Pharmacokinetics and Bioequivalence of Two Formulations of Azithromycin Tablets: A Randomized, Single-Dose, Three-Period, Crossover Study in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

BACKGROUND AND OBJECTIVE: Azithromycin is the first azalide antibiotic that is related to the macrolide family of antibiotics. Bioequivalence studies in China are initiated by the National Medical Products Administration (NMPA), which supports a generic consistency evaluation program for ensuring that generic products manufactured in China meet the required standards and provide equivalent therapeutic effects to their reference products. This study aimed to assess the bioequivalence of two azithromycin tablets under both fasting and fed conditions in healthy Chinese volunteers. METHODS: This was a single-center, open-label, single-dose, randomized, three-way crossover trial with two independent groups (fasting group and fed group). A total of 72 healthy Chinese subjects (36 subjects in the fasting state and 36 subjects in the fed state) were enrolled and randomized to treatment. Blood samples were collected from 0 to 120 h after a single oral dose of a 250-mg generic azithromycin tablet (test, T) or branded azithromycin tablet (reference, R). The plasma concentrations of azithromycin were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC‒MS/MS). A non-compartmental analysis method was used to estimate the pharmacokinetic parameters. Adverse events were documented. RESULTS: In a fasting state, the bioequivalence of maximum plasma concentration (Cmax) was evaluated using the reference-scaled average bioequivalence (RSABE) approach (within-subject standard deviation, SWR > 0.294), and the bioequivalence of area under the concentration-time curve from time 0 to the time of the last measurable plasma concentration (AUC0-t) and area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) were evaluated by the average bioequivalence (ABE) method (SWR <  0.294). The geometric mean ratio (GMR) of T/R for Cmax was 106.49%, while the 95% upper confidence bound was <  0. The GMRs of AUC0-t and AUC0-∞ were 103.34% and 101.28%, and the 90% confidence intervals (CIs) of the test/reference were 95.90-111.35%/94.85-108.15%, respectively. In the fed state, the RSABE approach was applied to estimate the bioequivalence of Cmax (SWR >0.294), and the ABE approach was applied to estimate the bioequivalence of AUC0-t and AUC0-∞ (SWR <  0.294). The GMR for Cmax was 99.80%, while the 95% upper confidence bound value was <  0. The GMRs of AUC0-t and AUC0-∞ were 97.07% and 98.15%, and the 90% CIs of the T/R were 90.02-104.68% and 90.66-106.25%, respectively. All adverse events were mild and transient. CONCLUSIONS: The trial indicated that the test and the reference azithromycin tablets were bioequivalent and well tolerated in healthy Chinese volunteers under both fasting and fed conditions. TRIAL REGISTRATION: Clinicaltrials, ChiCTR2300071630 (retrospectively registered in 19/05/2023).

Effect of genetic polymorphisms on the pharmacokinetics of gefitinib in healthy Chinese volunteers.

Gefitinib is the first-generation drug of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) metabolised by the cytochrome P450 and transported by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2). In the present study, the pharmacokinetics of gefitinib in healthy Chinese volunteers was investigated and the effect of genetic polymorphisms on its variability was evaluted.Forty-five healthy volunteers were administered a single dose of gefitinib and the blood samples were used for quantifying the concentration of gefitinib and genotyping fifteen single-nucleotide polymorphisms of cytochrome P450 enzymes (CYP3A4, CYP3A5, CYP2D6, CYP2C9 and CYP2C19) and drug transporters (ABCB1 and ABCG2).CYP3A5*3 (rs776746) polymorphism showed a significant influence, with higher gefitinib AUC0-t in carrier of CC genotype than in CT/TT genotype (BH-adjusted p value <0.05). For CYP2C9*3 (rs1057910), significant differences in pharmacokinetics of gefitinib were detected between carriers of AA and AC genotypes, with higher AUC0-t, AUC0-∞ and Cmax in carrier of AC genotype than in AA gen-otype (BH-adjusted p value <0.05). No associations were found between SNPs in CYP3A4, CYP2D6, CYP2C19, ABCB1, ABCG2 and the pharmacokinetics of gefitinib.The SNPs in CYP3A5*3 (rs776746) and CYP2C9*3 (rs1057910) were found to be associated with altered gefitinib pharmacokinetics in healthy Chinese volunteers.

The influence of a mental health home visit service partnership intervention on the caregivers' home visit service satisfaction and care burden.

