. A non-compartmental analysis was used to estimate the PK parameters. A total of 35 subjects completed the study and the study drug was well-tolerated. The mean maximum concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ) for the test formulation were 52.67 ng/mL and 133.86 ng·h/mL, respectively, and 50.61 ng/mL and 133.49 h·ng/mL for the reference formulation, respectively. The geometric mean ratios (90% confidence intervals) of the Cmax and AUClast between the 2 formulations were 1.041 (0.944–1.148) and 1.003 (0.968–1.039), respectively. Tofacitinib aspartate exhibited bioequivalent PK profiles to those of the reference formulation.Trial Registration: ClinicalTrials.gov Identifier: NCT04278391

A Randomized Clinical Trial of Synbiotics in Irritable Bowel Syndrome: Dose-Dependent Effects on Gastrointestinal Symptoms and Fatigue / 가정의학회지

BACKGROUND: This double-blind, randomized controlled design study aimed to assess the dose-dependent effects of synbiotics on gastrointestinal symptoms of and fatigue in irritable bowel syndrome (IBS). METHODS: Thirty subjects with IBS were randomly assigned into the following three groups and received 2 capsules a day for 8 weeks: (1) high-dose (2 capsules of synbiotics); (2) low-dose (1 capsule of synbiotics and 1 capsule of placebo); and (3) placebo (2 capsules of placebo). At baseline and 8 weeks, they completed the study questionnaires. RESULTS: Two subjects in the high-dose group were lost to follow-up, leaving a total of 28 patients for the analysis. After 8 weeks, abdominal discomfort, abdominal bloating, frequency of formed stool, fatigue Visual Analog Scale (VAS), and Multidimensional Fatigue Inventory were significantly different among the groups (P=0.002, 0.006, 0.007, 0.028, and 0.041, respectively, by Kruskal-Wallis test). However, only abdominal discomfort, abdominal bloating, frequency of formed stool, and fatigue VAS were significantly improved in the high-dose group compared with those in the placebo group (P=0.002, 0.003, 0.002, and 0.013, respectively) by Mann-Whitney test with Bonferroni correction. No adverse drug reactions were reported. CONCLUSION: High-dose synbiotics were superior to placebo in improving bowel symptoms and fatigue of IBS patients, suggesting that synbiotic dosage plays an important role in the treatment of IBS.

Biological Aspects of Aggression and Violence in Schizophrenia

Although the majority of patients with schizophrenia are not actually violent, an increased tendency toward violent behaviors is known to be associated with schizophrenia. There are several factors to consider when identifying the subgroup of patients with schizophrenia who may commit violent or aggressive acts. Comorbidity with substance abuse is the most important clinical indicator of increased aggressive behaviors and crime rates in patients with schizophrenia. Genetic studies have proposed that polymorphisms in the promoter region of the serotonin transporter gene and in the catechol-O-methyltransferase gene are related to aggression. Neuroimaging studies have suggested that fronto-limbic dysfunction may be related to aggression or violence. By identifying specific risk factors, a more efficient treatment plan to prevent violent behavior in schizophrenia will be possible. Management of comorbid substance use disorder may help prevent violent events and overall aggression. Currently, clozapine may be the only effective antipsychotic medication to repress aggressive behavior. With the current medical field moving toward tailored medicine, it is important to identify vulnerable schizophrenia populations and provide efficient treatment.

Efficacy and Safety of "URSA Complex" in Subjects with Physical Fatigue: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Fatigue is a common symptom both in diseases status and in healthy subjects. Various supplements and nutraceuticals for relieving of fatigue have been used. However, there are a few studies to evaluate the efficacy and the safety of the drug for fatigue alleviation, we conducted using URSA Complex to evaluate the efficacy on physical fatigue via score changes in the checklist individual strength (CIS).</p><p><b>METHODS</b>The study was designed as a multicenter, randomized, double-blind, placebo-controlled trial, with subjects randomized to one of the two arms, receiving either placebo or URSA Complex administered as identical capsules. The primary efficacy endpoints of this clinical trials are the ratio of improving CIS scores < 76 points in patients at the end (4 weeks). Secondary efficacy variables are as follows one is an improvement of fatigue and the other is an improvement of the liver enzyme.</p><p><b>RESULTS</b>The fatigue recovery rate in who had improved CIS scores of < 76 points were 70.0%, 50.9% in the therapy group and placebo group, respectively (P = 0.019). The fatigue recovery rate in CIS score was higher in URSA Complex therapy group than placebo group. The difference between therapy group and placebo group was statistically significant at 4 weeks later, but not 2 weeks.</p><p><b>CONCLUSIONS</b>Our results provided that the URSA Complex was effective in alleviating physical fatigue. The adverse event frequency in the therapy groups was similar to that in the placebo group.</p>

