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BACKGROUND AND OBJECTIVE: Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants. METHODS: A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword "DNA-TG" with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher's z-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle-Ottowa quality assessment scale. RESULTS: In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (n = 16) or IBD (n = 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78-184.35), P < 0.00001; heterogeneity chi squared of 5.62, I2 of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23-197.29), P < 0.00001; heterogeneity chi squared of 0.20, I2 of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (- 22.93 to 138.35), P < 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds. CONCLUSIONS: This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
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Monitoreo de Drogas , Mercaptopurina , Tioguanina , Humanos , Mercaptopurina/farmacocinética , Mercaptopurina/uso terapéutico , Mercaptopurina/sangre , Tioguanina/farmacocinética , Monitoreo de Drogas/métodos , Azatioprina/uso terapéutico , Azatioprina/farmacocinética , ADN/genética , Biomarcadores/sangre , Pirofosfatasas/genética , Pirofosfatasas/metabolismo , Nucleótidos de Guanina/sangre , Tionucleótidos/sangre , Hidrolasas NudixRESUMEN
The severe fever with thrombocytopenia syndrome virus (SFTSV) is a novel phlebovirus, recently being officially renamed as Dabie bandavirus, and a causative agent for an emerging infectious disease associated with high fatality. Effective therapeutics and vaccines are lacking and disease pathogenesis is yet to be fully elucidated. In our effort to identify new SFTSV inhibitory molecules, 6-Thioguanine (6-TG) was found to potently inhibit SFTSV infection. 6-TG has been widely used as therapeutic agent since the approval of the Food and Drug Administration in the 1960s. In the current study, we showed that 6-TG was a potent inhibitor of SFTSV infection with 50% effective concentrations (EC50) of 3.465 µM in VeroE6 cells, and 1.848 µM in HUVEC cells. The selectivity index (SI) was >57 in VeroE6 cells and >108 in HUVEC cells, respectively. The SFTSV RNA transcription, protein synthesis, and progeny virions were reduced in a dose dependent manner by the presence of 6-TG in the in vitro infection assay. Further study on the mechanism of the anti-SFTSV activity showed that 6-TG downregulated the production of early growth response gene-1 (EGR1). Using gene silencing and overexpression, we further confirmed that EGR1 was a host restriction factor against SFTSV. Meanwhile, treatment of infected experimental animals with 6-TG inhibited SFTSV infection and alleviated multi-organ dysfunction. In conclusion, we have identified 6-TG as an effective inhibitor of SFTSV replication via the inhibition of EGR1 expression. Further studies are needed to evaluate of 6-TG as a potential therapeutic for treating SFTS.
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Antivirales , Proteína 1 de la Respuesta de Crecimiento Precoz , Células Endoteliales de la Vena Umbilical Humana , Phlebovirus , Tioguanina , Replicación Viral , Animales , Phlebovirus/efectos de los fármacos , Humanos , Replicación Viral/efectos de los fármacos , Tioguanina/farmacología , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ratones , Células Vero , Antivirales/farmacología , Chlorocebus aethiops , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Síndrome de Trombocitopenia Febril Grave/tratamiento farmacológico , Síndrome de Trombocitopenia Febril Grave/virología , Línea CelularRESUMEN
BACKGROUND: Thiopurine-induced leucopenia significantly hinders the wide application of thiopurines. Dose optimization guided by nudix hydrolase 15 (NUDT15) has significantly reduced the early leucopenia rate, but there are no definitive biomarkers for late risk leucopenia prediction. AIM: To determine the predictive value of early monitoring of DNA-thioguanine (DNATG) or 6-thioguanine nucleotides (6TGN) for late leucopenia under a NUDT15-guided thiopurine dosing strategy in patients with Crohn's disease (CD). METHODS: Blood samples were collected within two months after thiopurine initiation for detection of metabolite concentrations. Late leucopenia was defined as a leukocyte count < 3.5 × 109/L over two months. RESULTS: Of 148 patients studied, late leucopenia was observed in 15.6% (17/109) of NUDT15/thiopurine methyltransferase (TPMT) normal and 64.1% (25/39) of intermediate metabolizers. In patients suffering late leucopenia, early DNATG levels were significantly higher than in those who did not develop late leucopenia (P = 4.9 × 10-13). The DNATG threshold of 319.43 fmol/µg DNA could predict late leucopenia in the entire sample with an area under the curve (AUC) of 0.855 (sensitivity 83%, specificity 81%), and in NUDT15/TPMT normal metabolizers, the predictive performance of a threshold of 315.72 fmol/µg DNA was much more remarkable with an AUC of 0.902 (sensitivity 88%, specificity 85%). 6TGN had a relatively poor correlation with late leucopenia whether in the entire sample (P = 0.021) or NUDT15/TPMT normal or intermediate metabolizers (P = 0.018, P = 0.55, respectively). CONCLUSION: Proactive therapeutic drug monitoring of DNATG could be an effective strategy to prevent late leucopenia in both NUDT15/TPMT normal and intermediate metabolizers with CD, especially the former.
