เภสัชจลนศาสตร์ประชากรของยาวอริโคนาโซลในผู้ป่วยเด็กชาวไทย ที่เป็นโรคราแอสเปอร์จิลลัสชนิดรุกราน Population Pharmacokinetics of Voriconazole in Thai Children Patients with Invasive Aspergillosis

บทคัดย่อ วัตถุประสงค์: เพื่อประเมินเภสัชจลนศาสตร์ประชากรและปัจจัยที่เกี่ยวข้องของยาวอริโคนาโซลในผู้ป่วยเด็กที่ติดเชื้อราแอสเปอร์จิลลัสชนิดรุกราน วิธีการศึกษา: การศึกษานี้เก็บข้อมูลย้อนหลังจากโรงพยาบาล 2 แห่ง ในผู้ป่วยเด็กที่อายุน้อยกว่า 12 ปีที่ได้รับการวินิจฉัยเป็นโรคราแอสเปอร์จิลลัสชนิดรุกราน และได้รับการรักษาด้วยยาวอริโคนาโซล ตั้งแต่เดือนมกราคม 2557 ถึงเดือนธันวาคม 2561 วิเคราะห์เภสัชจลนศาสตร์ประชากรจากข้อมูลการตรวจติดตามระดับยาในเลือด โดยวิธี non-linear mixed-effect model ประเมินความถูกต้องเหมาะสมของแบบจำลองสุดท้ายด้วยวิธี bootstrap และ prediction corrected visual predictive check (pcVPC) ผลการศึกษา: จากข้อมูลระดับยาวอริโคนาโซลทั้งหมด 337 ตัวอย่าง จากผู้ป่วย 79 คน พบว่าแบบจำลอง one-compartment model with first-order absorption, linear elimination, and allometric scaling มีความเหมาะสมกับข้อมูลของการศึกษา ค่าเฉลี่ยของค่าการขจัดยาเท่ากับ 11.3 ลิตรต่อชั่วโมงต่อ 70 กิโลกรัม ค่าการกระจายตัวเท่ากับ 273 ลิตรต่อ 70 กิโลกรัม ค่าคงที่การดูดซึมยา1.19 ต่อชั่วโมง และค่าชีวประสิทธิผลของยารับประทาน เท่ากับ 0.796 ปัจจัยที่มีผลต่อค่าพารามิเตอร์คือ น้ำหนักโดยใช้สมการแอลโลเมตรี  (allometric equation) และ aspartate aminotransferase (AST) ต่อค่าการขจัดยา (P-value < 0.001) สรุป: แบบจำลองทางเภสัชจลนศาสตร์ประชากรสามารถนำมาช่วยประเมินพารามิเตอร์ทางเภสัชจลนศาสตร์ของยาวอริโคนาโซลและเป็นแนวทางในการกำหนดขนาดยาโดยคำนึงถึงปัจจัยที่เกี่ยวข้อง ได้แก่ น้ำหนักและ AST คำสำคัญ: เภสัชจลนศาสตร์ประชากร, ยาวอริโคนาโซล, เด็ก, ไทย, การติดเชื้อแอสเปอร์จิลลัสชนิดรุกรานAbstract Objective: To estimate the population pharmacokinetics of voriconazole, to identify factors influencing voriconazole pharmacokinetics in Thai children patients with invasive aspergillosis. Methods: This study was a two-center, retrospective study in children (<12 years) with invasive aspergillosis treated with voriconazole between January 2014 and December 2018. A population pharmacokinetics was conducted from routine voriconazole therapeutic drug monitoring data and was analyzed by a non-linear mixed-effect modeling approach. Bootstrap and prediction corrected visual predictive check (pcVPC) were used to validate the final models. Results: A total of 337 voriconazole plasma concentrations from 79 patients were collected in this study. The data were appropriately fitted by a one-compartment model with first-order absorption, linear elimination, and allometric scaling. The mean of clearance was 11.3 L/h/70 kg, volume of distribution was 273 L/70 kg, absorption rate constant was 1.19 h-1, and oral bioavailability was 0.796. Covariate analysis identified that body weight with allometric scaling improved the model, and aspartate aminotransferase (AST) presented a significant impact on clearance (P-value < 0.001). Conclusion: Final population pharmacokinetic model can be useful to assess the pharmacokinetic parameters of voriconazole and guide dosing strategies base on factors including body weight and AST. Keywords: population pharmacokinetics, voriconazole, pediatric, Thai, invasive aspergillosi

Analysis of Pulmonary Inflammation and Function in the Mouse and Baboon after Exposure to Mycoplasma pneumoniae CARDS Toxin