Coronary Calcification Is Reversely Related with Bone and Hair Calcium: The Relationship among Different Calcium Pools in Body

BACKGROUND: With aging, calcium efflux from bone is increased with age-related bone loss, and it can reduce bone mineral density (BMD). On the contrary, age-related calcium adoption into arterial wall progressively stiffens blood vessels. Theses process insinuates shift of calcium among different pools in body. However, their relationships have not been elucidated yet. So we investigated the correlation among calcium contents in different body pools, such as hair, bone, and blood vessels in women. METHODS: We analyzed 50 females retrospectively who measured Agatston coronary artery calcium score (CACS), BMD, and hair calcium concentration at a regular health check-up in a university hospital. CACS was achieved by coronary multidetector computed tomography, BMD was measured by dual energy X-ray absorptiometry in the lumbar spine and femur, and hair calcium level was checked by hair tissue mineral analysis. RESULTS: CACS inversely correlated with BMD (r=-0.280, P=0.049 with lumbar vertebrae 1-4, r=-0.310, P=0.028 with femur neck, r=-0.333, P=0.018 with femur total) and hair calcium concentration (r=-0.352, P=0.012). CONCLUSIONS: CACS has negative correlation with BMD and hair calcium level in women. Different body calcium pools such as bone, hair and blood vessel significantly correlated each other.

Reference Intervals for Plasma Amyloid β in Korean Adults Without Cognitive Impairment

Amyloid β (Aβ) peptides are important components of plaques in patients with Alzheimer's disease (AD). Recent studies suggest that a low plasma ratio of Aβ42 to Aβ40 may precede the development of the sporadic form of AD. The aim of this study was to establish reference intervals for plasma Aβ in Korean adults. A total of 370 apparently healthy individuals (181 males and 189 females aged 40-69 yr) without cognitive impairment were enrolled. Plasma concentrations of Aβ40 and Aβ42 were measured by using a human amyloid β assay kit (Immuno-Biological Laboratories, Japan). Reference intervals were established according to the "CLSI guidelines for defining, establishing, and verifying reference intervals in the clinical laboratory". There was no need to partition the data with respect to gender or age group. The 95th percentile reference intervals for Aβ40 and Aβ42 were 127-331 pg/mL and 2.31-19.84 pg/mL, respectively. The reference interval for the Aβ42/Aβ40 ratio was 0.011-0.092. Plasma Aβ concentrations obtained in this study could be used as reference intervals for clinical purposes.

Serum Gamma-glutamyl Transferase Concentration Within the Reference Range is Related to the Coronary Heart Disease Risk Prediction in Korean Men: Analysis of the Korea National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011) / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Limited data exist on the association of serum gamma-glutamyl transferase (GGT) level within the reference range with the increased risk of coronary heart disease (CHD) prediction in men. The study examined the association between serum GGT concentration within the reference range and the CHD risk prediction in Korean men.</p><p><b>METHODS</b>The study employed data from Korean National Health and Nutrition Examination Survey (V-1, 2010 and V-2, 2011) where a total of 1301 individuals were analyzed. A 10-year CHD risk prediction was computed using the Framingham Risk Score (FRS) modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III).</p><p><b>RESULTS</b>Positive correlations were established between log-transformed GGT concentration and FRS (r = 0.237, P < 0.001). After adjustment of body mass index, the amount of alcohol intake and low-density lipoprotein-cholesterol, the odds ratio (95% confidence interval) for intermediate risk and beyond of 10-year CHD prediction (10-year risk ≥10%) with lowest quartile of participants was 1.21 (0.78-1.87) for second quartiles, 1.39 (0.88-2.21) for third quartiles and 2.03 (1.23-3.34) for highest quartiles.</p><p><b>CONCLUSIONS</b>Higher serum GGT within its reference range was significantly correlated with a 10-year CHD risk prediction estimation using NCEP ATP III in Korean men.</p>

