A phase I, randomized study to evaluate the safety, tolerability, and pharmacokinetics of mefunidone in healthy subjects.

Background: Mefunidone is a novel synthetic compound and is better when compared to pirfenidone for the anti-fibrotic treatment of renal fibrosis in end-stage renal disease. We conducted this first-in-human, phase I clinical trial to determine the safety, tolerability, and pharmacokinetic (PK) (including food effect) profiles of mefunidone administered orally as single and multiple ascending doses in healthy subjects. Methods: Part A assessed single ascending doses of mefunidone from 25 mg to 800 mg or placebo once daily in the fasting state. Part A also assessed the effect of food on tolerability and PK in the 100 mg cohort. Part B consisted of three treatment groups who received 100 mg, 200 mg, or 400 mg of mefunidone or placebo twice daily (BID, bis in die) on days 1-6 and once in the morning on day 7. Results: Single oral doses of mefunidone up to 800 mg and multiple doses of mefunidone up to 400 mg BID were all well-tolerated. Mefunidone behaved with ideal dose proportionality within the single-dose range of 50 mg-600 mg and the multiple-dose range of 100 mg BID to 400 mg BID by day 7. High-fat fed conditions led to a delay in Tmax by approximately 1 h and a slight reduction of approximately 20% in Cmax compared to that in fasting conditions, but it did not significantly affect systemic exposure. Conclusion: Mefunidone exhibited favorable pharmacokinetics and safety profiles. The present study informed and supported further developmental clinical studies of mefunidone. Clinical Trial Registration: clinicaltrials.gov, identifier CXHL1900206.

Harnessing the dental cells derived from human induced pluripotent stem cells for hard tissue engineering.

INTRODUCTION: Most mineralized tissues in our body are present in bones and teeth. Human induced pluripotent stem cells (hiPSCs) are promising candidates for cell therapy to help regenerate bone defects and teeth loss. The extracellular matrix (ECM) is a non-cellular structure secreted by cells. Studies on the dynamic microenvironment of ECM are necessary for stem cell-based therapies. OBJECTIVES: We aim to optimize an effective protocol for hiPSC differentiation into dental cells without utilizing animal-derived factors or cell feeders that can be applied to humans and to mineralize differentiated dental cells into hard tissues. METHODS: For the differentiation of both dental epithelial cells (DECs) and dental mesenchymal cells (DMCs) from hiPSCs, an embryoid body (EB) was formed from hiPSCs. hiPSC were differentiated into neural crest cells with an induction medium utilized in our previous study, and hiPSC-derived DECs were differentiated with a BMP-modulated customized medium. hiPSC-dental cells were then characterized, analyzed, and validated with transcriptomic analysis, western blotting, and RT-qPCR. To form mineralized tissues, hiPSC-derived DECs were recombined with hiPSC-derived DMCs encapsulated in various biomaterials, including gelatin methacryloyl (GelMA), collagen, and agar matrix. RESULTS: These hiPSC-derived dental cells are highly osteogenic and chondro-osteogenic in photocrosslinkable GelMA hydrogel and collagen type I microenvironments. Furthermore, hiPSC-derived dental cells in agar gel matrix induced the formation of a bioengineered tooth. CONCLUSION: Our study provides an approach for applying hiPSCs for hard tissue regeneration, including tooth and bone. This study has immense potential to provide a novel technology for bioengineering organs for various regenerative therapies.

Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects.