Mycoplasma pneumoniae produces an ADP-ribosylating and vacuolating toxin known as the CARDS (Community Acquired Respiratory Distress Syndrome) toxin that has been shown to be cytotoxic to mammalian cells in tissue and organ culture. In this study we tested the ability of recombinant CARDS (rCARDS) toxin to elicit changes within the pulmonary compartment in both mice and baboons. Animals responded to a respiratory exposure to rCARDS toxin in a dose and activity-dependent manner by increasing the expression of the pro-inflammatory cytokines IL-1α, 1β, 6, 12, 17, TNF-α and IFN-γ. There was also a dose-dependent increase in several growth factors and chemokines following toxin exposure including KC, IL-8, RANTES, and G-CSF. Increased expression of IFN-γ was observed only in the baboon; otherwise, mice and baboons responded to CARDS toxin in a very similar manner. Introduction of rCARDS toxin to the airways of mice or baboons resulted in a cellular inflammatory response characterized by a dose-dependent early vacuolization and cytotoxicity of the bronchiolar epithelium followed by a robust peribronchial and perivascular lymphocytic infiltration. In mice, rCARDS toxin caused airway hyper-reactivity two days after toxin exposure as well as prolonged airway obstruction. The changes in airway function, cytokine expression, and cellular inflammation correlate temporally and are consistent with what has been reported for M. pneumoniae infection. Altogether, these data suggest that the CARDS toxin interacts extensively with the pulmonary compartment and that the CARDS toxin is sufficient to cause prolonged inflammatory responses and airway dysfunction

Post-licensure, phase IV, safety study of a live attenuated Japanese encephalitis recombinant vaccine in children in Thailand

AbstractBackgroundJapanese encephalitis is a mosquito-borne viral disease endemic in most countries in Asia. A recombinant live, attenuated Japanese encephalitis virus vaccine, JE-CV, is licensed in 14 countries, including Thailand, for the prevention of Japanese encephalitis in adults and children.MethodsThis was a prospective, phase IV, open-label, multicentre, safety study of JE-CV conducted from November 2013 to April 2015, to evaluate rare serious adverse events (AEs). JE-CV was administered to 10,000 healthy children aged 9months to <5years in Thailand as a primary (Group 1) or booster (Group 2) vaccination. Serious AEs (SAEs), including AEs of special interest, up to 60days after administration were evaluated. Immediate Grade 3 systemic AEs up to 30min after JE-CV administration were also described.ResultsThe median age of participants was 1.1years in Group 1 and 3.8years in Group 2. SAEs were reported in 204 (3.0%) participants in Group 1 and 59 (1.9%) participants in Group 2. Among a total of 294 SAEs in 263 participants, only three events occurring in two participants were considered related to vaccination. All three cases were moderate urticaria, none of which met the definition of AEs of special interest for hypersensitivity. AEs of special interest were reported in 28 (0.4%) participants in Group 1 and 4 (0.1%) participants in Group 2; none were considered related to vaccination. Febrile convulsion was the most frequently reported AE of special interest: 25 (0.4%) participants in Group 1; and 2 (<0.1%) in Group 2. There were no cases of Japanese encephalitis reported. No Grade 3 immediate systemic AEs were reported after any JE-CV vaccination.ConclusionsOur study did not identify any new safety concerns with JE-CV and confirms its good safety profile.This study was registered on www.clinicaltrials.gov (NCT01981967; Universal Trial Number: U1111-1127-7052)

Immunogenicity and Reactogenicity of mRNA BNT162b2 COVID-19 Vaccine among Thai Adolescents with Chronic Diseases

