Use of allopurinol to manage skewed 6-mercaptopurine metabolism in pediatric maintenance acute lymphoblastic leukemia treatment.

BACKGROUND: 6-mercaptopurine is a cornerstone of maintenance therapy for pediatric ALL. Response to 6MP is typically determined by the ANC. Therapeutic ANC range while receiving 6MP is between 500 and 1500/µL. In addition to desired myelosuppression, 6MP is associated with multiple adverse drug effects. Increased doses of 6MP can lead to therapeutic ANC values; however, patients may experience adverse effects before obtaining therapeutic myelosuppression, often deemed "skewed metabolism." Allopurinol may potentially correct skewed 6MP metabolism. PROCEDURE: Pediatric patients with ALL with 6MMP and 6TGN metabolites drawn during maintenance therapy were analyzed for allopurinol use. The primary outcome evaluated the percentage of time spent in therapeutic ANC range before and after allopurinol initiation. In addition, the difference in 6MMP:6TGN ratios before and after allopurinol initiation, incidence of hepatotoxicity, and rates of relapse, were analyzed. RESULTS: Ninety-five patients were included for analysis. Thirty-two (34%) patients received allopurinol. There were no significant differences in baseline demographics between the patients who received allopurinol and those who did not. When comparing ANC values pre- and post-allopurinol initiation, a statistically significant increase in the percentage of time spent in therapeutic range was observed (27% vs. 43%; p = .03). In addition, when comparing metabolite ratios pre- and post-allopurinol initiation, a statistically significant decrease in 6MMP:6TGN metabolite ratio values was observed (86.7 vs. 3.6; p < .0001). CONCLUSIONS: Allopurinol significantly increased the percent time in therapeutic ANC range and can be safely utilized to significantly lower the ratio of 6MMP:6TGN metabolites, alleviating the undesirable side effects of 6MMP, and optimizing the anti-leukemic effects associated with 6TGN.

NUDT15 Polymorphism and Its Association With Mercaptopurine Hematotoxicity in Acute Lymphoblastic Leukemia in Indonesian Children.

BACKGROUND/AIM: Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP. PATIENTS AND METHODS: A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher's exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity. RESULTS: All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity. CONCLUSION: The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.

Visible Light-mediated Late-stage Thioetherification of Mercaptopurine Derivatives.

We present herein a novel photo-mediated homolytic C-S bond formation for the preparation of alkylthiopurines and alkylthiopurine nucleosides. Despite the presence of reactive sites for the Minisci reaction, chemoselective S-alkylation remained the predominant pathway. This method allows for the late-stage introduction of a broad spectrum of alkyl groups onto the sulfur atom of unprotective mercaptopurine derivatives, encompassing 2-, 6-, and 8-mercaptopurine rings. Organoborons serve as efficient and eco-friendly alkylating reagents, providing advantages in terms of readily availability, stability, and reduced toxicity. Further derivatization of the thioetherified nucleosides, together with anti-tumor assays, led to the discovery of potent anti-tumor agents with an IC50 value reaching 6.1 µM (Comp. 31 for Jurkat).

Detailed resume of S-methyltransferases: Categories, structures, biological functions and research advancements in related pathophysiology and pharmacotherapy.

Methylation is a vital chemical reaction in the metabolism of many drugs, neurotransmitters, hormones, and exogenous compounds. Among them, S-methylation plays a significant role in the biotransformation of sulfur-containing compounds, particularly chemicals with sulfhydryl groups. Currently, only three S-methyltransferases have been reported: thiopurine methyltransferase (TPMT), thiol methyltransferase (TMT), and thioether methyltransferase (TEMT). These enzymes are involved in various biological processes such as gene regulation, signal transduction, protein repair, tumor progression, and biosynthesis and degradation reactions in animals, plants, and microorganisms. Furthermore, they play pivotal roles in the metabolic pathways of essential drugs and contribute to the advancement of diseases such as tumors. This paper reviews the research progress on relevant structural features, metabolic mechanisms, inhibitor development, and influencing factors (gene polymorphism, S-adenosylmethionine level, race, sex, age, and disease) of S-methyltransferases. We hope that a better comprehension of S-methyltransferases will help to provide a reference for the development of novel strategies for related disorders and improve long-term efficacy.

Modulation of mercaptopurine intestinal toxicity and pharmacokinetics by gut microbiota.

The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.

A convenient smartphone-assisted colorimetric for 6-Mercaptopurine detection using enhanced oxidase-like activity of ß-cyclodextrin modified MnO2 nanosheets.