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Enfermedad de Crohn , Leucopenia , Metiltransferasas , Purinas , Compuestos de Sulfhidrilo , Humanos , Enfermedad de Crohn/tratamiento farmacológico , ADN , Leucopenia/inducido químicamente , Leucopenia/diagnóstico , Purinas/efectos adversos , Compuestos de Sulfhidrilo/efectos adversos , Tioguanina/análisisRESUMEN
BACKGROUND AND AIMS: The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio ofâ >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies. METHODS: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician. RESULTS: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [pâ <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [pâ =â 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], pâ <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, pâ =â 0.005) and shunting in third trimester [6.20, 1.21-30.73, pâ =â 0.028] and at delivery [14.18, 1.62-123.9, pâ =â 0.016] were associated with an increased risk of ICP. CONCLUSIONS: Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.
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Colestasis Intrahepática , Enfermedades Inflamatorias del Intestino , Mercaptopurina , Complicaciones del Embarazo , Humanos , Embarazo , Femenino , Complicaciones del Embarazo/tratamiento farmacológico , Adulto , Colestasis Intrahepática/inducido químicamente , Estudios Prospectivos , Mercaptopurina/análogos & derivados , Mercaptopurina/administración & dosificación , Mercaptopurina/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Inmunosupresores/efectos adversos , Inmunosupresores/administración & dosificación , Tioguanina/administración & dosificación , Tioguanina/efectos adversos , Azatioprina/efectos adversos , Azatioprina/administración & dosificación , Factores de RiesgoRESUMEN
Mouse tumour models are extensively used as a pre-clinical research tool in the field of oncology, playing an important role in anticancer drugs discovery. Accordingly, in cancer genomics research, the demand for next-generation sequencing (NGS) is increasing, and consequently, the need for data analysis pipelines is likewise growing. Most NGS data analysis solutions to date do not support mouse data or require highly specific configuration for their use. Here, we present a genome analysis pipeline for mouse tumour NGS data including the whole-genome sequence (WGS) data analysis flow for somatic variant discovery, and the RNA-seq data flow for differential expression, functional analysis and neoantigen prediction. The pipeline is based on standards and best practices and integrates mouse genome references and annotations. In a recent study, the pipeline was applied to demonstrate the efficacy of low dose 6-thioguanine (6TG) treatment on low-mutation melanoma in a pre-clinical mouse model. Here, we further this study and describe in detail the pipeline and the results obtained in terms of tumour mutational burden (TMB) and number of predicted neoantigens, and correlate these with 6TG effects on tumour volume. Our pipeline was expanded to include a neoantigen analysis, resulting in neopeptide prediction and MHC class I antigen presentation evaluation. We observed that the number of predicted neoepitopes were more accurate indicators of tumour immune control than TMB. In conclusion, this study demonstrates the usability of the proposed pipeline, and suggests it could be an essential robust genome analysis platform for future mouse genomic analysis.
