Low-Dose Azathioprine in Combination with Allopurinol: The Past, Present and Future of This Useful Duo.

The inflammatory bowel diseases (IBD) are complex immune-mediated inflammatory diseases that are associated with significant morbidity around the world. As our understanding of IBD, and other immune-mediated inflammatory diseases, advances the number of therapeutic targets has increased which has rapidly driven the development and introduction of new therapies. While these new therapies have shown promise they come with the significant drawback of high costs. For many IBD patients around the world the cost of newer therapies is prohibitive which means treating clinicians often need to turn to optimising simpler, older, and inexpensive medications. The concept of optimising well established cheaper medications is not unique to the management of IBD as health systems all over the world look to reduce costs while simultaneously improving patient outcomes. Despite thiopurines being used in the management IBD for over 60 years, many clinicians are still hesitant to use them due to perceptions around limited efficacy and poor tolerance. One method identified to potentially increase utilisation of thiopurines involves the coadministration of allopurinol. In this review we will explore the history, pharmacology, recent studies and give recommendations for the utilisation of the usual duo of azathioprine combined with allopurinol.

Patterns of faecal glucocorticoid metabolite levels in captive roan antelope (Hippotragus equinus) in relation to reproductive status and season.

Populations of roan antelope (Hippotragus equinus) in southern Africa have experienced a drastic decline over the past few decades and this situation has led to the development of intensive breeding programmes to support conservation efforts. However, little is known about related welfare aspects, including stress-related physiological biomarkers. The present study set out to establish a non-invasive method to monitor faecal glucocorticoid metabolite (fGCM) concentrations as a measure of stress and determine fGCM concentrations in relation to male reproductive activity and female reproductive status in the roan antelope. An adrenocorticotrophic hormone challenge was performed using two adult roan antelope (one male and one female) at Lapalala Wilderness Nature Reserve, South Africa, to determine the suitability of five enzyme immunoassays (EIA) for monitoring adrenocortical function in roan antelope. An 11-oxoaetiocholanolone I EIA detecting 11,17 dioxoandrostanes performed best showing 17-20 folds increases in fGCM concentrations after 12 h-17 h post-injection. The identified EIA was then used to monitor fGCM concentrations during active and non-active reproductive periods in males (n = 3), and during periods of cyclicity, gestation, and postpartum in females (n = 10). Males showed an overall 80% increase in fGCM concentrations when reproductively active and females showed a progressively significant increase in fGCM levels throughout pregnancy, with overall fGCM concentrations being 1.5 to 2.6-fold higher than the respective fGCM concentrations during periods of postpartum and cyclicity, respectively. Furthermore, fGCM concentrations remained above baseline for up to 21 days post-partum. A correlation between ecological parameters (rainfall and temperature) and fGCM concentrations revealed elevated fGCM concentrations during the dry season for males, but not females. The non-invasive method validated in this study provides a valuable tool to quantify stress-related biomarkers in roan antelope, and findings can be used to support management decisions in conservation breeding facilities.

Evolving Role of Thiopurines in Inflammatory Bowel Disease in the Era of Biologics and New Small Molecules.

In recent years, with the increasing availability of biologic therapies and due to safety concerns, the role of thiopurines in the management of inflammatory bowel disease has been questioned. While acknowledging that the benefit/risk ratio of biologic therapies is very high, they are expensive and are not required by a majority of patients. Therefore, thiopurines do retain an important role as steroid-sparing and maintenance agents when used as monotherapy, and in combination therapy with biologics due to their clinical and pharmacokinetic optimization of anti-tumor necrosis factor agents in particular. Safety concerns with thiopurines are real but also relatively rare, and with careful pre-treatment screening and ongoing monitoring thiopurine benefits outweigh risks in the majority of appropriately selected patients. Measurement of newer pharmacogenomic markers such as nudix hydrolase 15 (NUDT15), when combined with knowledge of existing known mutations (e.g., thiopurine S-methyltransferase-TPMT), will hopefully minimize the risk of potentially life-threatening leukopenia by allowing for pre-treatment dosing stratification. Further optimization of thiopurine dosing via measurement of thiopurine metabolites should be performed routinely and is superior to weight-based dosing. The association of thiopurines with malignancies including lymphoproliferative disorders needs to be recognized in all patients and individualized in each patient. The decrease in lymphoma risk after thiopurine cessation provides an incentive for thiopurine de-escalation in appropriate patients after a period of prolonged deep remission. This review will summarize the current role of thiopurines in inflammatory bowel disease management and provide recommendations for commencing and monitoring therapy, and when to consider de-escalation.

Continuous monitoring of multiple biomarkers with an ultrasensitive 3D-structured wearable biosensor.

Chronic diseases call for routine management of frequent monitoring of specific biomarkers. Traditional in vitro diagnostics technologies suffer from complex sampling processes and long detection intervals, which cannot meet the need of continuous monitoring. Wearable devices taking advantage of compact size, rapid detection process, and small sample consumption are promising to take the place of endpoint detection, providing more comprehensive information about human health. Here, we proposed a fully integrated wearable system with an ultrasensitive 3D-structured biosensor for real-time monitoring of multiple metabolites. The 3D-structured biosensor shows wide linear ranges of 400-1,400 µM and 0.1-8 mM and high sensitivities of 460.5 and 283.09 µA/(mM·cm2) for lactate and glucose detection, respectively. We have conducted in vivo animal experiments, and the proposed wearable biosensor demonstrated high consistency with established methods. We envision that this system could provide a real-time wearable detection platform for multiple biomarker detection.