6-mercaptopurine (6-MP) is widely used in the treatment of many diseases, but exhibits some serious side effects due to its toxicity. Therefore, it is important and imperative to effectively control and monitoring concentration of 6-MP. Herein, we designed a smartphone-assisted colorimetric sensing platform for 6-MP detection, based on an excellent ß-cyclodextrin modified MnO2 nanosheets (ß-CD@MnO2 NNS) mediated oxidase-like activity. ß-CD@MnO2 NNS can directly oxidizes 3,3',5,5'-tetramethylbenzidine (TMB) into oxidized TMB with color changes, yielding more than 3-fold higher oxidase-like catalytic activity compared with individual MnO2 NNS. After adding 6-MP, ß-CD@MnO2 NNS can be reduced to Mn2+ and lose their oxidase-like properties, resulting in a color and absorbance change for sensitive and selectivity detection of 6-MP. Meanwhile, the smartphone-based color recognition application can intuitively and simply measure the concentration of 6-MP. The limits of detection UV-vis instrument and smartphone were 0.35 µM and 0.86 µM, respectively. This method has also been successfully applied to the detection of real samples. Finally, this study provides a new promising platform for detection of 6-MP and is expected to be used in application of pharmaceutical analysis and biomedicine.

Evaluation of tolerance to mercaptopurine in patients with inflammatory bowel disease and gastrointestinal intolerance to azathioprine / Evaluación de la tolerancia a la mercaptopurina en los pacientes con enfermedad inflamatoria intestinal e intolerancia gastrointestinal a la azatioprina

Background Thiopurines such as azathioprine (AZA) and mercaptopurine (MP) are commonly utilized to treat inflammatory bowel disease (IBD). Their use is frequently restricted due to gastrointestinal intolerance (GI). Previous retrospective studies have reported that AZA-intolerant patients may benefit from a switch to MP; yet the effectiveness of this strategy has not been prospectively evaluated.AimsTo assess GI tolerance to MP in patients who are intolerant to AZA, and to identify clinical predictors of GI intolerance to AZA or MP.MethodsA prospective, observational, single-cohort study was performed in 92 thiopurine-naïve IBD patients. They were started on a 50mg dose of AZA and escalated to 2.5mg/kg per day by week 2. Those with GI intolerance were rechallenged with a 50% dose of AZA, after which another dose escalation attempt was made. If symptoms persisted, they were switched to MP.ResultsThirty (32.6%) of the recruited patients suffered from GI intolerance to AZA. Of these, 15 did not present recurrence of symptoms after rechallenge with lower doses. Of 15 intolerant patients, 14 were switched to MP. Within the MP cohort, 8 patients (57%) were also intolerant to MP, 5 (36%) had no symptoms, and 1 (7%) was lost to follow-up. Female gender was the only independent predictor of GI intolerance to AZA.ConclusionsUp to half of the AZA-intolerant patients tolerated a 50% dose rechallenge that was successfully escalated. A switch to MP was tolerated in over a third of cases whom rechallenge failed. Our strategy (challenge–rechallenge–switch) achieved an overall GI tolerance to thiopurines in most of the patients. (AU)

Antecedentes Las tiopurinas como la azatioprina (AZA) y la mercaptopurina (MP) se utilizan comúnmente para tratar la enfermedad inflamatoria intestinal (EII). Su uso está frecuentemente restringido debido a la intolerancia gastrointestinal. Estudios retrospectivos anteriores han informado que los pacientes intolerantes a la AZA pueden beneficiarse de un cambio a MP; sin embargo, la eficacia de esta estrategia no ha sido evaluada prospectivamente.ObjetivosEvaluar la tolerancia gastrointestinal a MP en pacientes que son intolerantes a AZA e identificar predictores clínicos de intolerancia gastrointestinal a AZA o MP.MétodosSe realizó un estudio prospectivo, observacional y de cohorte única en 92 pacientes con EII que nunca habían recibido tiopurinas. Comenzaron con una dosis de 50mg de AZA y se aumentó a 2,5mg/kg por día en la semana 2. En aquellos con intolerancia gastrointestinal se administró una dosis del 50% de AZA que se fue incrementando en función de la tolerancia. Si los síntomas persistían, se cambiaba a MP.ResultadosTreinta (32,6%) de los pacientes reclutados presentaron intolerancia gastrointestinal a la AZA. De estos, 15 no presentaron recurrencia de los síntomas después de la nueva exposición. De los 15 pacientes que no toleraron una dosis más baja, 14 recibieron MP. De los que recibieron MP, 8 pacientes (57%) también eran intolerantes a MP, 5 (36%) no tenían síntomas y uno (7%) se perdió durante el seguimiento. El género femenino fue el único predictor independiente de intolerancia gastrointestinal a la AZA.ConclusionesHasta la mitad de los pacientes intolerantes a la AZA toleran una nueva exposición al 50% de la dosis. Se toleró un cambio a MP en más de un tercio de los casos en los que la reexposición fracasó. Nuestra estrategia logró la tolerancia gastrointestinal a tiopurinas en la mayoría de los pacientes. (AU)

