The mediation effect of health literacy on social support and health lifestyle of patients with chronic diseases.

BACKGROUND: Previous studies have identified the antecedents of the lifestyle of many patients with chronic diseases. However, the mechanism of social support affecting the lifestyle of patients with chronic diseases is unclear, and the role of health literacy in social support affecting the lifestyle of patients with chronic diseases has not been found. Therefore, this study aims to explore the status quo of social support, health literacy and healthy lifestyle of patients with chronic diseases in China and the relationship among them. METHODS: Through convenient sampling, 356 patients with chronic diseases were surveyed using a health promoting lifestyle scale, a chronic disease patients' health literacy scale and a social support scale. RESULTS: There was a pairwise positive correlation between social support, health lifestyle and health literacy (R = 0.397,0.356,0.556, P < 0.01). After controlling gender, age and education level, it is found that social support has a positive impact on health lifestyle, and health literacy plays an intermediary role between social support and health lifestyle, accounting for 45.78 % of the total effect. CONCLUSION: To promote the healthy lifestyle of patients with chronic diseases and delay the development of the disease, we should strengthen social support for patients with chronic diseases; We should simultaneously take various measures to improve their health literacy.

Safety, tolerability, pharmacokinetics, and antiviral activity of the novel core protein allosteric modulator ZM-H1505R (Canocapavir) in chronic hepatitis B patients: a randomized multiple-dose escalation trial.

BACKGROUND: Hepatitis B virus (HBV) core protein-targeting antivirals (CpTAs) are promising therapeutic agents for treating chronic hepatitis B (CHB). In this study, the antiviral activity, pharmacokinetics (PK), and tolerability of ZM-H1505R (Canocapavir), a chemically unique HBV CpTA, were evaluated in patients with CHB. METHODS: This study was a double-blind, randomized, placebo-controlled phase 1b trial in Chinese CHB patients. Noncirrhotic and treatment-naive CHB patients were divided into three cohorts (10 patients per cohort) and randomized within each cohort in a ratio of 4:1 to receive a single dose of 50, 100, or 200 mg of Canocapavir or placebo once a day for 28 consecutive days. RESULTS: Canocapavir was well tolerated, with the majority of adverse reactions being grade I or II in severity. There were no serious adverse events, and no patients withdrew from the study. Corresponding to 50, 100, and 200 mg doses of Canocapavir, the mean plasma trough concentrations of the drug were 2.7-, 7.0-, and 14.6-fold of its protein-binding adjusted HBV DNA EC50 (135 ng/mL), respectively, with linear PK and a low-to-mild accumulation rate (1.26-1.99). After 28 days of treatment, the mean maximum HBV DNA declines from baseline were -1.54, -2.50, -2.75, and -0.47 log10 IU/mL for the 50, 100, and 200 mg of Canocapavir or placebo groups, respectively; and the mean maximum pregenomic RNA declines from baseline were -1.53, -2.35, -2.34, and -0.17 log10 copies/mL, respectively. CONCLUSIONS: Canocapavir treatment is tolerated with efficacious antiviral activity in CHB patients, supporting its further development in treating HBV infection. TRIAL REGISTRATION: ClinicalTrials.gov, number NCT05470829).

MicroRNA-138 Regulates Spinal Cord Development by Activating the Shh in Fetal Rats.

