Characterization of Inflammatory Mediators and Metabolome in Interstitial Fluid Collected with Dermal Open Flow Microperfusion before and at the End of Dupilumab Treatment in Atopic Dermatitis.

Dupilumab is a monoclonal antibody approved for the treatment of atopic dermatitis (AD); however, its effects on molecular, cellular, and immunological levels remain to be elucidated. In this study, blood and dermal interstitial fluid (ISF) from nonlesional (NL) and lesional (L) skin were collected from eight patients with moderate to severe AD, before (visit 2-v2) and at the end of a 16-week treatment with dupilumab (visit 10-v10). Clinical treatment effect was demonstrated by significantly decreased AD severity scores at the end of treatment. At v10 versus v2, the percentages of CD4+ interleukin-producing cells showed a decreasing trend in ISF L and NL, unbound IL-4 levels in plasma were increased, IL-5 levels in ISF L reduced, and levels of factors involved in anti-inflammatory pathways and re-epithelization increased. At v2, ISF L showed that AD lesions might have altered amino acid pathways and lipid signaling compared to ISF NL. At v10, ISF L exhibited raised levels of long- and very-long-chain fatty acids and lipids compared to v2. Furthermore, dupilumab administration caused reduced expression of miR-155-5p and miR-378a-3p in ISF L. In conclusion, results from the present study provided novel knowledge by linking local immune and metabolic alterations to AD pathogenesis and treatment response.

Cutaneous pharmacokinetics-based bioequivalence: A clinical dermal open flow microperfusion verification study using lidocaine and prilocaine combination topical products.

BACKGROUND: Using accurate, sensitive, reproducible and efficient in vivo cutaneous pharmacokinetics (PK)-based bioequivalence (BE) approaches can promote the development of topical generic drug products. A clinical dermal open flow microperfusion (dOFM) study has previously demonstrated the BE of topical drug products containing a hydrophilic drug. However, the utility of dOFM to evaluate the topical BE of drug products containing moderately lipophilic drugs, more representative of most topical drugs, has not yet been established. OBJECTIVE: To evaluate the ability of a clinical dOFM study to assess BE of topical products containing two moderately lipophilic drugs that have only minor differences in chemical and physical properties. METHODS: The study included 20 healthy subjects. Four application sites on each thigh were treated with fixed dose lidocaine/prilocaine combination products, and dermal drug concentrations were monitored with two dOFM probes per application site for 12 h. A reference cream was compared to itself and to an approved generic cream (both serving as positive controls for BE), and to a gel (negative control). BE was established based on AUC0to12h and Cmax using the scaled-average-BE approach. Systemic exposure of both drugs was assessed throughout the study. RESULTS: BE was successfully demonstrated for the positive controls, and not for the negative control, for both drugs. The systemic exposure of both drugs was negligible. CONCLUSIONS: dOFM accurately demonstrated BE between bioequivalent topical creams, sensitively discriminated between different formulations and differentiated the cutaneous PK of both study drugs, even though they differ only slightly in chemical and physical properties. These results support the utility of dOFM as a cutaneous PK-based BE approach for topical lipophilic drugs, including lidocaine and prilocaine.

Dermal open flow microperfusion for PK-based clinical bioequivalence studies of topical drug products.

Topically applied drug products have experienced an extraordinary price increase in the United States, mostly due to a lack of generic products. Generic drug development is hindered by high costs and risks associated with clinical endpoint studies required to show bioequivalence (BE) of prospective generic products relative to their reference products. There is a continued need for cost- and time-efficient alternatives to clinical endpoint studies to determine BE of topically applied dermal drug products. Cutaneous PK-based BE studies present such an alternative and dOFM (dermal open flow microperfusion) has already been successfully used in several verifications studies to show an accurate and sensitive assessment of the rate and extent at which drugs become available in the skin. dOFM technology is discussed as well as the dOFM setup of clinical pilot and main studies to achieve BE assessment with a minimum number of participants and an outlook is given on the use of dOFM technology for other drug products.