The frequency of NUDT15 rs116855232 and its impact on mercaptopurine-induced toxicity in Syrian children with acute lymphoblastic leukemia.

Introduction: Polymorphisms in NUDT15 may result in differences in mercaptopurine-induced toxicity. This study aimed to identify the frequency of the NUDT15 (c.415C>T; rs116855232) polymorphism and investigate the effect of this polymorphism on mercaptopurine-induced toxicity in a population of Syrian patients with childhood acute lymphoblastic leukemia (ALL). Methods: This is a retrospective study that included children with ALL reaching at least 6 months of maintenance therapy. The NUDT15 genotyping was determined using standard targeted sequencing of polymerase chain reaction products. The odds ratio (OR) for the association between toxicity and genotype was evaluated. Results: A total of 92 patients were enrolled. The majority of the patients in the study population were low-risk (63.04%), followed by intermediate-risk (25%), and high-risk (11.96%). There were 5 patients (5.4%) with NUDT15 (c.415C>T; rs116855232) CT genotype, and 1 patient (1.08%) with NUDT15 TT genotype, with allele frequencies of C=0.962 and T=0.038. The mercaptopurine median dose intensity was 100%, 54.69%, and 5% for the genotypes CC, CT, and TT, respectively (P=0.009). Early onset leukopenia was significantly associated with the NUDT15 polymorphism (OR: 6.16, 95% CI: 1.11-34.18, P=0.037). There was no association between the NUDT15 genotype and hepatotoxicity. Conclusion: Approximately 6.5% of the study population exhibited reduced NUDT15 activity. The mercaptopurine dose intensity was considerably low in NUDT15 rs116855232 TT genotype compared with CT and CC. The dosage of mercaptopurine should be adjusted according to the NUDT15 genotype in pediatric patients with ALL.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

A novel turn-on fluorescence sensor based on the Nd (III) complex for the ultrasensitive detection of 6-mercaptopurine.

6-mercaptopurine (6MP) is a chemotherapeuticdrug widely used for treating inflammatory bowel diseases and several cancers. Nevertheless, determining and monitoring its concentration in the human body is highly important because over or under-doses of 6MP can lead to critical health issues. In this paper, we have developed a turn-on fluorescent probe for the determination of the anticancer drug 6-mercaptopurine (6-MP) based on coordination complex [Nd (Anth)3 (H2O)3]. [Nd (Anth)3 (H2O)3] has been synthesized through a simple precipitation process taking the stoichiometric ratio of Nd (III) nitrate hexahydrate and 2-aminobenzoic acid (2-ABA), commonly known as anthranilic acid (Anth). The synthesis and structure have been investigated and validated by different characterizations like UV-visible spectroscopy, FT-IR, HRMS, XPS, and SEM. The synthesized complex displayed excellent fluorescence properties, and the fluorescence intensity was enhanced with the addition of 6MP in the form of a [Fe (6MP)3]2+ mixed complex (Fe-6MP), which is formed by dissolving it in FeCl3. The fabricated sensors displayed the best linear response in a wide range of concentrations from 2.55 µM to 45.51 µM of 6MP. The lower limit of detection (LOD) of the developed sensor was found to be 0.26 µM with a linear correlation coefficient (R2) of 0.99. The synthesized probe gives an acceptable response for the sensing of 6MP in the presence of several interfering agents.

Clinical pharmacists' knowledge, attitude, perception, and beliefs about the role of pharmacogenetic testing for genes polymorphisms when prescribing mercaptopurine.