BACKGROUND AND OBJECTIVE: TG103 is a novel GLP-1/Fc fusion protein, developed for the treatment of type 2 diabetes and obesity. This trial was designed to assess the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) profiles after single ascending dose of TG103 in healthy Chinese subjects. METHOD: In this double-blind, randomized, placebo-controlled phase I study, Chinese healthy subjects were admitted consecutively to TG103 3 mg, 7.5 mg, 15 mg, and 22.5 mg group with 8 subjects per group and randomized in a 3:1 ratio to receive TG103 treatment or placebo. Following a single subcutaneous(s.c.) injections of TG103, safety and tolerability were evaluated and blood samples were collected for PK and PD analysis at the specified time-points. RESULT: Overall, 32 healthy subjects were enrolled and completed the study. During the study, a total of 84 adverse effects (AEs) were reported in 25 subjects, all were mild or moderate and resolved spontaneously without intervention. The most common treatment related AEs in TG103 group were decreased appetite (41.7%), nausea, flatulence, elevated urinary ß2-microglobulin, increased serum total bile acid (20.8% each), decreased high-density lipoprotein (16.7%), abdominal distension (12.5%). After a single s.c. administration of TG103 3-22.5 mg, the median Tmax was 36∼48 h, and mean t1/2 was about 147.16∼184.72 h. The mean Cmax for each group was 94.35±52.19, 337.67±56.71, 757.67±206.99, 1236.33±666.25 ng/mL, with AUC0-t of 14.93±7.67, 59.15±7.39, 91.79±20.41, 163.61±55.99 µg·h/mL, respectively. It showed a linear pharmacokinetic profile in the single dose of TG103 3 mg to 22.5 mg. Compared with placebo, fasting blood glucose decreased in all dose groups, most notably in the 15 mg group, which was consistent with the changes in blood glucose during OGTT, while 2-hour postprandial glucose decreased in all dose groups except 3 mg group. CONCLUSION: TG103 offers a potential option for hypoglycemic therapy with good tolerability and safety. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03990090; registered 18 June 2019.

A Single-center, Open-label, Parallel Control Study Comparing the Pharmacokinetics and Safety of a Single Oral Dose of Roflumilast and Its Active Metabolite Roflumilast N-oxide in Healthy Chinese and Caucasian Volunteers.

Roflumilast is a phosphodiesterase-4 inhibitor which treats chronic obstructive pulmonary disease (COPD). Roflumilast N-oxide is the major metabolite of roflumilast with a similar mechanism of action to roflumilast. Although racial differences in roflumilast drug disposition have been observed, the necessity of dose adjustment is subject to debate. This study compares the pharmacokinetics of a single 500 µg dose of roflumilast in healthy Chinese and Caucasian subjects under uniform conditions. Chinese subjects were found to have longer t1/2 and higher AUC0-t and Cmax than Caucasian subjects. The point estimates on the geometric mean of AUC0-t in Chinese subjects were 22% higher for roflumilast and 46% higher for roflumilast N-oxide. Point estimates on the geometric mean of Cmax were 9% and 24% higher for roflumilast and roflumilast N-oxide, respectively. Total phosphodiesterase-4 (PDE4) inhibitory (tPDE4i) activity, a theoretical parameter that describes the combined contribution to PDE4 inhibitory activity of roflumilast and roflumilast N-oxide, was 44% higher in Chinese subjects than in Caucasian subjects. With about a 10-fold higher plasma AUC compared to the parent roflumilast and a much longer observed half-life, roflumilast N-oxide has been estimated to contribute about 90% of tPDE4i, with 10% attributed to the parent compound roflumilast. Following body weight normalization, these figures were lower but remained significant. Safety analysis showed signs of reduced tolerance or different pharmacodynamic response to roflumilast in Chinese recipients than in Caucasians. Our results suggest that Chinese patients should receive a dose of roflumilast lower than 500 µg daily during future clinical trials.

Abnormal liver tests are not sufficient for diagnosis of hepatic graft-versus-host disease in critically ill patients.

Hepatic graft-versus-host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15-day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = -0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period -30 (days 30 to 16 before death) to period -15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.

Burden of Neisseria meningitidis infections in China: a systematic review and meta-analysis.