Optimization of topical formulations using a combination of in vitro methods to quantify the transdermal passive diffusion of drugs.

This paper describes a new approach to the early-stage optimization of topical products and selection of lead formulation candidates. It demonstrates the application of open flow microperfusion in vitro in conjunction with the Franz diffusion cell to compare time-resolved, 24-hour profiles of diclofenac passive diffusion through all skin layers (including the skin barrier, dermis, and subcutis) resulting from nine topical formulations of different composition. The technique was successfully validated for in vitro sampling of diclofenac in interstitial fluid. A multi-compartmental model integrating the two datasets was analyzed and revealed that the passive diffusion of diclofenac through the dermis and subcutis does not correlate with its diffusion through the skin barrier and cannot be predicted using Franz diffusion cell data alone. The combined application of the two techniques provides a new, convenient tool for product development and selection enabling the comparison of topical formulation candidates and their impact on drug delivery through all skin layers. This approach can also generate the experimental data required to improve the robustness of mechanistic PBPK models, and when combined with clinical sampling via open flow microperfusion - for the development of better in vivo-in vitro correlative models.

Digital algorithm-guided insulin therapy in home healthcare for elderly persons with type 2 diabetes: A proof-of-concept study.

GlucoTab@MobileCare, a digital workflow and decision support system with integrated basal and basal-plus insulin algorithm was investigated for user acceptance, safety and efficacy in persons with type 2 diabetes receiving home health care by nurses. During a three months study nine participants (five female, age 77 ± 10 years, HbA1c 60 ± 13 mmol/mol (study start) vs. 57 ± 12 mmol/mol (study end) received basal or basal-plus insulin therapy as suggested by the digital system. In total 95% of all suggested tasks (blood glucose (BG) measurements, insulin dose calculations, insulin injections) were performed according to the digital system. Mean morning BG was 171 ± 68 mg/dL in the first study month vs. 145 ± 35 mg/dL in the last study month, indicating a reduced glycemic variability of 33 mg/dL (standard deviation). No hypoglycemic episode < 54 mg/dL occurred. User's adherence was high and the digital system supported a safe and effective treatment. Larger scale studies are needed to confirm findings under routine care. German Clinical Trials Register ID: DRKS00015059.

Comparative in vitro release testing (IVRT) of acyclovir products.

The aim was to evaluate whether an in vitro release test (IVRT) could differentiate the release rates from five pharmaceutically equivalent acyclovir cream products and one ointment compared to that from a reference product, Zovirax cream (USA), to identify a test product with an inequivalent drug release rate that could serve as negative control for bioequivalence (BE) in a separate in vivo study. The reference product showed equivalent drug release rates compared to itself. The six test products failed to show equivalent drug release rates compared to the reference product. Aciclovir 1A pharma cream was selected to serve as a negative control for subsequent BE studies, since it exhibited the greatest difference in release rate among all creams, compared to the reference product. The results of this study indicate that IVRT results can be highly sensitive and may discriminate clinically relevant differences between products. Results from an appropriately validated IVRT method can support a demonstration of BE by showing that the drug release rates from test and reference products are statistically equivalent, mitigating the risk that differences may exist between the products which may influence in vivo performance of the drug product.

Characterizing Cutaneous Drug Delivery Using Open-Flow Microperfusion and Mass Spectrometry Imaging.

Traditionally, cutaneous drug delivery is studied by skin accumulation or skin permeation, while alternative techniques may enable the interactions between the drug and the skin to be studied in more detail. Time-resolved skin profiling for pharmacokinetic monitoring of two Janus Kinase (JAK) inhibitors, tofacitinib and LEO 37319A, was performed using dermal open-flow microperfusion (dOFM) for sampling of perfusate in an ex vivo and in vivo setup in pig skin. Additionally, matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was performed to investigate depth-resolved skin distributions at defined time points ex vivo in human skin. By dOFM, higher skin concentrations were observed for tofacitinib compared to LEO 37319A, which was supported by the lower molecular weight, higher solubility, lipophilicity, and degree of protein binding. Using MALDI-MSI, the two compounds were observed to show different skin distributions, which was interpreted to be caused by the difference in the ability of the two molecules to interact with the skin compartments. In conclusion, the techniques assessed time- and depth-resolved skin concentrations and were able to show differences in the pharmacokinetic profiles of two JAK inhibitors. Thus, evidence shows that the two techniques can be used as complementary methods to support decision making in drug development.