Adolescents with underlying diseases are at risk of severe COVID-19. The immune response of BNT162b2 may be poor among immunocompromised adolescents. We aim to describe immunogenicity of mRNA BNT162b2 among adolescents who are immunocompromised or have chronic diseases. We recruited adolescents 12&ndash;18 years of age; group A impaired-immunity (post-transplantation, cancer, on immunosuppressive drugs) and group B chronic diseases. A two-dose regimen of BNT162b2 was given. Immunogenicity was determined by surrogate virus neutralization test (sVNT) and IgG against receptor-binding domain (RBD). From August to October 2021, 312 adolescents, with a median age (IQR) of 15 years (13.7&ndash;16.5), were enrolled (group A 100, group B 212). The geometric means (GMs) of sVNT (% inhibition) against Delta strain and anti-RBD IgG (BAU/mL) after the 2nd dose among group A were: post-transplantation recipients 52.9 (95% CI 37.7&ndash;74.2) and 233.6 (95% CI 79&ndash;690.6); adolescents with cancer 62.3 (95% CI 29.2&ndash;133.1) and 214.9(95% CI 34.2&ndash;1348.6); and adolescents with other immunosuppressive conditions 66.7 (95% CI 52.4&ndash;84.8) and 849.8 (95% CI 393.4&ndash;1835.8). In group B were: adolescents living with HIV 98 (95% CI 97.3&ndash;98.8) and 3240.3 (95% CI 2699&ndash;3890.2), and adolescents with other chronic disease 98.6 (95% CI 98.3&ndash;98.9) and 3818.5 (95% CI 3490.4&ndash;4177.4). At day 90, immunity declined; among impaired-immunity participants were 43.9 (95% CI 30.8&ndash;62.4) and 178.7 (95% CI 91.2&ndash;350.1) and adolescents with chronic diseases were 90.6 (95% CI 88.4&ndash;92.8) and 1037.1 (95% CI 933.3&ndash;1152.5). In conclusion, adolescents with impaired immunity had a poor response to 2-doses of BNT162b2, additional dose should be considered. Adolescents with chronic diseases had excellent response but immunity waned after 3 m, booster dose may be required

B cell subset alteration and the expression of tissue homing molecules in dengue infected patients

Abstract Background B cells play an essential role during dengue viral infection. While a major expansion of antibody secreting cells (ASCs) was observed, the importance of these increased frequencies of ASCs remains unclear. The alteration of B cell subsets may result from the expression of tissue specific homing molecules leading to their mobilization and distribution to different target organs during acute dengue viral infection. Methods In this study, whole blood samples were obtained from thirty pediatric dengue-infected patients and ten healthy children and then stained with fluorochrome-conjugated monoclonal antibodies against CD3, CD14, CD19, CD20, CD21, CD27, CD38, CD45, CD138 and homing molecules of interest before analyzed by polychromatic flow cytometry. B cell subsets were characterized throughout acute infection period. Results Data shows that there were no detectable differences in frequencies of resting, activated and tissue memory cells, whereas the frequency of ASCs was significantly increased and associated with the lower frequency of naïve cells. These results were found from patients with both dengue fever and dengue hemorrhagic fever, suggesting that such change or alteration of B cells was not associated with disease severity. Moreover, several homing molecules (e.g., CXCR3 and CCR2) were found in ASCs, indicating that ASCs may distribute to inflamed tissues and various organs. Conclusions Findings from this study provide insight into B cell subset distribution. Furthermore, organ mobilization according to homing molecule expression on different B cell subsets during the course of dengue viral infection also suggests they are distributed to inflamed tissues and various organs

Variation in Colonization, ADP-Ribosylating and Vacuolating Cytotoxin, and Pulmonary Disease Severity among Mycoplasma pneumoniae Strains

Rationale: Mycoplasma pneumoniae was recently discovered to produce an ADP-ribosylating and vacuolating cytotoxin, designated CARDS toxin, which is hypothesized to be a primary pathogenic mechanism responsible for M. pneumoniae–induced pulmonary inflammation. It is unknown if cytotoxin production varies with M. pneumoniae strain or if variation in cytotoxin production affects pulmonary disease severity

Response of Severe EV71-Infected Patients to Hyperimmune Plasma Treatment: A Pilot Study

Hand, foot, and mouth disease (HFMD) is highly prevalent in East and Southeast Asia. It particularly affects children under five years of age. The most common causative agents are coxsackieviruses A6 and A16, and enterovirus A71 (EV71). The clinical presentation is usually mild and self-limited, but, in some cases, severe and fatal complications develop. To date, no specific therapy or worldwide vaccine is available. In general, viral infection invokes both antibody and cell-mediated immune responses. Passive immunity transfer can ameliorate the severe symptoms of diseases such as COVID-19, influenza, MERS, and SARS. Hyperimmune plasma (HIP) from healthy donors with high anti-EV71 neutralizing titer were used to transfuse confirmed EV71-infected children with neurological involvement (n = 6). It resulted in recovery within three days, with no neurological sequelae apparent upon examination 14 days later. Following HIP treatment, plasma chemokines were decreased, whereas anti-inflammatory and pro-inflammatory cytokines gradually increased. Interestingly, IL-6 and G-CSF levels in cerebrospinal fluid declined sharply within three days. These findings indicate that HIP has therapeutic potential for HFMD with neurological complications. However, given the small number of patients who have been treated, a larger cohort study should be undertaken. Successful outcomes would stimulate the development of anti-EV71 monoclonal antibody therapy