INTRODUCTION: Dysregulation of spinal cord development can lead to serious neuronal damage and dysfunction, causing significant health problems in newborns. MiRNA-138 appears to be crucial for proliferation, differentiation, and apoptosis of cells. However, the regulation of miRNA-138 and downstream molecules in embryonic spinal cord development remain elusive. The aim of this experiment is to determine whether overexpression of miRNA-138 or RNA interference (RNAi) can regulate the development of spinal cord in fetal rats. METHODS: Two plasmid vectors including pLenti-III-mico-GFP (miRNA-138 open reading frame [ORF]) and pLenti-III-miR-Off (miRNA-138 short hairpin) were constructed and injected into the tail vein of rats on the 14th day of pregnancy. Hematoxylin-eosin (HE) staining was used to observe the cell morphology. QRT-PCR, Western blot, and immunostaining confirmed the regulatory relationship between miRNA-138 and downstream molecules sonic hedgehog (Shh). RESULTS: Overexpression of miRNA-138 increased neuron regeneration significantly and decreased neuronal apoptosis when compared with the control. Silencing of miRNA-138 increased neuronal apoptosis and spinal cord atrophy significantly. Furthermore, miRNA-138 ORF treatment effectively increased the expression level of miRNA-138 and also upregulated the level of Shh. Comparatively, knockdown of miRNA-138 downregulated Shh levels in myelodysplastic regions. CONCLUSION: These findings indicated that miRNA-138 overexpression could protect the spinal cord development of fetal rats, and the underlying mechanisms were associated with Shh expression. The present study provides a novel strategy to promote the molecular mechanism of embryonic spinal cord development.

Regulatory emotional self-efficacy and psychological distress among medical students: multiple mediating roles of interpersonal adaptation and self-acceptance.

BACKGROUND: Psychological distress (depression, anxiety and stress) is more common among medical students than in the general population, and is an important cause of insomnia, internet addiction, substance abuse, decreased academic performance and increased suicidality in medical students. METHODS: To examine the mechanism by which regulatory emotional self-efficacy affects medical students' psychological distress, a questionnaire of 539 medical students using an interpersonal adaptability scale, regulatory emotional self-efficacy scale, self-acceptance scale and depression-anxiety-stress scale was conducted. RESULTS: ① Regulatory emotional self-efficacy, interpersonal adaptability and self-acceptance are positively correlated, but they are negatively correlated with psychological distress. ② The mediation model shows that interpersonal adaptation and self-acceptance are the mediation variables of the effect of regulatory emotional self-efficacy on psychological distress, and the total mediation effect value is -0.37, accounting for 86.05% of the total effect (-0.43). Specifically, the effect involves three paths: first, regulatory emotional self-efficacy indirectly affects psychological distress through interpersonal adaptation (effect value-0.24); second, regulatory emotional self-efficacy indirectly affects psychological distress through interpersonal adaptation and self-acceptance (effect value-0.08); and third, regulatory emotional self-efficacy indirectly affects psychological distress through self-acceptance (effect value -0.05). CONCLUSIONS: Interpersonal adaptation and self-acceptance have a significant mediating effect between regulatory emotional self-efficacy and psychological distress, and the chain mediating effect of interpersonal adaptation and self-acceptance is also significant.

Antiviral Activity and Pharmacokinetics of the Hepatitis B Virus (HBV) Capsid Assembly Modulator GLS4 in Patients With Chronic HBV Infection.

BACKGROUND: GLS4 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator (class I) that can inhibit HBV replication by interfering with the assembly and disassembly of HBV nucleocapsid. Here, we evaluated its antiviral activity, pharmacokinetics, and tolerability in a double-blind, randomized, parallel, entecavir-controlled study. METHODS: Twenty-four patients with chronic HBV were randomized to receive a 28-day course of GLS4 (120 or 240 mg) and ritonavir (100 mg) combination (cohorts A and B, respectively) or entecavir treatment (cohort C) at a 1:1:1 ratio. Patients were followed up for 40 days in a phase 1b study. RESULTS: The GLS4/ritonavir combination was a tolerated combination for the treatment of chronic HBV infection. A total of 2, 3, and 3 subjects presented with alanine aminotransferase flare in cohorts A, B, and C, respectively. This contributed to the withdrawal of 1, 2, and 1 patient from cohorts A, B, and C, respectively. The mean Ctrough of GLS4 was 205-218 ng/mL, which was approximately 3.7-3.9 times the 90% effective concentration (55.8 ng/mL), with a lower accumulation (accumulation rate, 1.1-2.0). In cohorts A, B, and C, the mean declines in HBV DNA after 28 days of treatment were -1.42, -2.13, and -3.5 log10 IU/mL; in hepatitis B surface antigen were -0.06, -0.14, and -0.33 log10 IU/mL; in pregenomic RNA were -0.75, -1.78, and -0.96 log10 copies/mL; and in hepatitis B core antigen were -0.23, -0.5, and -0.44 log10 U/mL, respectively. CONCLUSIONS: Treatment with 120 mg GLS4 was tolerated and had antiviral activity in patients with chronic HBV infection. CLINICAL TRIALS REGISTRATION: Chinese Clinical Trial Registry; CTR20160068. http://www.chinadrugtrials.org.cn.