Clinical utility of thiopurine metabolite monitoring in inflammatory bowel disease and its impact on healthcare utilization in Singapore.

Background and Aim: Thiopurines are recommended for maintenance of steroid-free remission (SFR) in inflammatory bowel disease (IBD). Thiopurine metabolite monitoring (MM) is increasingly used in the West but remains novel in Singapore, with limited information on its therapeutic and economic benefits. Hence, this study aims to investigate MM's clinical utility and its impact on healthcare resource utilization in Singaporean IBD patients. Methods: A retrospective observational study was conducted at Singapore General Hospital outpatient IBD Centre. Patients with IBD, baseline MM during 2014-2017, and weight-based thiopurine doses for ≥4 weeks were followed up for 1 year. Actions were taken to optimize therapy, and metabolite levels before and after the first action were documented. Outcomes assessed included SFR, no therapy escalation or surgery, healthcare resource utilization, and direct healthcare costs. Results: Ninety IBD patients (50 Crohn's disease, 40 ulcerative colitis) were included. Among them, 40% had baseline metabolite levels within therapeutic range, 31.1% sub-therapeutic, 21.1% supra-therapeutic, and 7.8% shunters. Repeated MM with subsequent dose optimization helped 67.2% of patients achieve therapeutic levels after 1 year. Overall, 87.8% of patients achieved SFR and 90% had no therapy escalation or surgery. Despite greater outpatient visits and laboratory investigations with MM, the median total healthcare costs at 1 year only increased marginally (S$6407.66 [shunters] vs S$5215.20 [supra-therapeutic] vs S$4970.80 [sub-therapeutic] vs S$4370.48 [control (within therapeutic range)], P = 0.592). Conclusion: MM guided timely therapy escalation for non-responders, identification of non-adherence, and reversal of shunting. Therefore, it is a useful clinical tool to optimize thiopurines without significantly increasing healthcare costs.

Mechanical Tolerance of Cascade Bioreactions via Adaptive Curvature Engineering for Epidermal Bioelectronics.

Epidermal bioelectronics that can monitor human health status non-invasively and in real time are core to wearable healthcare equipment. Achieving mechanically tolerant surface bioreactions that convert biochemical information to detectable signals is crucial for obtaining high sensing fidelity. In this work, by combining simulations and experiments, a typical epidermal biosensor system is investigated based on a redox enzyme cascade reaction (RECR) comprising glucose oxidase/lactate oxidase enzymes and Prussian blue nanoparticles. Simulations reveal that strain-induced change in surface reactant flux is the key to the performance drop in traditional flat bioelectrodes. In contrast, wavy bioelectrodes capable of curvature adaptation maintain the reactant flux under strain, which preserves sensing fidelity. This rationale is experimentally proven by bioelectrodes with flat/wavy geometry under both static strain and dynamic stretching. When exposed to 50% strain, the signal fluctuations for wavy bioelectrodes are only 7.0% (4.9%) in detecting glucose (lactate), which are significantly lower than the 40.3% (51.8%) in flat bioelectrodes. Based on this wavy bioelectrode, a stable human epidermal metabolite biosensor insensitive to human gestures is further demonstrated. This mechanically tolerant biosensor based on adaptive curvature engineering provides a reliable bio/chemical-information monitoring platform for soft healthcare bioelectronics.

Therapeutic Drug Monitoring in Inflammatory Bowel Disease: History and Future Directions.

Clinical trials for the most effective drugs in the armamentarium of medications for inflammatory bowel disease (IBD) have shown only a 50-60% response rate, and this drops to 30% in maintenance. However, therapeutic drug monitoring (TDM) to adjust dosing to account for patient-specific characteristics, which has been shown to improve outcomes, was not utilized in these trials. This review will detail the development of TDM within the IBD space as it evolved from thiopurines to biologics and continues to evolve with loftier treat-to-target goals and more sophisticated dashboard systems.

Epidermal Microfluidic Electrochemical Detection System: Enhanced Sweat Sampling and Metabolite Detection.

Despite tremendous recent efforts, noninvasive sweat monitoring is still far from delivering its early analytical promise. Here, we describe a flexible epidermal microfluidic detection platform fabricated through hybridization of lithographic and screen-printed technologies, for efficient and fast sweat sampling and continuous, real-time electrochemical monitoring of glucose and lactate levels. This soft, skin-mounted device judiciously merges lab-on-a-chip and electrochemical detection technologies, integrated with a miniaturized flexible electronic board for real-time wireless data transmission to a mobile device. Modeling of the device design and sweat flow conditions allowed optimization of the sampling process and the microchannel layout for achieving attractive fluid dynamics and rapid filling of the detection reservoir (within 8 min from starting exercise). The wearable microdevice thus enabled efficient natural sweat pumping to the electrochemical detection chamber containing the enzyme-modified electrode transducers. The fabricated device can be easily mounted on the epidermis without hindrance to the wearer and displays resiliency against continuous mechanical deformation expected from such epidermal wear. Amperometric biosensing of lactate and glucose from the rapidly generated sweat, using the corresponding immobilized oxidase enzymes, was wirelessly monitored during cycling activity of different healthy subjects. This ability to monitor sweat glucose levels introduces new possibilities for effective diabetes management, while similar lactate monitoring paves the way for new wearable fitness applications. The new epidermal microfluidic electrochemical detection strategy represents an attractive alternative to recently reported colorimetric sweat-monitoring methods, and hence holds considerable promise for practical fitness or health monitoring applications.