BACKGROUND: Neisseria meningitidis is a leading cause of bacterial meningitis and septicemia in children and young adults worldwide. The disease burden associated with N. meningitidis infections has not been systematically assessed in China. Therefore, we undertook this study to determine the burden of meningococcal disease in China. METHOD: We performed a systematic review and meta-analysis of articles on N. meningitidis incidence, carriage, seroprevalence and mortality rates in China by searching the Chinese BioMedical Database (CBM), China National Knowledge Infrastructure (CNKI), Wanfang database and PubMed for publications from January 2005 to Aug 2015. RESULTS: In total, 50 articles were included in our analysis. The overall incidence of meningococcal disease and associated mortality were estimated to be 1.84 (95% confidence interval (CI) 0.91-3.37) per 100 000 persons per year and 0.33 (95% CI 0.12-0.86) per 100 000 persons per year, respectively. N. meningitidis carriage rate among the healthy population was estimated to be 2.7% (95% CI 2.0-3.5%). Prevalence of antibodies against N. meningitidis serogroup A and C were estimated to be 77.3% (95% CI 72.4%-81.6%) and 33.5% (95% CI 27.0%-40.8%), respectively. No studies were found for serogroup specific disease burden. CONCLUSIONS: The overall incidence of meningococcal disease in China is low. The lower seroprevalence of serogroup C within the population suggests that it may pose a greater risk for meningococcal disease outbreak than serogroup A. The lack of data on serogroup disease burden by age groups suggests the implementation of laboratory based meningococcal surveillance systems are urgently needed in China.

Occupational stress among counselors in institutes of higher education in Guangdong Province / 中国职业医学

OBJECTIVE: To explore the occupational stress status and its influence factors among counselors in institutes of higher education in Guangdong Province. METHODS: By clustering random sampling method,260 counselors from 9universities in Guangdong Province were chosen as study subjects. The sub-questionnaires of Occupational Stress Inventory Revised Edition,included the Occupational Role Questionnaire( ORQ),Personal Strain Questionnaire( PSQ) and the Personal Resources Questionnaire( PRQ) were used to investigate their occupational tasks,stress reaction and coping resources,respectively. The related influence factors were also analyzed. RESULTS: The total scores of ORQ and PSQ of counselors in universities of Guangdong Province were higher than the national norm( P < 0. 01),while the PRQ total score was lower than the national norm( P < 0. 01); the counselors who had over professional task accounted for 13. 85%( 36 /260); the counselors who had occupational stress reaction accounted for 15. 77%( 41 /260); the counselors who lacked the personal coping resource accounted for 16. 54%( 43 /260). The logistic regression analysis indicated that the counselors in non-medical colleges had higher risk of more occupational tasks than those in medical college( P < 0. 05);the counselors aged 30 years or above were more prone to lack of personal coping resource than those aged under 30 years( P < 0. 01). CONCLUSION: Compared with the general population,the university counselors in Guangdong Province have more professional task,higher degree of occupational stress and more shortage of personal coping resources. Therefore,some intervention measures aiming at the main influence factors should be carried out to relieve the occupational stress.

[Analysis of diagnosis and treatment towards CHB patients complicated with fatty liver with complete virological response while biochemical suboptimal response].

OBJECTIVE: To analyze the reason of biochemical suboptimal response in CHB patients with complete virological response after more than 2 years standard treatment with Nucleos(t)-ide analogs (NUCs).To evaluate the efficacy and safety profiles of bicyclol tablets plus on the basis of the original treatment and lifestyle intervention. in CHB patients complicated with fatty liver. METHODS: In 40 patients with chronic hepatitis B meeting the inclusion criteria,the liver biopsy was conducted.And patients complicated with fatty liver were treated with bicyclol tablets (25 mg, t.i.d) additional consecutive 48 weeks. The changes of serum biochemistry indexes and liver fibrosis index were observed before and after treatment. RESULTS: Among 40 patients, 27 were complicated with fatty liver(69.23%), fatty degree in liver cell and liver inflammatory were closely related to the advanced fibrosis (x² =4.746, P=0.029; x² =5.072, P=0.024). The expression of HBsAg in serum and liver tissue showed no correlation with the advanced fibrosis (x² = 0.273, P=0.601; x² = 0.020, P =0.887) After bicyclol tablets treatment, serum biochemistry of patients complicated with fatty liver significantly decreased (F=58.045, P =0.000), plasma GST-PX significantly increased (t=15.109, P =0.000), plasma MDA significantly decreased (t=-10.786, P=0.000); LSM significantly decreased (t=2.255, P=0.036; t =5.376, P =0.002). CONCLUSION: For the antiviral purpose of guide treatment, CHB patients treated with Nucleos(t)-ide analogs (NUCs) with biochemical suboptimal response, other risk factors should be considered as early as possible. Bicyclol plus lifestyle intervention was effective for chronic hepatitis B combined fatty liver patients with poor biochemical responses.