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Melanoma , Tioguanina , Animales , Ratones , Tioguanina/farmacología , Genómica/métodos , Mutación , RNA-SeqRESUMEN
Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and hepatotoxicity, often related to inter-individual differences, involving the activity of important enzymes at the basis of their biotransformation, such as thiopurine S-methyltransferase (TPMT). Surface Enhanced Raman Scattering (SERS) spectroscopy is emerging as a bioanalytical tool and represents a valid alternative in terms of affordable costs, shorter analysis time and easier sample preparation in comparison to the most employed methods for pharmacokinetic analysis of drugs. The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed. SERS analysis of the cell lysates was carried out using SERS substrates constituted by Ag nanoparticles deposited on paper and parallel samples were used for quantification of thiopurine nucleotides with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A direct SERS detection method has been set up that could be a tool to study thiopurine drug pharmacokinetics in in vitro cellular models to qualitatively discriminate between cells that do and do not overexpress the TPMT enzyme, as an alternative to other more laborious techniques. Results underlined decreased levels of TGN and increased levels of methylated metabolites when TPMT was overexpressed, both after mercaptopurine and thioguanine treatments. A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1 x 106 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm-1). In future studies, we aim to apply this method to investigate TPMT activity in pediatric patients' leukocytes.
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Leucemia , Nanopartículas del Metal , Humanos , Niño , Mercaptopurina/metabolismo , Tioguanina/metabolismo , Cromatografía Liquida , Plata , Espectrometría de Masas en Tándem , Metiltransferasas , Nucleótidos , Análisis EspectralRESUMEN
AIMS: Azathioprine (AZA) and 6-mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. METHODS: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. RESULTS: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P < .0001). ALL received 6-mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. CONCLUSION: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.
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Enfermedades Inflamatorias del Intestino , Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Niño , Mercaptopurina/efectos adversos , Tioguanina/metabolismo , Tioguanina/uso terapéutico , Nucleótidos/uso terapéutico , Azatioprina/efectos adversos , Azatioprina/metabolismo , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Inmunosupresores/efectos adversosRESUMEN
Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds great promise to eradicate HIV-1 or to provide long-term remission through a continuous supply of anti-HIV-1 gene-modified cells without ongoing antiretroviral therapy. However, achieving sufficient engraftment levels of anti-HIV gene-modified HSPC to provide therapeutic efficacy has been a major limitation. Here, we report an in vivo selection strategy for anti-HIV-1 gene-modified HSPC by introducing 6-thioguanine (6TG) chemoresistance through knocking down hypoxanthine-guanine phosphoribosyl transferase (HPRT) expression using RNA interference (RNAi). We developed a lentiviral vector capable of co-expressing short hairpin RNA (shRNA) against HPRT alongside two anti-HIV-1 genes: shRNA targeting HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor, C46, for efficient in vivo selection of anti-HIV-1 gene-modified human HSPC. 6TG-mediated preconditioning and in vivo selection significantly enhanced engraftment of HPRT-knockdown anti-HIV-1 gene-modified cells (>2-fold, p < 0.0001) in humanized bone marrow/liver/thymus (huBLT) mice. Viral load was significantly reduced (>1 log fold, p < 0.001) in 6TG-treated HIV-1-infected huBLT mice compared to 6TG-untreated mice. We demonstrated that 6TG-mediated preconditioning and in vivo selection considerably improved engraftment of HPRT-knockdown anti-HIV-1 gene-modified HSPC and repopulation of anti-HIV-1 gene-modified hematopoietic cells in huBLT mice, allowing for efficient HIV-1 inhibition.