Background: Single nucleotide polymorphisms in the gene encoding proteins involved in mercaptopurine metabolism can influence drug efficacy and safety. This study aims to assess clinical pharmacists' knowledge about mercaptopurine-related genes and their polymorphisms and investigate their attitudes, perceptions, and beliefs about the need for and importance of pharmacogenetic testing for mercaptopurine. Methods: A cross-sectional descriptive study was conducted among oncology/hematology clinical pharmacists in Saudi Arabia using an online-questionnaire developed by experts in the field. The questionnaire consists of four-sections exploring clinical pharmacists' knowledge, attitudes, perceptions, and beliefs about the importance of gene testing and genes polymorphism when prescribing mercaptopurine. Descriptive statistics were used to analyze the data in the study. Results: A total of 41 oncology/hematology clinical pharmacists responded to the survey invitation. Almost half of them had more than 10 years of work experience, but only 17 % of them received formal training in pharmacogenetics. The overall level of knowledge about pharmacogenetics among participants was low, with a mean score of 2.8 points (1.7) out of 8 items. However, around 76 % agreed that it is important to perform pharmacogenetic screening prior to prescribing mercaptopurine, and almost 93 % state that it will influence their dosage recommendation. Most of the participants had a good perception (95.1 %) of their role in genetic testing for medication selection, dosing, and monitoring; however, about 10 % of surveyed pharmacists reported not being completely responsible about recommending pharmacogenetic testing. The surveyed pharmacists had a good belief in the importance of pharmacogenetic testing and their overall attitude was positive toward the use of pharmacogenetic testing, with emphasis on the importance of training on the proper assessment and interpretation of pharmacogenetic tests. Conclusions: Pharmacists demonstrated good perception and positive attitude toward pharmacogenetic testing, despite the low level of knowledge and limited formal training. Thus, more attention to developing national guidelines on pharmacogenetic testing is warranted to ensure successful pharmacogenetic testing implementation.

Efficacy of optimised thiopurine therapy in patients with moderate-to-severe ulcerative colitis: retrospective long-term follow-up from two randomised trials.

OBJECTIVE: The long-term outcome of thiopurine therapy in patients with ulcerative colitis (UC) enrolled in prospective trials have not been evaluated. We aimed to assess the effects of optimised thiopurine maintenance therapy for UC. METHODS: Long-term data were obtained from patients from our center enrolled in two randomised, prospective, open-label, controlled studies comprising 66 thiopurine-naïve moderate-to-severe patients with UC consisting of a low dose azathioprine (AZA)/allopurinol combination or AZA monotherapy. Following the randomised trials, treatment was adjusted according to adverse effects and metabolites. Patients requiring optimisation initially on AZA monotherapy treatment were switched to low dose AZA in combination with allopurinol, low dose 6-mercaptopurin in combination with allopurinol, or 6-mercaptopurin treatment alone, and those treated with low dose AZA in combination with allopurinol were switched to low dose 6-mercaptopurin in combination with allopurinol or 6-mercaptopurin alone. RESULTS: A total of 62 patients were included in the analysis; 31 were initially treated with AZA monotherapy and 31 with low dose AZA in combination with allopurinol. Initial treatment was tolerated by 67% patients (7 AZA monotherapy and 28 low dose AZA in combination with allopurinol), increasing to 94% (58 patients) post-adjustment. After a median 52-month follow-up period, 38 (93%) out of the 41 primary responding patients-maintained clinical remission without steroids, biologics or surgery. The four intolerant patients and the 17 not responding to optimisation were more likely to require colectomy (odds ratio 16.36; 95% confidence interval 3.08-87.03, p < 0.0001). CONCLUSION: Optimised thiopurine therapy demonstrated effective long-term treatment for patients with ulcerative colitis.

Zinc-doped hydroxyapatite as a pH responsive drug delivery system for anticancer drug 6-mercaptopurine.

6-Mercaptopurine (6MP) is commonly used in the treatment of acute lymphoblastic leukemia as an important agent in maintenance therapy. Despite its therapeutic benefits, 6MP has some limitations during therapy. Taking into account the disadvantages during 6MP therapy, there is a great need to create an appropriate delivery system for this drug. 6MP contains in its structure nitrogen and sulfur atoms capable of forming coordination compounds with metal ions, for example zinc. Therefore, in this work, we prepared biocompatible hydroxyapatite (HAp) doped with zinc ions, and used it as a carrier for 6MP. Doped HAp has not been used as a carrier for this drug before. The work proved that the prepared carrier-drug system has a particle size of about 130 nm, which indicates its potential for intravenous delivery. In addition, in an acidic environment (imitating cancer cells), the carrier agglomerates allow targeted release of the drug. The drug is evenly distributed, which indicates that the doses released from it will always be comparable. The release of the drug in a neutral environment is long-lasting in controlled doses, whereas in an acidic environment it is immediate. The obtained results indicate the high potential of the material in both slow-release and cancer-targeted release of 6MP.