AIMS AND OBJECTIVES: To investigate a community-based and hospital-based home visit partnership intervention in improving caregivers' satisfaction with home service and reducing caregiver burden. BACKGROUND: The community-oriented mental healthcare model prevails internationally. After patients return to the community, family caregivers are the patients' main support system and they also take the most of the burden of caring for patients. It is important to assist these caregivers by building good community healthcare models. DESIGN: A longitudinal quasi-experimental quantitative design. METHODS: The experimental group (n = 109) involved "partnership" intervention, and the control group (n = 101) maintained routine home visits. The results were measured before the intervention, 6 and 12 months after the partnership intervention. RESULTS: Six months after the partnership intervention, the satisfaction of the experimental group was higher than the control group for several aspects of care. Although the care burden was reduced in the experimental group, there was no significant difference between the two groups. CONCLUSIONS: This study confirms that the partnership intervention can significantly improve caregiver satisfaction with home services, without reducing the care burden. RELEVANCE TO CLINICAL PRACTICE: The community-based and hospital-based mental health home visit service partnership programme could improve the main caregiver's satisfaction with the mental health home visit services, while the reduction in care burden may need government policies for the provision of more individual and comprehensive assistance.

Intervening conditions of hospital-based home care for people with severe mental illness.

OBJECTIVE: This study discusses the intervening conditions of hospital-based home care (HBHC) for people with severe mental illness in Taiwan. DESIGN AND SAMPLE: Grounded theory of the Strauss and Corbin approach was used. Participants were selected from six hospitals in Central Taiwan, including 21 clients, 19 caregivers, and 25 professionals. MEASURES: Semi-structured one-on-one interviews were used to collect data. Data analysis consisted of three stages: open, axial, and selective coding. Data analysis, data collection, and sampling were conducted through the constant comparative analysis process. RESULTS: Two categories were generated as positive and negative intervening conditions of HBHC services. Eight positive effects and nine negative effects were generated from the data. CONCLUSIONS: Several positive and negative intervening conditions were found in this study to affect the delivery of HBHC. Government support and several limitations regarding HBHC services quality should be noticed and improved.

The functions of hospital-based home care for people with severe mental illness in Taiwan.

AIMS AND OBJECTIVES: The purposes of this study were to understand the functions of hospital-based home care for people with severe mental illness in Taiwan, and the factors that affect functions of professionals who provide hospital-based home care. BACKGROUND: Hospital-based home care is a service which provides those people with serious mental illnesses who are in crisis and who are candidates for admission to hospital. Home care has been shown to have several advantages over inpatient treatment. However, there is a lack of knowledge about the functions of hospital-based home care for people with severe mental illness in Taiwan. DESIGN: This qualitative study was based on the grounded theory method of Strauss and Corbin. METHODS: The study was conducted in six different hospital areas in central Taiwan in 2007-2008. Data were collected using semi-structured face-to-face interviews. Constant comparative analysis continued during the open, axial and selective coding processes until data saturation occurred. Participants were selected by theoretical sampling. When theoretical saturation was achieved, 21 clients with mental illness, 19 carers and 25 professionals were interviewed. RESULTS: Several functions were found when these professionals provided hospital-based home care services for people with severe mental illness in Taiwan, including stabilising the clients illness, supplying emergency care services, improving life-coping abilities, employment and welfare assistance, emotional support for both clients and carers, assistance with future and long-term arrangements and assistance with communication between carers and clients. CONCLUSION: Hospital-based home care provides several important services for helping clients and their families to live in the community. RELEVANCE TO CLINICAL PRACTICE: The recommendations based on the findings of this study can be used as a guide to improve the delivery of hospital-based home care services to community-dwelling clients with severe mental illness and their carers.

Hospital-based home care for people with severe mental illness in Taiwan: a substantive grounded theory.

AIM AND OBJECTIVES: The purpose of this study is to generate a substantive theory of hospital-based home care for people with severe mental illness in Taiwan. BACKGROUND: Despite the documented advantages of hospital-based home care services, there is a lack of information and understanding regarding the practices, functions and limitations. Currently, there is no model for how those services are to be provided and what factors will affect these services. DESIGN: The grounded theory method of Strauss and Corbin (Basics of Qualitative Research: Grounded Theory Procedures and Techniques, SAGE Publications, 1990) was used to develop a substantive theory through a paradigm model, including causal conditions, context, intervening conditions, action/interaction strategies and consequences. METHODS: This study was conducted in six different hospital areas in Central Taiwan in 2007-2008. Data were collected using semi-structured face-to-face interviews. Constant comparative analysis continued during the open, axial and selective coding process until data saturation occurred. Participants were selected by theoretical sampling. When theoretical saturation was achieved, 21 clients with mental illness, 19 carers and 25 professionals were interviewed. RESULTS: A substantive theory of hospital-based home care for people with severe mental illness in Taiwan was developed. The core category was the process of hospital-based home care in helping people with severe mental illness, with 15 categories and 33 sub-categories of the substantive theory. CONCLUSION: The substantive theory is the first to emerge from hospital-based home care services in Taiwan. Results showed those services had several effective functions for helping people with severe mental illness and their families. RELEVANCE TO CLINICAL PRACTICE: The recommendations based on the findings of this research can be used as a guide to improve the delivery of hospital-based home care services to community-dwelling people with severe mental illness and their carers.