Safety, Tolerability, and Pharmacokinetics of the Novel Hepatitis B Virus Capsid Assembly Modulator GST-HG141 in Healthy Chinese Subjects: a First-in-Human Single- and Multiple-Dose Escalation Trial.

Hepatitis B virus capsid assembly modulators (HBV CAMs) are promising, clinically validated therapeutic agents for the treatment of chronic hepatitis B (CHB). The safety, tolerability, and pharmacokinetic (PK) profiles of GST-HG141, a novel HBV CAM, were evaluated in healthy Chinese volunteers. This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (50, 100, 200, 300, 400, or 500 mg) study comprising a food-effect investigation (300 mg) and a multiple-ascending-dose (MAD) (100 or 200 mg twice daily) study. GST-HG141 reached the maximum plasma concentration (Cmax) at 1.25 to 3.00 h (median Tmax). The exposure exhibited a linear increase, while the mean half-life (t1/2) ranged from 13.096 h to 22.121 h. The exposure of GST-HG141 (300 mg) was higher after food intake by about 2.4-fold. In the MAD study, steady state was reached at around day 5, and the mean trough steady-state concentrations were 423 and 588 ng/ml for 50- and 100-mg cohorts, respectively. The ratios of GST-HG141 accumulation were <1.5. GST-HG141 was well tolerated in healthy Chinese subjects. The rates of adverse events in the GST-HG141 cohort did not differ from those of the placebo cohort. GST-HG141 was tolerated in healthy Chinese subjects. The safety and PK profiles of GST-HG141 support the further evaluation of its efficacy in individuals with CHB. (This study has been registered in ClinicalTrials.gov under identifier NCT04536337.).

Sulfation predominates the pharmacokinetics, metabolism, and excretion of forsythin in humans: major enzymes and transporters identified.

Forsythin extracted from Forsythiae Fructus is widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, ~75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.

Pharmacokinetics and pharmacodynamics of rongliflozin, a novel selective inhibitor of sodium-glucose co-transporter-2, in people with type 2 diabetes mellitus.

AIMS: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of rongliflozin in a cohort of healthy Chinese people and people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: We examined the effects of a single ascending dose (SAD) of rongliflozin (10-200 mg) in combination with food (20 mg) in 50 healthy people, and a multiple ascending dose (MAD) of rongliflozin (10-50 mg once daily for 12 days) in 36 people with T2DM. RESULTS: No serious adverse events (AEs) or discontinuations as a result of AEs (related to rongliflozin) occurred in either study. In healthy participants and those with T2DM, rongliflozin was rapidly absorbed, with a time to maximum plasma concentration of 0.63 to 1.75 hours. Systemic exposure (maximum observed serum concentration and area under the curve) to rongliflozin and its inactive major metabolites (T1444, T1454 and T1830) increased in proportion to dose. In the SAD and MAD studies, there was a dose-related increase in urinary glucose excretion (UGE) ranging from 10 to 50 mg rongliflozin. This increase in UGE was associated with dose-related decreases in serum glucose values in people with T2DM in the MAD group. In the SAD group, UGE plateaued at 50 to 200 mg. CONCLUSIONS: Rongliflozin was well tolerated in all participants. The PK and PD measurements obtained for rongliflozin demonstrate a dose-response relationship when the drug is administered at doses ranging from 10 to 50 mg in healthy people and in people with T2DM.