Profound Hypoglycemia and High Anion Gap Metabolic Acidosis in a Pediatric Leukemic Patient Receiving 6-Mercaptopurine.

A 13-year-old male undergoing maintenance chemotherapy with methotrexate and 6-mercaptopurine (6MP), for very high-risk B-cell acute lymphoblastic leukemia (ALL), presented with vomiting due to severe hypoglycemia with metabolic acidosis. While his laboratory values were concerning for a critically ill child, the patient was relatively well appearing. Hypoglycemia is a rare but serious side effect of 6MP with an unexpectedly variable presentation; therefore, a high index of suspicion is needed for its prompt detection and treatment. This patient also had severe metabolic acidosis, likely secondary to hypoglycemia, creating a serious clinical picture despite a well-appearing child. This example of incongruity between laboratory tests and clinical appearance adds nuance to the existing literature. Moreover, although 6MP-associated hypoglycemia is rare, it may be more prevalent than the literature suggests, as symptoms of hypoglycemia-nausea, vomiting, and somnolence-mirror common chemotherapy side effects. 6MP-induced hypoglycemia can be ameliorated with the addition of allopurinol to shunt metabolism in favor of the production of therapeutic metabolites over hepatotoxic metabolites. Additionally, a morning administration of 6MP and frequent snacks may also help to prevent hypoglycemia. Overall, this case adds to the literature of unusual reactions to 6MP including hypoglycemia in an older child without traditional risk factors.

Uphill battle: Innovation of thiopurine therapy in global inflammatory bowel disease care.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that encompasses two major conditions: Crohn's disease (CD) and ulcerative colitis (UC). Historically, IBD has been primarily reported in western countries, but over the past decades, its prevalence is rapidly increasing, especially in lower and middle-income countries (LMICs) such as India and China and also in Sub-Saharan Africa. The prevalence of IBD in LMICs has been the subject of growing concern due to the impact of access to public healthcare and the burden it places on healthcare resources. The classical thiopurines face significant challenges due to cessation of therapy in approximately half of patients within one year due to side effects or ineffectiveness. In this article, we highlight innovating thiopurine treatment for IBD patients in downregulating side effects and improving efficacy.

Assessment on the use of allopurinol to improve safety and efficacy of mercaptopurine in pediatric patients with Acute Lymphoblastic Leukemia and Lymphoma during maintenance therapy.

BACKGROUND: Mercaptopurine is an important component of acute lymphoblastic leukemia (ALL) and lymphoma (LLy) maintenance therapy. The 6-thioguanine nucleosides (6-TGN) are believed to be the primary contributor to myelosuppression and immunosuppressive effects, while 6-methylmercaptopurine (6-MMPN) is believed to be responsible for several toxicities including hepatotoxicity, pancreatitis, and hypoglycemia. Previous reports suggest the addition of allopurinol may reduce these toxicities. AIMS: To assess the use of allopurinol to improve both safety and efficacy of mercaptopurine in pediatric patients with ALL and LLy during maintenance therapy. Secondary objectives included evaluating patient tolerability and skewed metabolism. In addition, we also analyzed mercaptopurine daily dose reduction upon allopurinol initiation. METHODS AND RESULTS: The primary endpoint was time within goal ANC prior to and after initiation of allopurinol. Secondary endpoints included; improvement in selective toxicities (hepatotoxicity, pancreatitis, and hypoglycemia) and 6-MMPN to 6-TGN ratio prior to and after allopurinol initiation. In addition, an exploratory endpoint assessing mercaptopurine daily dose reduction prior to and after allopurinol initiation was included. Sixteen patients met inclusion criteria and 15 (94%) of which were included in this study. Median percent of maintenance days within goal ANC prior to and after initiation of allopurinol was 27.8 (IQR 22.6-44.9) and 41.6 (IQR 20.2-58.2) respectively. All patients experienced selective toxicities; 15 (100%) hepatotoxicity, 1 (7%) pancreatitis, and 3 (20%) hypoglycemia. Improvement of toxicities was seen in 13/15 (87%), 1/1 (100%), and 2/3 (67%) respectively. Average 6-MMPN:6-TGN ratio prior to allopurinol initiation was 304:1 and after, allopurinol initiation improved to 15:1, resulting in a 95% reduction. Average mercaptopurine dose prior to and after allopurinol initiation decreased by about 56% (63 to 28 mg/m2 /day). CONCLUSION: Results suggest that the use of allopurinol in pediatric patients with ALL and LLy receiving mercaptopurine during maintenance therapy is both safe and effective.