[Relationship between intestinal mucosal inflammation and mental disorders in patients with irritable bowel syndrome].

OBJECTIVE: To examine the relationship between inflammation and the comorbidity of mental disorders with irritable bowel syndrome (IBS) by comparing intestinal mucosa inflammatory biomarkers in patients with and without mental disorders. METHODS: A total of 43 consecutive IBS patients fulfilling the Rome III criteria and 15 volunteers serving as controls without digestive symptoms were recruited and interviewed with Composite International Diagnostic Interview (CIDI) by the well-trained staff and thus classified as with or without mental disorders. All subjects underwent colonoscopy and biopsies were acquired from the mucosa of distal ileum and colon. CD3(+) lymphocytes, mast cells, 5-HT positive cells and (indoleamine 2,3-dioxygenase) IDO positive cells were identified immunohistologically in mucosa biopsies in volunteers (n = 13), IBS patients without mental disorder (n = 24) and IBS patients with mental disorder (n = 19). RESULTS: The incidence of mental disorders in IBS patients was significantly higher than that in the volunteers (19/43 vs 2/15, P = 0.012), including 9 patients with anxiety disorders and 8 with mood disorders. (1) The number of mast cells in IBS patients with mental disorder and that in IBS patients without mental disorder has no statistical significance ((16.7 ± 3.6)/HP vs (15.4 ± 3.1)/HP in distal ileum, (12.8 ± 2.2)/HP vs (12.3 ± 2.5)/HP in sigmoid, both P > 0.05). Similar results were seen in 5-HT positive cells ((3.7 ± 0.9)/HP vs (3.4 ± 0.8)/HP in distal ileum, (6.1 ± 1.8)/HP vs (5.2 ± 1.8)/HP in sigmoid, both P > 0.05). In distal ileum, the number of CD3(+) cells in IBS patients with mental disorder has no statistical significance with that in the IBS patients without mental disorder ((62 ± 16)/HP vs (55 ± 22)/HP, P > 0.05). Similar results were seen in IDO positive cells (6(2, 8)/HP vs 2(1, 5)/HP, P > 0.05). (2) The number of IDO positive cells from distal ileum in IBS patients with anxiety disorder was significantly higher than that in the IBS patients without mental disorder (6 (4,8) vs 2 (1,5), P = 0.018). The number of mast cells from distal ileum in the IBS patients with mood disorder were significantly higher than that in those without mental disorders ((18.3 ± 3.2)/HP vs (15.4 ± 3.1)/HP, P = 0.032). CONCLUSIONS: Mental disorders in the IBS patients may be associated with intestinal mucosal inflammation. The activation of IDO may cause the comorbidity of IBS with anxiety disorder while the activation of mast cells probably leads to the comorbidity of IBS with mood disorder.

[Psychiatric comorbidities in patients referred for irritable bowel syndrome].