Relationship of plasminogen activator inhibitor 1 gene 4G/5G polymorphisms to hypertension in Korean women / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Hypertension (HTN) is a major determinant of various cardiovascular events. Plasma levels of plasminogen activator inhibitor 1 (PAI-1) modulate this risk. A deletion/insertion polymorphism within the PAI-1 loci (4G/4G, 4G/5G, 5G/5G) affects the expression of this gene. The present study investigated the association between PAI-1 loci polymorphisms and HTN in Korean women.</p><p><b>METHODS</b>Korean women (n = 1312) were enrolled in this study to evaluate the association between PAI-1 4G/5G gene polymorphisms and HTN as well as other metabolic risk factors. PAI-1 loci polymorphisms were investigated using polymerase chain reaction amplification and single-strand conformation polymorphism analysis.</p><p><b>RESULTS</b>The three genotype groups differed with respect to systolic blood pressure (P = 0.043), and diastolic blood pressure (P = 0.009) but not with respect to age, body mass index, total cholesterol, low or high density lipoprotein cholesterol, triglycerides, or fasting blood glucose. Carriers of the PAI-1 4G allele had more hypertension significantly (PAI-1 4G/5G vs. PAI-1 5G/5G, P = 0.032; PAI-1 4G/4G vs. PAI-1 5G/5G, P = 0.034). When stratified according to PAI-1 4G/5G polymorphism, there was no significant difference in all metabolic parameters among PAI-1 genotype groups in patients with HTN as well as subjects with normal blood pressure. The estimated odds ratio of the 4G/4G genotype and 4G/5G for HTN was 1.7 (P = 0.005), and 1.6 (P = 0.015), respectively.</p><p><b>CONCLUSION</b>These findings might indicate that PAI-1 loci polymorphisms independently contribute to HTN and that gene-environmental interaction may be not associated in Korean women.</p>

Combination of high-sensitivity C-reactive protein and homocysteine may predict an increased risk of coronary artery disease in Korean population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The association of emerging biomarkers such as high-sensitivity C-reactive protein (hs-CRP), homocysteine and fibrinogen with the risk of coronary artery disease (CAD) is still uncertain in Asian population including Koreans and little is known about the combined effect of biomarkers on the risk of CAD.</p><p><b>METHODS</b>A total of 10 650 subjects (6538 men and 4112 women) were enrolled in this study. A 10-year CAD risk was calculated using Framingham risk score modified by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) and levels of circulating hs-CRP, homocysteine and fibrinogen were measured using validated assays.</p><p><b>RESULTS</b>The 10-year CAD risk gradually augmented with increase in the circulating levels of hs-CRP, homocysteine and fibrinogen. For the highest quartile of hs-CRP, odds ratio (OR) of high-risk for CAD (10-year risk ≥ 20%) compared with the lowest quartile was 3.97 (95%CI: 2.51 - 6.29). For homocysteine and fibrinogen, ORs in the highest quartile compared to the lowest quartile were 5.10 (95%CI: 3.05 - 8.53, P < 0.001) and 1.46 (95%CI: 0.69 - 3.11, P = 0.325), respectively. OR of high-risk for CAD in both the highest quartile of hs-CRP and homocysteine was 9.05 (95%CI: 5.30 - 15.45) compared with the below median of hs-CRP and homocysteine.</p><p><b>CONCLUSIONS</b>The present study demonstrated that hs-CRP and homocysteine are well associated with the 10-year CAD risk estimated using NCEP ATP III in Koreans and combination of hs-CRP and homocysteine can have strong synergy in predicting the development of CAD.</p>