Pharmacokinetics, pharmacodynamics and tolerability of single and multiple doses of janagliflozin, a sodium-glucose co-transporter-2 inhibitor, in Chinese people with type 2 diabetes mellitus.

AIMS: To evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and tolerability of janagliflozin, a novel sodium-glucose co-transporter-2 inhibitor, in Chinese people with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: In this study, 36 people with T2DM were randomly assigned in a 1:1:1:1 ratio to receive janagliflozin 25 mg, janagliflozin 50 mg, dapagliflozin 10 mg or placebo. Participants received a single dose on day 1, and were treated once daily from day 4 to day 17. RESULTS: Following oral administration, janagliflozin was rapidly absorbed, reaching Cmax at 2 hours. The mean half-life (t1/2 ) at steady state was approximately 21 to 23 hours. There was no significant accumulation with multiple doses (accumulation factor < 2). In participants treated with janagliflozin 25 mg, janagliflozin 50 mg, dapagliflozin 10 mg or placebo, change in mean 24-hour urinary glucose excretion from baseline was 92.35, 94.17, 87.61 and 6.26 g after multiple doses, and change in mean fasting plasma glucose level from baseline to day 17 was -2.18, -2.66, -2.79 and 1.70%, respectively. Most adverse events (AEs) were mild or moderate with no deaths, serious AEs, or discontinuations due to AEs. CONCLUSIONS: Single and multiple oral administration (14 days) of janagliflozin 25 mg and 50 mg exhibited favourable PK, PD and tolerability profiles in Chinese people with T2DM, which were comparable to those of dapagliflozin 10 mg. Janagliflozin 25 mg and 50 mg are recommended for further clinical investigation.

Virtual Reality Rehabilitation Versus Conventional Physical Therapy for Improving Balance and Gait in Parkinson's Disease Patients: A Randomized Controlled Trial.

BACKGROUND The aim of this study was to investigate the effect of virtual reality (VR) technology on balance and gait in patients with Parkinson's disease (PD). MATERIAL AND METHODS The study design was a single-blinded, randomized, controlled study. Twenty-eight patients with PD were randomly divided into the experimental group (n=14) and the control group (n=14). The experimental group received VR training, and the control group received conventional physical therapy. Patients performed 45 minutes per session, 5 days a week, for 12 weeks. Individuals were assessed pre- and post-rehabilitation with the Berg Balance Scale (BBS), Timed Up and Go Test (TUGT), Third Part of Unified Parkinson's Disease Rating Scale (UPDRS3), and Functional Gait Assessment (FGA). RESULTS After treatment, BBS, TUGT, and FGA scores had improved significantly in both groups (P<0.05). However, there was no significant difference in the UPDRS3 between the pre- and post-rehabilitation data of the control group (P>0.05). VR training resulted in significantly better performance compared with the conventional physical therapy group (P<0.05). CONCLUSIONS The results of this study indicate that 12 weeks of VR rehabilitation resulted in a greater improvement in the balance and gait of individuals with PD when compared to conventional physical therapy.

A phase I, randomized, double-blinded, single-dose study evaluating the pharmacokinetic equivalence of the biosimilar IBI305 and bevacizumab in healthy male subjects
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OBJECTIVE: To compare the pharmacokinetic (PK) profiles, immunogenicity, and safety of the proposed biosimilar IBI305 with those of bevacizumab in healthy male subjects. DESIGN: A phase I, randomized, double-blinded, two-arm, parallel-group study. SETTINGS: The study was conducted in The First Hospital of Jilin University, Changchun, China, from March 2017 to November 2017. PARTICIPANTS: A total of 100 healthy male subjects were enrolled, with 48 in the IBI305 group and 50 in bevacizumab group included in the final analysis. INTERVENTION: In a 16-week study course, participants were randomized at a 1:1 ratio to receive intravenous administration of either a single dose of 3 mg/kg IBI305 (n = 50) or bevacizumab (n = 50). OUTCOME MEASURES: The primary endpoints were area under the concentration-time curve from zero to the time of the last measurable concentration (AUC0-t) and AUC curve from zero to infinity (AUC0-∞). The secondary endpoints include the other PK parameters, immunogenicity, and safety measurements. RESULTS: AUC0-t, AUC0-∞, maximum concentration observed (Cmax), half-life (T1/2), drug clearance, and volume of distribution were similar between IBI305- and bevacizumab-treated subjects. For AUC0-∞, AUC0-t, and Cmax, the 90% confidence intervals for the ratios of geometric means were fully within the range 0.80 - 1.25, confirming the bioequivalence of the two investigational agents. Furthermore, no apparent difference in adverse events was found between the two groups. CONCLUSION: This study demonstrated the similarity of PK, immunogenicity, and safety profiles of IBI305 to those of bevacizumab.