Dietary spermidine improves cognitive function.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.

OFM-recirculation and OFM-suction: advanced in-vivo open flow microperfusion (OFM) methods for direct and absolute quantification of albumin in interstitial fluid.

OBJECTIVE: To implement OFM-recirculation and OFM-suction capable of direct and absolute in-vivo quantification of albumin in the ISF of pigs. APPROACH: OFM-recirculation and OFM-suction were used to collect ISF in-vivo in pigs and lymph was collected from the same pigs after OFM sampling. Blood was collected before and after OFM sampling, plasma was isolated and mean albumin plasma concentrations per pig were used to yield albumin ISF-to-plasma ratios. We characterized the quality of the collected undiluted ISF via (1) stable albumin ISF-to-plasma ratio in OFM-recirculation and in OFM-suction samples, (2) comparison of albumin ISF-to-plasma ratios from OFM-recirculation and OFM-suction and (3) comparison of normalized albumin concentrations in the ISF and lymph. MAIN RESULTS: Both advanced OFM methods were successfully implemented and albumin was quantified from the collected ISF samples. OFM-recirculation reached stable albumin ISF-to-plasma ratios after 20 recirculation cycles. Absolute ISF albumin concentrations were 11.2 mg ml-1 (OFM-recirculation) and 14.2 mg ml-1 (OFM-suction). Albumin ISF-to-plasma ratios were 0.39 ± 0.04 (OFM -recirculation) and 0.47 ± 0.1 (OFM-suction). SIGNIFICANCE: Knowledge of the ISF protein content is of major importance when assessing PK/PD effects, especially of highly protein bound drugs. Up to now, only blood albumin values have been available to determine the degree of protein binding in several tissues. OFM-recirculation and OFM-suction allow direct, absolute quantification of albumin in ISF for the first time and enable investigation of the degree of protein binding of a drug directly in its target tissue.

Electronic Diabetes Management System Replaces Paper Insulin Chart: Improved Quality in Diabetes Inpatient Care Processes Due to Digitalization.

BACKGROUND: GlucoTab, an electronic diabetes management system (eDMS), supports healthcare professionals (HCPs) in inpatient blood glucose (BG) management at point-of-care and was implemented for the first time under routine conditions in a regional hospital to replace the paper insulin chart. METHOD: To investigate quality of the eDMS for inpatients with type 2 diabetes mellitus a monocentric retrospective before-after evaluation was conducted. We compared documentation possibilities by assessing a blank paper chart vs the eDMS user interface. Further quality aspects were compared by assessing filled-in paper charts (n = 106) vs filled-in eDMS documentation (n = 241). HCPs (n = 59) were interviewed regarding eDMS satisfaction. RESULTS: The eDMS represented an improvement of documentation possibilities by offering a more structured and comprehensive user interface compared to the blank paper chart. The number of good diabetes days averaged to a median value of four days in both groups (paper chart: 4.38 [0-7] vs eDMS: 4.38 [0-7] days). Median daily BG was 170 (117-297) mg/dL vs 168 (86-286) mg/dL and median fasting BG was 152 (95-285) mg/dL vs 145 (69-333) mg/dL, and 0.1% vs 0.4% BG values <54 mg/dL were documented. Diabetes documentation quality improved when using eDMS, for example, documentation of ordered BG measurement frequency (1% vs 100%) and ordered BG targets (0% vs 100%). HCPs stated that by using eDMS errors could be prevented (74%), and digital support of work processes was completed (77%). Time saving was noted by 8 out of 11 HCPs and estimated at 10-15 minutes per patient day by two HCPs. CONCLUSIONS: The eDMS completely replaced the paper chart, showed comparable glycemic control, was positively accepted by HCPs, and is suitable for inpatient diabetes management.

Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies.

PURPOSE: To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants. METHODS: Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement. RESULTS: Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7-33-fold higher than the dISF concentrations. CONCLUSIONS: Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion.

PURPOSE: Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study. METHODS: Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products. RESULTS: The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject's skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability. CONCLUSIONS: Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.

Study protocol for assessing the user acceptance, safety and efficacy of a tablet-based workflow and decision support system with incorporated basal insulin algorithm for glycaemic management in participants with type 2 diabetes receiving home health care: A single-centre, open-label, uncontrolled proof-of-concept study.

INTRODUCTION: Diabetes management can be especially complex for older adults who receive health care at home. Thus, international guidelines recommend basal-insulin regimens due to simpler handling and low hypoglycaemia risk. A basal-insulin algorithm (including basal-plus) was developed to also include participant's health status and subsequently implemented into a tablet-based workflow and decision support system, GlucoTab@MobileCare. This study protocol describes a proof-of-concept study to investigate user acceptance, safety and efficacy of the GlucoTab@MobileCare system in participants receiving home health care. METHODS: The open-label, single-centre, uncontrolled study will recruit a maximum of ten participants with insulin treated type-2-diabetes (age ≥18 years) who receive home health care. During a three month study period participants will receive basal- or basal-plus-insulin therapy once daily as suggested by the GlucoTab@MobileCare system. Statistical analysis will be conducted on an intention-to-treat basis. The primary endpoint is the percentage of tasks (BG measurements, insulin dose calculations, insulin injections) that were performed according to GlucoTab@MobileCare suggestions relative to the total of suggested tasks. Secondary endpoints include user acceptance, safety and efficacy parameters. The study was approved by the ethics committee and regulatory authorities. Before obtaining written informed consent, all participants will receive oral and written information about all aspects of the study. Results will be published in a peer-reviewed journal and at diabetes and geriatric conferences. DISCUSSION: Potential implications may be improved quality and safety of basal-insulin therapy in older adults as well as support for health-care-providers in daily routine including evidence-based knowledge. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00015059).

Alternate Day Fasting Improves Physiological and Molecular Markers of Aging in Healthy, Non-obese Humans.

Caloric restriction and intermittent fasting are known to prolong life- and healthspan in model organisms, while their effects on humans are less well studied. In a randomized controlled trial study (ClinicalTrials.gov identifier: NCT02673515), we show that 4 weeks of strict alternate day fasting (ADF) improved markers of general health in healthy, middle-aged humans while causing a 37% calorie reduction on average. No adverse effects occurred even after >6 months. ADF improved cardiovascular markers, reduced fat mass (particularly the trunk fat), improving the fat-to-lean ratio, and increased ß-hydroxybutyrate, even on non-fasting days. On fasting days, the pro-aging amino-acid methionine, among others, was periodically depleted, while polyunsaturated fatty acids were elevated. We found reduced levels sICAM-1 (an age-associated inflammatory marker), low-density lipoprotein, and the metabolic regulator triiodothyronine after long-term ADF. These results shed light on the physiological impact of ADF and supports its safety. ADF could eventually become a clinically relevant intervention.

Insulin Distribution in Human Adipose Tissue via a Novel Insulin Infusion Catheter.