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VIH-1 , Trasplante de Células Madre Hematopoyéticas , Humanos , Ratones , Animales , VIH-1/fisiología , Hipoxantina Fosforribosiltransferasa/genética , Hipoxantina Fosforribosiltransferasa/metabolismo , Células Madre Hematopoyéticas/metabolismo , Médula Ósea/metabolismo , Tioguanina/metabolismo , Tioguanina/farmacología , ARN Interferente Pequeño/genéticaRESUMEN
BACKGROUND: 6-Mercaptopurine (6MP) is the mainstay chemotherapy for acute lymphoblastic leukemia (ALL) and is conventionally available as 50 mg tablets. A new 6MP powder for oral suspension (PFOS 10 mg/mL) was developed recently by IDRS Labs, India, intended for pediatric use. A comparative pharmacokinetics of PFOS with T. mercaptopurine was conducted to determine the dose equivalence. METHODS: An open-label, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study was conducted on 51 healthy adult subjects. Post hoc, a population pharmacokinetic (PopPK) model was developed using the healthy volunteer data to perform simulations with various PFOS doses and select a bioequivalent dose. Further, to confirm the safety of PFOS in pediatrics, a simulation of 6MP and 6-thioguanine exposures was performed by incorporating the formulation-specific parameters derived from the healthy volunteer study into the PopPK model in childhood ALL available in literature. RESULTS: The 6MP PFOS had 47% higher oral bioavailability compared to the reference product. Simulations using a two-compartmental PopPK model with dissolution and transit compartments showed that 40 mg of PFOS was found to be equivalent to 50 mg tablets. The simulated 6-thioguanine nucleotide concentrations in children using the dose adjusted for PFOS were between 114 and 703.6 pmol/8 × 108 RBC, which was within the range reported in pediatric ALL studies. CONCLUSION: 6MP PFOS 10 mg/mL should be administered at a 20% lower dose than the tablet to achieve comparable exposure. 6MP PFOS addresses an unmet medical need for a liquid formulation of 6MP in the Indian subcontinent.
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Mercaptopurina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Niño , Humanos , Administración Oral , Estudios Cruzados , Mercaptopurina/administración & dosificación , Polvos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Comprimidos , Equivalencia Terapéutica , TioguaninaRESUMEN
Feeder cells play a crucial role in maintaining the pluripotency of embryonic stem cells (ESCs) by secreting various extrinsic regulators, such as extracellular matrix (ECM) proteins and growth factors. Although primary mouse embryonic fibroblasts (MEFs) are the most widely used feeder cell type for the culture of ESCs, they have inevitable disadvantages such as batch-to-batch variation and labor-intensive isolation processes. Here, we revealed that the Sandoz inbred Swiss Mouse (SIM) thioguanine-resistant ouabain-resistant (STO) cell line, an immortalized cell line established from mouse SIM embryonic fibroblasts, can be used as a feeder layer for in vitro culture of authentic pig ESCs instead of primary MEFs. First, the expression of genes encoding ECM proteins and growth factors was analyzed to compare their secretory functions as feeder cells. Quantitative real-time polymerase chain reaction (qPCR) showed that the gene expression of these pluripotency-associated factors was downregulated in STO cells compared to primary MEFs of similar density. Therefore, subsequent optimization of the culture conditions was attempted using higher STO cell densities. Notably, pig ESCs cultured on STO cell density of 3 × (187,500 cells/cm2) exhibited the most similar pluripotent state to pig ESCs cultured on primary MEF density of 1 × (62,500 cells/cm2), as determined by alkaline phosphatase staining, qPCR, and immunocytochemistry. In addition, pig ESCs cultured on STO cell density of 3 × formed complex teratoma containing multiple types of tissues derived from all three germ layers. Our culture conditions using optimal STO cell density can be applied to fields requiring reproducible and scalable production of pig ESCs, such as preclinical research and cellular agriculture.
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Ouabaína , Tioguanina , Animales , Porcinos , Ratones , Células Nutrientes , Tioguanina/metabolismo , Ouabaína/metabolismo , Fibroblastos , Células Madre Embrionarias , Línea Celular , Diferenciación CelularRESUMEN
6-Thioguanine is an immunosuppressive drug, an analogue of guanine, applied to treat acute leukemia and inflammatory bowel disease. Excessive use of 6-thioguanine during clinical treatment may cause side effects. Moreover, providing a dose too low will be ineffective. Therefore, there is a critical need for a rapid, selective and routine approach to quantifying 6-thioguanine in body fluids to support a clinical application. A fully validated HPLC method has been developed to determine 6-thioguanine in whole blood samples using 5-bromouracil as an internal standard. 6-Thioguanine nucleotides were released from erythrocytes by perchloric acid, and then hydrolysed at 100 °C to the parent thiopurine, 6-thioguanine. The following validation parameters of the method were determined: specificity/selectivity, linearity range (479-17,118 ng/mL, R > 0.992), limits of detection (150 ng/mL) and quantification (479 ng/mL), accuracy (- 5.6 < Bias < 14.7), repeatability (CV 1.30-3.24%), intermediate precision (CV 4.19-5.78%), extraction recovery (79.1-103.6%) and carryover. Furthermore, the stability of the drug in whole blood samples under various storage conditions was investigated. The suggested method is suitable for determining 6-thioguanine in whole blood erythrocyte samples for drug level monitoring, thus correct dosing.