Pharmacokinetics and safety profile of desmopressin oral tablet formulations in healthy Chinese subjects under fasting and fed conditions.

OBJECTIVE: Desmopressin acetate (DDAVP®) is a synthetic analogue of the pituitary hormone vasopressin. Until now, few studies of desmopressin have focused on the pharmacokinetics (PK) or food effects in Asian populations. This study aimed to assess the effect of food intake on the PK of desmopressin and bioequivalence of two tablet formulations in Chinese subjects. MATERIALS AND METHODS: A single-center, single-dose, randomized, open-label, two-period crossover study was conducted in 104 healthy Chinese volunteers under fasted or fed conditions (52 volunteers for each condition). Blood samples were collected up to 14 hours after administration of oral desmopressin tablets (0.6 mg; 0.2 mg × 3) in each period. Plasma desmopressin concentrations were analyzed by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK and bioavailability parameters were calculated. Adverse events (AEs) were also recorded. RESULTS: No significant differences in mean (standard deviation, SD) PK parameters were observed between formulation 1 (F1) and formulation 2 (DDAVP®; F2) under both fasted and fed conditions. All AEs observed were mild and resolved quickly without treatment. The maximum concentration (Cmax) and area under the curve (AUC) were significantly decreased (p < 0.01) when the drug was taken with food, compared with fasted subjects. CONCLUSION: These findings suggest that both tablet formulations were well tolerated. Food can significantly decrease the exposure of desmopressin.
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Evaluation of reference-scaled average bioequivalence of two oral formulations of abiraterone acetate in healthy Chinese subjects
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OBJECTIVE: This study was designed to evaluate the pharmacokinetic (PK) properties and bioequivalence (BE) of two 250-mg tablet formulations of abiraterone acetate: a newly developed generic formulation (test) and a branded formulation (reference) in healthy adult Chinese subjects under fasted (n = 40) and fed (n = 40) conditions. MATERIALS AND METHODS: The comparison was performed using a single-dose, open, randomized, and four-way replicate study. The concentration of abiraterone in blood samples taken over 48 hours was determined by liquid chromatography tandem mass spectrometry (LC-MS/MS). To assess the BE of the test and reference formulations, confidence intervals (CI, 90%) for the peak plasma concentration (Cmax) and area under the concentration-time curves (AUC0-t and AUC0-∞) were calculated using the reference-scaled average bioequivalence (RSABE) method. RESULTS: The results showed that the 90% CIs for the ratios of Cmax, AUC0-t, and AUC0-∞ in the fasted study were 90.14 - 114.11, 93.96 - 115.07, and 93.72 - 113.331, respectively. For the fed study, the 90% CIs were 81.83 - 102.51, 91.51 - 104.89, and 91.46 - 104.58, respectively. CONCLUSION: In conclusion, the tested 250-mg abiraterone tablets were bioequivalent to 250-mg Zytiga tablets (reference) under both fasted and fed conditions. In addition, food intake increased the systemic exposure and Cmax of abiraterone by 3-fold and 7-fold, respectively.
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Tolerability, pharmacokinetics and antiviral activity of rHSA/IFNα2a for the treatment of chronic hepatitis B infection.