The first experiences of clinical practice of psychiatric nursing students in Taiwan: a phenomenological study.

AIMS AND OBJECTIVES: The purpose of this study is to understand the experiences of psychiatric nursing students during their first encounters with psychiatric patients in a clinical setting. The objective is to assist educational professionals in mental health to improve teaching strategies. BACKGROUND: In clinical settings, student psychiatric nurses have to face complex problems and situations that can result in distress. Sometimes the student nurse will be uncertain of their own ability and this is reflected in a sense of fear on the part of some nurses. However, little research has been conducted into the first clinical experiences of such nursing students in Taiwan. DESIGN: A qualitative phenomenological study was devised to explore what psychiatric nursing students perceived during their first experiences of clinical practice and narratives were analysed using Colaizzi's seven-step method. METHOD: A phenomenological approach and purposive sampling were used in the study. Face-to-face interviews were conducted to collect the data and during the process of data analysis we established epochs (bracketing) and focused on the reality of the student nurses' experience to keep the data objective. RESULTS: Four themes were identified: breaking the stigma of mental illness, developing a trusting relationship with the patient, gaining professional knowledge and skills and the process of student growth. CONCLUSION: The findings from this study demonstrate that it is important to understand the perceptions of students during their first experiences of psychiatric nursing in a clinical setting and highlight the importance of educational programs. RELEVANCE TO CLINICAL PRACTICE: By understanding the emotional process that psychiatric nursing students may go through during their clinical practice, educators can be better able to design suitable training courses in the future.

The experiences of primary caregivers raising school-aged children with attention-deficit hyperactivity disorder.

AIMS AND OBJECTIVES: To understand the experiences of primary caregivers who are bringing up school-aged children with attention-deficit hyperactivity disorder. The research findings will help address the problems related to caring for school-aged children with attention-deficit hyperactivity disorder. BACKGROUND: In Taiwan, the rate of school-aged children diagnosed with attention-deficit hyperactivity disorder ranges from 7.9-11.7%. This study is the first, which tries to understand the experiences of primary caregivers who are bringing up school-aged children with attention-deficit hyperactivity disorder in Taiwan. DESIGN: The study used a qualitative phenomenological approach to explore the experiences of caregivers raising school-aged children with attention-deficit hyperactivity disorder. METHODS: Purposive sampling and in-depth, face-to-face interviews were used to collect data. The unstructured interview guide allowed the major caregivers to express their experiences of raising school-aged children with attention-deficit hyperactivity disorder. When data saturation was reached, the sample size comprised 12 major caregivers. Narratives were analysed according to Colaizzi's seven-step method. RESULTS: Three themes and seven sub-themes emerged from this study: the burdens of caring (parenting burdens, emotional burdens and family conflicts), the lack of adequate support systems (lack of support from professionals, spouses and other family members) and the mechanisms of coping (cognitive coping strategies and social coping strategies). Furthermore, several other factors that affected the caregivers of children with attention-deficit hyperactivity disorder are also revealed in the study. CONCLUSION: The findings of the study demonstrate the importance of understanding the experiences of primary caregivers, bringing up school-aged children with attention-deficit hyperactivity disorder. Improving professional services in family care should be a major concern for all healthcare professionals. RELEVANCE TO CLINICAL PRACTICE: The recommendations that have been made based on the findings of this research can be used as a guide to improve the delivery of caring by people who have school-aged children with attention-deficit hyperactivity disorder and by the wider family.

Array-MLPA: comprehensive detection of deletions and duplications and its application to DMD patients.