The drug-survival of low-dose thioguanine in patients with inflammatory bowel disease: a retrospective observational study.

Background: Thiopurines are commonly used to treat inflammatory bowel disease but withdrawal due to side effects are common. Thioguanine has been suggested to be better tolerated than conventional thiopurines. Objectives: We studied drug-survival of low dose of thioguanine in real-life clinical practice in comparison to conventional thiopurines. Design: Retrospective observational study. Methods: All patients born 1956 and later, and who at least once started thiopurine treatment between 2006 and 2022 were included. A medical chart review was performed that noted drug-survival for every thiopurine treatment attempt. The Mantel-Cox rank test was used to test differences in drug-survival for different thiopurines. Blood chemistry analysis and faecal calprotectin levels were registered for the first 5 years of treatment. Results: In the study population, there was 379 initiated thiopurine treatments (210 for Crohn's disease and 169 for ulcerative colitis) in 307 patients with inflammatory bowel disease (IBD). Low-dose thioguanine (median dose 11 mg; 25-75th percentile 7-19 mg) had been initiated in 31 patients. Overall, when including all thiopurine attempts, thioguanine had the longest drug-survival [Mantel-Cox rank test: thioguanine versus azathioprine p = 0.014; thioguanine versus 6-mercaptopurine (6-MP) p < 0.001]. For second-line thiopurine treatment thioguanine had longer drug-survival than 6-MP (Mantel-Cox rank test: p = 0.006). At 60 months, 86% of the patients who started low-dose thioguanine were still on treatment compared to 42% of the patients who started 6-MP (p = 0.022). The median 6-thioguanine nucleotide levels in patients treated with thioguanine was 364 pmol/8 × 108. Patients on thioguanine treatment showed significantly lower values of median mean corpuscular volume at follow-up than patients treated with azathioprine and 6-MP. Patients treated with 6-MP showed significantly lower levels of FC in the third year of treatment compared to patient treated with azathioprine (59 versus 109 µg/g; p = 0.023), but there was no significant difference in FC levels for thioguanine compared to azathioprine (50 versus 109 µg/g; p = 0.33). Conclusion: Treatment with a low dose of thioguanine is well-tolerated in patients with IBD and had a significantly higher drug-survival than conventional thiopurines.

Low-dose of the immunomodulator drug thioguanine are well tolerated by patients with inflammatory bowel disease Thiopurines are commonly used to treat inflammatory bowel disease but it is common that patients end treatment due to side-effects. The thiopurine thioguanine has been suggested to be better tolerated than other thiopurines. We aimed to study if a low-dose of thioguanine had been tolerated better and used longer than other thiopurines in patients with inflammatory bowel disease at our clinic. In the study population there was 379 initiated thiopurine treatments in 307 patients with inflammatory bowel disease. Among those patients a low-dose thioguanine had been initiated in 31 patients. Overall, when including all thiopurine attempts, thioguanine had longest drug-survival of all thiopurines. For second line thiopurine treatment thioguanine had longer drug-survival than the thiopurine 6-mercaptopurine that are usually used as second line thiopurine treatment. At 60 months, 86% of the patients who started low dose thioguanine was still on treatment compared to 42% of the patients who started 6-mercaptopurine.There was a similar response on inflammatory markers the first five years from starting treatment with thioguanines compared to conventional used thiopurines. We conclude that treatment with a low-dose of thioguanine is well tolerated in patients with inflammatory bowel disease and have a significantly higher drug survival than conventional thiopurines.

A stable and sensitive 2D SERS sensor for bioanalytical applications.

In this study, we describe a 2D-SERS sensor obtained by deposition of spherical gold nanoparticles (AuNPs) onto a suitably functionalized metal surface. Morphological analysis of the SERS surface by SEM and AFM demonstrated a uniform and stable distribution of the active nanoparticles. Following p-mercaptoaniline (pMA) functionalization, the sensor was characterized by co-localized Raman measurements, demonstrating a significant enhancement in Raman signals with homogeneous SERS activity across the entire sampled area. The as-prepared SERS sensor was demonstrated to be suitable for Therapeutic Drug Monitoring (TDM) of 6-mercaptopurine (6-MP), exhibiting a linear correlation between analyte concentration and SERS intensity in the range 5 - 20 µM. This work highlights the potential of 2D-SERS sensors for hypersensitive and accurate analytical measurements, particularly in the biomedical field.