AIMS: A recombinant human serum albumin-interferon alpha2a fusion protein (rHSA/IFNα2a) is expected to extend the half-life of IFNα2a. This study aims to evaluate the tolerability, safety and efficacy of rHSA/IFNα2a. METHODS: This is an open, randomized, positive control, multiple-dose ascending Phase Ib study. A panel of 32 treatment naïve and non-cirrhotic chronic hepatitis B patients were divided into four cohorts, and each received 600, 750 or 900 µg of rHSA/IFNα2a or 180 µg of PEG-IFNα2a for 3 months. Tolerability, pharmacokinetics and antiviral responses were assessed. RESULTS: Thirty-one of 32 enrolled patients completed the treatment study. The rHSA/IFNα2a treatment was better tolerated than the PEG-IFNα2a 180 µg treatment, as evidenced by blood cell counts and higher serum albumin levels. Half-life (t1/2 ) of rHSA/IFNα2a was estimated to be 120-140 h, and is potentially suitable for a dosing interval of 2 weeks or longer. Pharmacokinetics of the last dose between rHSA/IFNα2a 750 µg and PEG-IFNα2a 180 µg, with the exception of t1/2 , was comparable, and a similar kinetics of inhibiting HBV DNA replication was observed in both groups. Mean reductions in serum HBV DNA levels after treatment were -1.32, -2.13, -1.10 and -2.48 log10 IU/ml in the 600, 750 and 900 µg rHSA/IFNα2a groups and PEG-IFNα2a group, respectively. CONCLUSIONS: The rHSA/IFNα2a treatment was well tolerated and can be administered biweekly. Similar efficacy in inhibiting HBV replication was observed in both PEG-IFNα2a and rHSA/IFNα2a 750 µg groups.

Relationship between EGFR gene mutation and local metastasis of resectable lung adenocarcinoma.

BACKGROUND: Resectable lung adenocarcinoma is dominated by peripheral distribution, and surgical resection is the main treatment protocol. However, high recurrence rate remains after surgery. Lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation has strong invasion ability, but the effects of this mutation on local invasion in early lung adenocarcinoma have been rarely studied. This study aimed to assess the effects of EGFR mutation on local invasion in resectable lung adenocarcinoma. METHODS: A retrospective analysis of 103 patients clinically diagnosed with peripheral lung adenocarcinoma was included. They underwent preoperative bronchoscopy, which indicated grades 2 or 3 bronchial involvement (lumen of the lobe or segment). The associations of EGFR mutation with pleural invasion, endobronchial metastasis, and lymph node metastasis were analyzed according to pathologies of pleural invasion and lymph node metastasis, as well as EGFR gene mutation detected by postoperative pathological specimens. Statistical analyses were performed by unpaired Chi-square test using the SPSS16.0 software. RESULTS: In patients with EGFR mutation, pleural invasion, endobronchial metastasis, and lymph node metastasis rates were 62.5, 39.1, and 34.4%, respectively, indicating statistically significant differences (p = 0.003). Meanwhile, the pleural invasion rate in patients with wild-type EGFR was 43.6%, significantly reduced compared with patients with mutated EGFR (62.5%; p = 0.018). In addition, the endobronchial metastasis rate in patients with wild-type EGFR was 17.9%, significantly lower than in patients with EGFR mutation (39.1%; p = 0.005). However, lymph node metastasis rates were similar between EGFR mutated and wild-type patients (34.4 vs 25.6%, respectively, p > 0.05). CONCLUSIONS: Early resectable lung adenocarcinoma patients with EGFR mutation showed a higher rate of local invasion compared with those harboring wild-type EGFR. This finding provides a basis for improved therapy. TRIAL REGISTRATION: This study was supported by Project of Medical and Health Science Technology in Shandong Province ( 2015WS0376 ).

Bioequivalence and Pharmacokinetic Profiles of Agomelatine 25-mg Tablets in Healthy Chinese Subjects: A Four-Way Replicate Crossover Study Demonstrating High Intra- and Inter-Individual Variations.