Multiplex ligation-dependent probe amplification (MLPA) is widely used to screen genes of interest for deletions and duplications. Since MLPA is usually based on size-separation of the amplification products, the maximum number of target sequences that can be screened in parallel is usually limited to approximately 40. We report the design of a robust array-based MLPA format that uses amplification products of essentially uniform size (100-120 bp) and distinguishes between them by virtue of incorporated tag sequences. We were thus able to increase probe complexity to 124, with very uniform product yields and signals that have a low coefficient of variance. The assay designed was used to screen the largest set studied so far (249 patients) of unrelated Duchenne muscular dystrophy (DMD) cases from the Chinese population. In a blind study we correctly assigned 98% of the genotypes and detected rearrangements in 181 cases (73%); i.e., 163 deletions (65%), 13 duplications (5%), and five complex rearrangements (2%). Although this value is significantly higher for Chinese patients than previously reported, it is similar to that found for other populations. The location of the rearrangements (76% in the major deletion hotspot) is also in agreement with other findings. The 96-well flow-through microarray system used in this research provides high-throughput and speed; hybridization can be completed in 5 to 30 minutes. Since array processing and data analysis are fully automated, array-MLPA should be easy to implement in a standard diagnostic laboratory. The universal array can be used to analyze any tag-modified MLPA probe set.

Derivation of human embryonic stem cell lines from parthenogenetic blastocysts.

Parthenogenesis is one of the main, and most useful, methods to derive embryonic stem cells (ESCs), which may be an important source of histocompatible cells and tissues for cell therapy. Here we describe the derivation and characterization of two ESC lines (hPES-1 and hPES-2) from in vitro developed blastocysts following parthenogenetic activation of human oocytes. Typical ESC morphology was seen, and the expression of ESC markers was as expected for alkaline phosphatase, octamer-binding transcription factor 4, stage-specific embryonic antigen 3, stage-specific embryonic antigen 4, TRA-1-60, and TRA-1-81, and there was absence of expression of negative markers such as stage-specific embryonic antigen 1. Expression of genes specific for different embryonic germ layers was detected from the embryoid bodies (EBs) of both hESC lines, suggesting their differentiation potential in vitro. However, in vivo, only hPES-1 formed teratoma consisting of all three embryonic germ layers (hPES-2 did not). Interestingly, after continuous proliferation for more than 100 passages, hPES-1 cells still maintained a normal 46 XX karyotype; hPES-2 displayed abnormalities such as chromosome translocation after long term passages. Short Tandem Repeat (STR) results demonstrated that the hPES lines were genetic matches with the egg donors, and gene imprinting data confirmed the parthenogenetic origin of these ES cells. Genome-wide SNP analysis showed a pattern typical of parthenogenesis. All of these results demonstrated the feasibility to isolate and establish human parthenogenetic ESC lines, which provides an important tool for studying epigenetic effects in ESCs as well as for future therapeutic interventions in a clinical setting.

Multiorgan engraftment and differentiation of human cord blood CD34+ Lin- cells in goats assessed by gene expression profiling.

To investigate multitissue engraftment of human primitive hematopoietic cells and their differentiation in goats, human CD34+ Lin- cord blood cells transduced with a GFP vector were transplanted into fetal goats at 45-55 days of gestation. GFP+ cells were detected in hematopoietic and nonhematopoietic organs including blood, bone marrow, spleen, liver, kidney, muscle, lung, and heart of the recipient goats (1.2-36% of all cells examined). We identified human beta2 microglobulin-positive cells in multiple tissues. GFP+ cells sorted from the perfused liver of a transplant goat showed human insulin-like growth factor 1 gene sequences, indicating that the engrafted GFP+ cells were of human origin. A substantial fraction of cells engrafted in goat livers expressed the human hepatocyte-specific antigen, proliferating cell nuclear antigen, albumin, hepatocyte nuclear factor, and GFP. DNA content analysis showed no evidence for cellular fusion. Long-term engraftment of GFP+ cells could be detected in the blood of goats for up to 2 yr. Microarray analysis indicated that human genes from a variety of functional categories were expressed in chimeric livers and blood. The human/goat xenotransplant model provides a unique system to study the kinetics of hematopoietic stem cell engraftment, gene expression, and possible stem cell plasticity under noninjured conditions.

In utero transplantation of human hematopoetic stem cells into fetal goats under B-type ultrasonographic scan: an experimental model for the study of potential prenatal therapy.

OBJECTIVE: Using fetal goats as animal models, to establish the methodology of in utero transplantation of human hematopoeitic stem cell (HSC) under B-scan ultrasonographic guidance for prenatal therapy. STUDY DESIGN: Human HSC were directly injected into the peritoneal cavities of the recipient fetal goats at 45-55 days of gestation (term: 145 days) under the guidance of B-type ultrasound scan. After birth, the peripheral blood was collected for fluorescence assisted cell sorting (FACS), quantitative real-time PCR and fluorescence in situ hybridization (FISH) to detect and analyze the presence of human cells in the recipients. RESULTS: The 32 recipients were born alive except one miscarriage. To test for the presence of human-goat chimeras, cells from 13 randomly selected transplanted goats were collected. FACS analyses showed the presence of human cells in all the transplanted goats tested. The average proportion of CD34+ cells and GPA+(glycophorin A) cells in the peripheral blood were 1.34 +/- 1.10% and 2.80 +/- 2.10%, respectively. No CD34+ or GPA+ cells were found in the non-transplanted goats tested. The results of the quantitative real-time PCR in three engraftment goats were 1.2 x 10(4), 2.9 x 10(4), and 3.2 x 10(4) copies of human GPA DNA per mug of genomic DNA. FISH experiments showed that cells containing human specific alpha-satellite DNA sequence were present in the peripheral blood of the transplanted goats. CONCLUSIONS: The method described herein is safe and reliable, with low miscarriage risk and high chimerism rate. This approach may provide a promising animal model for potential prenatal treatment.