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Líquidos Corporales , Tioguanina , Cromatografía Líquida de Alta Presión , Eritrocitos , BromouraciloRESUMEN
BACKGROUND: Termination of pregnancy (TOP) is not an uncommon procedure. Availability varies greatly between jurisdictions; however, additional institutional processes beyond legislation can also impact care and service delivery. This study serves to examine the role institutional processes can play in the delivery of TOP services, in a jurisdiction where TOP is lawful at all gestations (Victoria, Australia). As per the Abortion Law Reform Act 2008, TOPs post-24 weeks require the approval of two medical practitioners. However, in Victoria, hospitals that offer post-24 week TOPs generally require these cases to additionally go before a termination review committee for assessment prior to the service being provided. These committees are not stipulated in legislation. Information about these committees and how they operate is scarce and there is minimal information available to the public. METHODS: To trace the history, function, and decision-making processes of these committees, we conducted a qualitative interview study. We interviewed 27 healthcare professionals involved with these committees. We used purposive sampling to gain perspectives from a range of professions across 10 hospitals. Interviews were transcribed verbatim, identifying details removed and inductive thematic analysis was performed. RESULTS: Here, we report the three main functions of the committees as described by participants. The functions were to protect: (1) outward appearances; (2) inward functionality; and/or, (3) service users. Function (1) could mean protecting the hospital's reputation, with the "Herald Sun test"-whether the TOP would be acceptable to readers of the Herald Sun, a tabloid newspaper-used as a heuristic. Function (2) related to logistics within the hospital and protecting the psychological wellbeing and personal reputation of healthcare professionals. The final function (3) related to ensuring patients received a high standard of care. CONCLUSIONS: The primary functions of these committees appear to be about protecting hospitals and clinicians within a context where these procedures are controversial and stigmatized. The results of this study provide further clarity on the processes involved in the provision of TOPs at later gestations from the perspectives of the healthcare professionals involved. Institutional processes beyond those required by legislation are put in place by hospitals. These findings highlight the additional challenges faced by patients and their providers when seeking TOP at later gestations.
Abortion can be difficult to access. In Victoria, Australia, under the law, abortion is allowed at any time during a pregnancyalthough after you have been pregnant for more than 24 weeks, the approval of two doctors is required. However, hospitals in Victoria that offer late abortions require more than the approval of two doctors. Hospitals have put in place committees that review each case and make a decision about whether the hospital will provide the abortion. There is not a lot of information about these committeeswe do not know exactly why they exist, what they are for, or how they work. To find out, we interviewed doctors and other healthcare professionals (like midwives) who were involved in these committees. In this paper, we report the reasons these people gave for why the committees exist and what they are for. There were three main reasons. The first purpose of the committee is so the hospital does not get criticised in newspapers or by other people outside the hospital for performing these late abortions. The second reason is to help and protect those inside the hospital. For example, having a committee means that the doctors do not have to make the decisions themselves. People also said that the committees think about how the staff are feeling. The third reason is so that the hospitals provide the best care they can, and that they can continue to provide late abortions in the future. With this study, we found out some more important information about these committees that we did not have before. What we found shows that it is not just the law that mattersother things can also affect whether you can get an abortion.
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Aborto Inducido , Tioguanina , Femenino , Embarazo , Humanos , Victoria , Comités Consultivos , Aborto Inducido/psicología , Investigación CualitativaRESUMEN
Drug rediscovery refers to the principle of using 'old' drugs outside the indications mentioned in the summary of product characteristics. In the past decades, several drugs were rediscovered in a wide variety of medical fields. One of the most recent examples is the unconditional registration of thioguanine (TG), a thiopurine derivative, in patients with inflammatory bowel disease in the Netherlands. In this paper, we aim to visualise potential hurdles that hamper drug rediscovery in general, emphasise the global need for optimal use and development of potentially useful drugs, and provide an overview of the registration process for TG in the Netherlands. With this summary, we aim to guide drug rediscovery trajectories in the near future.