The present study was designed to assess the bioequivalence of two agomelatine formulations (25-mg tablets) in healthy Chinese male subjects. This single-dose, open-label, randomized, four-way replicate study with a 1-week washout period was conducted in 60 healthy Chinese male volunteers under fasting conditions. Blood samples were collected over a 12-h period after a single dose of the 25-mg agomelatine test (T) formulation or a reference (R) formulation, and the drug concentrations were assayed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters were calculated using a non-compartmental model. Bioequivalence between the formulations was assessed. Tolerability and safety were monitored by physical examination, electrocardiogram (12-lead ECG), clinical laboratory tests, and adverse events (AEs). A total of 56 out of 60 subjects completed the study. No AEs were observed. The values of maximum plasma concentration (Cmax), maximum concentration (Tmax), area under curve (AUC)0-t and t1/2 were 12.032 ng/mL, 0.658 h, 12.637 ng·h/mL, and 0.813 h, respectively, for the test formulation, and 10.891 ng/mL, 0.709 h, 11.572 ng·h/mL, and 0.96 h, respectively, for the reference formulation. The intra-individual variability of Cmax and AUC0-t were 78.3 and 61.8%, respectively. The inter-individual coefficients of variance (CVs) of Cmax and AUC0-t were approximately 100%. The 90% confidence intervals for the ratio of means for the log-transformed Cmax (97.7-124.9%), AUC0-t (98.2-118%), and AUC0-∞ (97.8-117.2%) were within the guideline range of bioequivalence (80-125%). The test and reference formulations of agomelatine met the regulatory criteria for bioequivalence of the Chinese Food and Drug Administration. Significant intra-individual and inter-individual variations were found.

Clinical Application of High-Resolution Computed Tomographic Imaging Features of Community-Acquired Pneumonia.

BACKGROUND: This article discusses the value of high-resolution computed tomography (HRCT) in the diagnosis and treatment of pulmonary infections. Lung infection caused by pathogens is an important cause of death. Traditional methods to treat lung infection involved empirical antibiotic therapy. Thin-slice CT scanning is widely used in the clinical setting, and HRCT scan can very clearly show alveolar and bronchiolar involvement of infection. MATERIAL/METHODS: In total, 178 patients with community-acquired pneumonia (CAP) were enrolled. All the patients underwent CT scan, qualified sputum, and blood samples for culture or immunological biochemical tests. CT imaging features, pathogenic bacteria, and treatment results were used for statistical analysis. RESULTS: In 77 patients with lobar consolidation, the rate of detection was 43.26% (77/178), and in 101 patients with lobular pneumonia it was 56.74% (101/178). In 51 patients, pathogenic bacteria were detected (28.65%, 51/178). Sixteen of 33 patients detected with bacteria had cavities (48.5%, 16/33) and 35 of 145 patients detected with bacteria had no cavities (24.1%, 35/145). The difference between the 2 groups was statistically significant (χ(2)=7.795, P=0.005). According to the pathogenic bacteria, 38 patients were cured (74.51%, 38/51), and according to the CT imaging features 81 patients were cured (71.05%, 81/114). No statistically significant difference was found between them (χ(2)=0.209, P=0.647). CONCLUSIONS: Treatment effect of CAP based on HRCT findings is not inferior to treatment effect guided by microbial characterization.

In vitro cytotoxicity, pharmacokinetics and tissue distribution in rats of MXN-004, a novel conjugate of polyethylene glycol and SN38.