OBJECTIVE: To assess the prevalence of psychiatric comorbidities in patients referred for irritable bowel syndrome (IBS) with questionnaires for mental disorders. METHODS: A total of 83 IBS patients at our hospital were enrolled and assessed with the Personality Diagnostic Questionnaire for DSM-IV, version 4 (PDQ-4) and Composite International Diagnostic Interview, version 3.0 and 2.1 (CIDI-3.0 & CIDI-2.1) by trained interviewers. Such items as personality dysfunction, mental disorder and somatization disorder were examined. RESULTS: The male-female ratio was 1.08/1. Their mean age was (38 ± 14) years old. Among them, 20 patients (24.1%) were constipation-predominant, 31 (37.3%) diarrhea-predominant, 15 (18.1%) mixed and 17 (20.5%) unclassified type. (1) Sixty-two (74.7%) patients scored positive for any personality dysfunction. There was no significant gender difference. The cluster C (anxious-fearful) personality disorder was most commonly found in IBS patients (n = 58, 69.9%). The prevalence of somatoform disorders plus personality dysfunction was 46.8% (29/62). It was significantly higher than those without personality dysfunction [19.0% (4/21), P = 0.025]. (2) Thirty-seven patients (44.6%) had a lifetime CIDI-3.0 diagnosis. It was significantly higher than that in the general population. There was no gender difference. Anxiety and mood disorders were the most common types of psychiatric comorbidities [n = 21 (25.3%) and n = 19 (22.9%) respectively]. The lifetime prevalence of alcohol or nicotine abuse and(or) dependence and intermittent explosive disorder were 10.8% (n = 9) and 8.4% (n = 7). Psychiatric comorbidities were most commonly found in diarrhea-predominant patients (58.1%). But there was no significant difference among the subgroups. (3) Thirty-three patients (39.8%) had somatoform disorders. Neither gender nor subgroup difference was observed. The IBS patients with anxiety disorders presented significantly more somatoform disorders than the remainders [61.9% (13/21) vs 32.3% (20/62), P = 0.016]. CONCLUSION: Such psychiatric comorbidities as anxiety disorders and mood disorders are common in patients referred for IBS. The patients with personality dysfunction and(or) anxiety were more likely to suffer somatoform disorders. A gastroenterologist should grasp a thorough knowledge and make appropriate therapeutic recommendations for those patients.

[Personality traits in patients referred for functional dyspepsia].

OBJECTIVE: To assess the prevalence of Personality Diagnostic Questionnaire (PDQ)-personality deviations in patients referred for functional dyspepsia (FD) with reliable and universal psychological measures, and to explore the relationship between co-occurring PDQ-personality deviations and functional dyspepsia. METHODS: The sample comprised 246 patients referred for functional dyspepsia. Four groups were divided according to their patterns of gastrointestinal symptoms: the FD group, FD with reflux-like symptom group (FD + RS group), FD with irritable bowel syndrome group (FD + IBS group), and FD with reflux-like symptom and irritable bowel syndrome group (FD + RS + IBS group). Participants were assessed with the Personality Diagnostic Questionnaire for DSM-IV (PDQ-4) to evaluate the presence of personality deviations. RESULTS: Overall 65% patients scored positive for any personality deviation, male and female alike. Cluster C (anxious/fearful) personality was most commonly found in FD patients (142 patients, 57.7%). The FD + IBS group and the FD + RS + IBS group had significantly higher total PDQ scores than the FD group (23.39 ± 8.77 and 24.22 ± 10.97 vs 18.98 ± 11.88, P < 0.05, respectively), indicating that FD patients with greater level of personality deviations tend to report other symptoms involving the esophagus and lower gastrointestinal tract. Reflux-like symptom without actual pathological acid regurgitation indicated cluster A (odd/eccentric) personality deviations. CONCLUSIONS: The current study shows personality deviations are common in patients referred for functional dyspepsia. Negative emotions, maladaptive coping, and lack of social support, may strongly influence their healthcare-seeking behavior. There is no single personality type specific for some kind of gastrointestinal symptom. But FD patients with personality deviations tend to report other symptoms involving the esophagus and lower gastrointestinal tract.