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Gastroenterología , Enfermedades Inflamatorias del Intestino , Humanos , Tioguanina/uso terapéutico , Uso Fuera de lo Indicado , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Países Bajos , Azatioprina/uso terapéutico , Mercaptopurina/uso terapéutico , Inmunosupresores/uso terapéuticoRESUMEN
INTRODUCTION: Thiopurines are an important therapy for the maintenance of remission in inflammatory bowel disease (IBD). However, the use of thioguanine has been limited by concerns regarding its toxicity. We performed a systematic review to evaluate its effectiveness and safety in IBD. METHODS: Electronic databases were searched to identify studies reporting clinical responses and/or adverse events of thioguanine therapy in IBD. We calculated the pooled clinical response and clinical remission rates of thioguanine in IBD. Subgroup analyses were done for the dosage of thioguanine and the type of studies (prospective or retrospective). Meta-Regression was used to analyze the impact of dose on clinical efficacy and occurrence of nodular regenerative hyperplasia. RESULTS: A total of 32 studies were included. The pooled clinical response rate of thioguanine therapy in IBD was 0.66 (95% C.I. 0.62 - 0.70; I2 = 16%). The pooled clinical response rate with low-dose was similar to high-dose thioguanine therapy [0.65 (95% C.I. 0.59 - 0.70; I2 = 24%) and 0.68 (95% C.I. 0.61 - 0.75; I2 = 18%) respectively]. The pooled remission maintenance rate was 0.71 (95% C.I. 0.58 - 0.81; I2 = 86%). The pooled rates of occurrence of nodular regenerative hyperplasia, liver function tests abnormalities and cytopenia were 0.04 (95% C.I. 0.02 - 0.08; I2 = 75%), 0.11 (95% C.I. 0.08 - 0.16; I2 = 72%) and 0.06 (95% C.I. 0.04 - 0.09; I2 = 62%) respectively. Meta-regression suggested that the risk of nodular regenerative hyperplasia is related to the dose of thioguanine. CONCLUSION: TG is an efficacious and well-tolerated drug in most patients with IBD. Nodular regenerative hyperplasia, cytopenias, and liver function abnormalities occur in a small subset. Future studies should look into TG as primary therapy in IBD.
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Enfermedades Inflamatorias del Intestino , Tioguanina , Humanos , Tioguanina/efectos adversos , Hiperplasia , Estudios Retrospectivos , Estudios Prospectivos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológicoRESUMEN
PURPOSE: To detect the possible safety signal of purine antimetabolites associated with Pneumocystis jirovecii pneumonia through disproportionality analysis in the FDA Adverse Event Reporting System (FAERS) Database. METHODS: A case/non-case retrospective disproportionality analysis was performed in the publicly available FAERS database using AERSmine (2004Q1-2021Q3). Four models were developed to explore the signal strength of PAs among different populations with possible confounding factors. Reporting odds ratio (ROR) and Proportional reporting ratio (PRR) was used as the data mining algorithm for the analysis. A value of ROR-1.96SE > 1 and PRR ≥ 2 with an associated X2 value of 4 or more was considered the threshold for a signal. RESULTS: A total of 7073 reports associated with Pneumocystis jirovecii pneumonia were present in the database, of which 899 reports were associated with purine antimetabolites. A crude signal strength of ROR 15.76(14.70-16.91) was obtained for purine antimetabolites associated PJP, with the highest signal strength reported with fludarabine and thioguanine [ROR 19.63(17.42-22.13); 19.45(13.21-28.63)]. Stratifying the cases based on autoimmune disorders and the cancer population revealed an ROR of 3.33(2.46-4.50) and 2.93(2.26-3.79) respectively. The highest risk of PJP with use of PAs was observed amongst children with a higher risk of nearly 2 times than the adult population [ROR 11.57(9.16-14.62)]. CONCLUSIONS: Our study provided evidence on the occurrence of PJP with the use of purine antimetabolites among the autoimmune and cancer population. We identified signals for PJP with azathioprine, mercaptopurine, thioguanine, cladribine, fludarabine, and clofarabine. More research with a superior epidemiological study design of a defined population is required to validate these findings.