1. MXN-004 is a water-soluble PEGylated 7-ethyl-10-hydroxy-camptothecin (SN38). The aim of this study was to evaluate the in vitro cytotoxicity of MXN-004 and investigate pharmacokinetics and tissue distribution of MXN-004 and its active metabolite SN38 in rats. 2. In vitro cytotoxicity of MXN-004 was tested in A549, HepG2 and Caco-2 cancer cell lines by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and compared with irinotecan. The pharmacokinetics and tissue distribution of MXN-004, irinotecan and their identical active metabolite SN38 were investigated after intravenous administration of MXN-004 and irinotecan at a same dose level of 16 µmol/kg in rats. 3. In vitro cytotoxicity study showed that MXN-004 was more potent in comparison with irinotecan. In rats, MXN-004 exhibited a longer half-life (sixfold) and much greater Vss as compared with irinotecan. The AUC0-∞, T1/2 and Cmax of SN38 after intravenous administration of MXN-004 were higher than those of irinotecan (3.5-, 1.92- and 10.6-fold, respectively). In addition, the concentrations of SN38 released from MXN-004 were significantly higher in all tissues than those from irinotecan, especially in the lung. 4. These results suggested that MXN-004 might be a more potential water-soluble antitumor agent with prolonged half-life of SN38 compared to irinotecan.

Effect of triacontanol on the pharmacokinetics of docetaxel in rats associated with induction of cytochrome P450 3A1/2.

Triacontanol was confirmed to have a potential anti-cancer effect, the aim was to assess whether the co-administration of triacontanol alters the exposure of docetaxel via inducing hepatic CYP3A1/2 activity. The concentration of docetaxel in rats pretreated with triacontanol for seven successive days was determined, and the expression levels of CYP3A protein and mRNA were analyzed by the western blot and real time polymerase chain reaction (RT-PCR) technique, respectively. 2. The concentrations of docetaxel in rats pretreated with triacontanol were decreased, with 61.5%, 61.9% decrease in AUC0-24h and 65.7%, 54.9% reduction in Cmax (120 and 180 mg kg(-1), respectively) compared with the control. Hepatic clearance of docetaxel was enhanced in vitro and in vivo at dosage of 120 and 180 mg kg(-1), and CYP3A activity was up-regulated by measuring the formation rate of 1-hydroxymidazolam. Triacontanol preferentially induced protein expression level of CYP3A2 in a dose-dependent manner and of CYP 3A1 at dosage of 120 and 180 mg kg(-1). The mRNA expression of CYP3A1 was moderately different with the western blot results, but the trends appeared similar. CYP3A2 mRNA level was not markedly affected by triacontanol. 3. The significant triacontanol-docetaxel interaction was largely due to the induction of CYP3A1/2, which brought useful information in the clinical therapy when the combination is administered in human.

Efficacy, pharmacokinetics, and biodistribution of thermosensitive chitosan/ß-glycerophosphate hydrogel loaded with docetaxel.

Docetaxel (DTX) is a widely used anticancer drug for various solid tumors. However, its poor solubility in water and lack of specification are two limitations for clinical use. The aim of the study was to develop a thermosensitive chitosan/ß-glycerophosphate (C/GP) hydrogel loaded with DTX for intratumoral delivery. The in vitro release profiles, in vivo antitumor efficacy, pharmacokinetics, and biodistribution of DTX-loaded C/GP hydrogel (DTX-C/GP) were evaluated. The results of in vitro release study demonstrated that DTX-C/GP had the property of controlled delivery for a reasonable time span of 3 weeks and the release period was substantially affected by initial DTX strength. The antitumor efficacy of DTX-C/GP was observed at 20 mg/kg in H22 tumor-bearing mice. It was found that the tumor volume was definitely minimized by intratumoral injection of DTX-C/GP. Compared with saline group, the tumor inhibition rate of blank gel, intravenous DTX solution, intratumoral DTX solution, and DTX-C/GP was 2.3%, 29.8%, 41.9%, and 58.1%, respectively. Further, the in vivo pharmacokinetic characteristics of DTX-C/GP correlated well with the in vitro release. DTX-C/GP significantly prolonged the DTX retention and maintained a high DTX concentration in tumor. The amount of DTX distributed to the normal tissues was minimized so that the toxicity was effectively reduced. In conclusion, DTX-C/GP demonstrated controlled release and significant efficacy and exhibited potential for further clinical development.