Women with Fibromyalgia Have Lower Levels of Calcium, Magnesium, Iron and Manganese in Hair Mineral Analysis

Little is known about hair mineral status in fibromyalgia patients. This study evaluated the characteristics of hair minerals in female patients with fibromyalgia compared with a healthy reference group. Forty-four female patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria were enrolled as the case group. Age- and body mass index-matched data were obtained from 122 control subjects enrolled during visit for a regular health check-up. Hair minerals were analyzed and compared between the two groups. The mean age was 43.7 yr. General characteristics were not different between the two groups. Fibromyalgia patients showed a significantly lower level of calcium (775 microg/g vs 1,093 microg/g), magnesium (52 microg/g vs 72 microg/g), iron (5.9 microg/g vs 7.1 microg/g), copper (28.3 microg/g vs 40.2 microg/g) and manganese (140 ng/g vs 190 ng/g). Calcium, magnesium, iron, and manganese were loaded in the same factor using factor analysis; the mean of this factor was significantly lower in fibromyalgia group in multivariate analysis with adjustment for potential confounders. In conclusion, the concentrations of calcium, magnesium, iron, and manganese in the hair of female patients with fibromyalgia are lower than of controls, even after adjustment of potential confounders.

Carcinoembryonic Antigen Level Can be Overestimated in Metabolic Syndrome

Carcinoembryonic antigen (CEA) levels can be affected by many factors and metabolic syndrome is also a candidate. This study examined the relationship between CEA levels and metabolic syndrome using the data of 32,897 healthy Koreans. Fecal occult blood tests were also performed. Subjects with colorectal carcinoma were excluded. Subjects were classified by their smoking status, metabolic syndrome and its components. Prevalence of metabolic syndrome and its all components showed a significant increase according to the quartile of serum CEA concentration (P < 0.001). Increased numbers of metabolic syndrome components showed a positive association with CEA levels (P-trend < 0.001). The odds ratios for the highest CEA quartile vs the lowest serum CEA quartile significantly increased in the presence of metabolic syndrome and its components. After adjusting for age, gender and smoking status, metabolic syndrome, low high density lipoprotein cholesterol and elevated blood pressure had higher odds ratios (OR) of the highest CEA quartile compared with the lowest serum CEA quartile (OR = 1.125, 95% CI = 1.030 to 1.222, P = 0.009; OR = 1.296, 95% CI = 1.195 to 1.405, P < 0.001; OR = 1.334, 95% CI = 1.229 to 1.448, P < 0.001, respectively). These results indicate that metabolic syndrome is associated with CEA value, which may lead to a misunderstanding of the CEA levels.

Vitamin K Supplement Along with Vitamin D and Calcium Reduced Serum Concentration of Undercarboxylated Osteocalcin While Increasing Bone Mineral Density in Korean Postmenopausal Women over Sixty-Years-Old

There are inconsistent findings on the effects of vitamin K on bone mineral density (BMD) and undercarboxylated osteocalcin (UcOC). The present intervention study evaluated the effect in subjects over 60-yr-old. The vitamin K group (vitamin K + vitamin D + calcium supplement; 15 mg of vitamin K2 [menatetrenone] three times daily, 400 IU of vitamin D once a day, and 315 mg of calcium twice daily) and the control group (vitamin D + calcium supplement) were randomly assigned. During the six months of treatment, seventy eight women participated (38 in the vitamin K group and 40 in the control group) and 45 women completed the study. The baseline characteristics of study participants did not differ between the vitamin K and the control groups. In a per protocol analysis after 6 months, L3 bone mineral density has increased statistically significantly in the vitamin K group compared to the control group (0.01 +/- 0.03 g/cm2 vs -0.008 +/- 0.04 g/cm2, P = 0.049). UcOC concentration was also significantly decreased in the vitamin K group (-1.6 +/- 1.6 ng/dL vs -0.4 +/- 1.1 ng/dL, P = 0.008). In conclusion, addition of vitamin K to vitamin D and calcium supplements in the postmenopausal Korean women increase the L3 BMD and reduce the UcOC concentration.