[Analysis of human cells in transplanted goats using fluorescence in situ hybridization].

OBJECTIVE: To analyze the existence and the dynamic cell frequencies of human cells in goats transplanted in utero with human hematopoietic stem cell (hHSC) by using fluorescence in situ hybridization (FISH) technique. METHODS: Interphase FISH (IFISH) with human-specific 17-chromosome satellite DNA and/or human-specific Y-chromosome satellite DNA as probes was performed to analyze the presence and proportions of human cells in 13 transplanted goats. Samples were peripheral blood cells, bone marrow smears and liver touch imprint preparations. RESULTS: Of the 13 transplanted goats, eleven were identified to present human cells. Among them, two goats transplanted with human male HSC were found to have human male cells. The results demonstrated that these transplanted goats were human/goat HSC xenogeneic chimeras. Human cell frequencies decreased with the goat age (months), but the longest survival reached 21 months. During the detected life periods of goats, human cell frequencies in peripheral blood, bone marrow and liver tissues were less than 1@1000, but local human cell frequencies of 207.92@1000 and 392.41@1000 were detected in the liver tissues of 2 transplanted goats. CONCLUSIONS: The existence and long-term survival of human cells in transplanted goats detected by FISH indicated that goats were appropriate recipients for hHSC in utero transplantation. The lower human cell frequencies in blood and bone marrow, and the higher local human cell frequencies in liver tissues suggested that the microenvironment of goat liver tissues might favor the survival, proliferation and differentiation of human cells.

Analysis of human cells in transplanted goats using fluorescence in situ hybridization / 中国医学科学院学报

<p><b>OBJECTIVE</b>To analyze the existence and the dynamic cell frequencies of human cells in goats transplanted in utero with human hematopoietic stem cell (hHSC) by using fluorescence in situ hybridization (FISH) technique.</p><p><b>METHODS</b>Interphase FISH (IFISH) with human-specific 17-chromosome satellite DNA and/or human-specific Y-chromosome satellite DNA as probes was performed to analyze the presence and proportions of human cells in 13 transplanted goats. Samples were peripheral blood cells, bone marrow smears and liver touch imprint preparations.</p><p><b>RESULTS</b>Of the 13 transplanted goats, eleven were identified to present human cells. Among them, two goats transplanted with human male HSC were found to have human male cells. The results demonstrated that these transplanted goats were human/goat HSC xenogeneic chimeras. Human cell frequencies decreased with the goat age (months), but the longest survival reached 21 months. During the detected life periods of goats, human cell frequencies in peripheral blood, bone marrow and liver tissues were less than 1@1000, but local human cell frequencies of 207.92@1000 and 392.41@1000 were detected in the liver tissues of 2 transplanted goats.</p><p><b>CONCLUSIONS</b>The existence and long-term survival of human cells in transplanted goats detected by FISH indicated that goats were appropriate recipients for hHSC in utero transplantation. The lower human cell frequencies in blood and bone marrow, and the higher local human cell frequencies in liver tissues suggested that the microenvironment of goat liver tissues might favor the survival, proliferation and differentiation of human cells.</p>

[A study of inductive effect of hemin on expression of the beta-globin genes in K562 cells].

The recombinant plasmid HG was constructed,in which the reporter gene encoding the enhanced green fluorescent protein (EGFP) was driven by the beta-globin promoter and regulated under the HS2 element. The inductive effect of hemin on the expression of the beta-globin gene and transiently transfected beta-globin genes in K562 cells was analysed by FACS as well as RT-PCR method. The results showed that the level of gamma and beta-globin gene mRNA in K562 cells increased significantly after 24,48 and 72 hours induced with 30 micromol/LHm.And this inductive effect was stronger after 24 and 48 hours. Furthermore,the transient expression of plasmid HG in K562 cells increased significantly with hemin induction. These results indicated that the mechanism of inductive erythroid differentiation with hemin may be correlated with mechanism of gamma-->beta-globin gene.