Continuous subcutaneous insulin infusion (CSII) is a widely used treatment for diabetes patients. Insulin infusion sets (CSII-catheters) are continuously optimized regarding size, handling and safety, but recurring dysfunction (kinking or occlusion), due to different user situations, behavior or chain of events, demand new ways to improve the functionality and safety in patients experiencing these issues. A novel CSII-catheter design (Lantern) features additional lateral perforations, which guarantee functionality even in case of kinking or occlusion. This study aimed to compare functionality, insulin distribution, and failure rate of Lantern and standard catheters using excised human adipose tissue samples. Novel Lantern CSII-catheters (open and artificially occluded) and commercially available standard CSII-catheters were inserted into adipose tissue samples. A mixture of insulin and contrast agent was infused as single bolus (7 IU) with an insulin infusion pump at highest flow rate (1 IU/s). Microtomography images and surface-to-volume ratios were used to assess insulin distribution and depot volume indicating the functionality of CSII-catheters. Failure rate was measured by flow-stop alerts of the pump. We found no difference in the volume of insulin depots compared with the nominal volume of 70 µL. Surface-to-volume ratios showed no significant difference among CSII-catheters. None of the catheters triggered any flow-stop alarm. The novel Lantern CSII-catheter design achieved similar insulin distribution as commercially available CSII-catheters. Moreover, functionality of Lantern CSII-catheters was guaranteed during occlusion, which is an improvement compared with standard CSII-catheters. We conclude that the novel CSII-catheter design has the potential to provide a valuable contribution to patient well-being and safety.

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.

LC/MS/MS analyses of open-flow microperfusion samples quantify eicosanoids in a rat model of skin inflammation.

Eicosanoids are lipid-mediator molecules with key roles in inflammatory skin diseases, such as psoriasis. Eicosanoids are released close to the source of inflammation, where they elicit local pleiotropic effects and dysregulations. Monitoring inflammatory mediators directly in skin lesions could provide new insights and therapeutic possibilities. Here, we analyzed dermal interstitial fluid samples obtained by dermal open-flow microperfusion in a rat model of skin inflammation. We developed a solid-phase extraction ultra-HPLC/MS/MS method to reliably and precisely analyze small-volume samples and quantified 11 eicosanoids [thromboxane B2, prostaglandin (PG) E2, PGD2, PGF2α, leukotriene B4, 15-HETE, 12-HETE, 5-HETE, 12-hydroxyeicosapentaenoic acid, 13-HODE, and 17-hydroxydocosahexaenoic acid]. Our method achieved a median intraday precision of approximately 5% and interday precision of approximately 8%. All calibration curves showed excellent linearity between 0.01 and 50 ng/ml (R2 > 0.980). In the rat model, eicosanoids were significantly increased in imiquimod-treated inflamed skin sites compared with untreated control sites. Oral treatment with an anti-inflammatory glucocorticoid decreased eicosanoid concentrations. These results show that a combination of tissue-specific sampling with LC/MS analytics is well suited for analyzing small sample volumes from minimally invasive sampling methods such as open-flow microperfusion or microdialysis to study local inflammation and the effect of treatments in skin diseases.

Comparison of cerebral Open Flow Microperfusion and Microdialysis when sampling small lipophilic and small hydrophilic substances.

BACKGROUND: Assessment of drug concentration in the brain interstitial fluid (ISF) is crucial for development of brain active drugs, which are mainly small, lipophilic substances able to cross the blood-brain barrier (BBB). We aimed to compare the applicability of cerebral Open Flow Microperfusion (cOFM) and Microdialysis (MD) to sample the lipophilic substance amitriptyline (AMI), its metabolites Hydroxyamitriptyline (HYA), Nortriptyline (NOR), Amitriptyline-N-Oxide (ANO), deuterated water (D2O) and the hydrophilic substance sodium fluorescein (Naf) in brain ISF. NEW METHOD: cOFM has been refined to yield increased spatial resolution and performance. COMPARISON OF COFM AND MD AND RESULTS: Performance of cOFM and MD was assessed by in vivo AUC ratios of probe samples (AUCCOFM/AUCMD) and the in vivo relative recovery of D2O (RRvv,D2O). Adsorption of AMI and Naf to MD and cOFM was assessed by the in vitro relative recovery (RRvt) prior to the in vivo experiments. The in vivo AUC ratio of AMI and RRvv,D2O was about two times higher for cOFM than for MD (AUCOFM/AUCMD = 2.0, RRvv,D2O(cOFM)/RRvv,D2O(MD) = 2.1). cOFM detected all investigated AMI metabolites except NOR. MD did not detect HYA, NOR, ANO and Naf. In vitro adsorption of AMI and Naf to the MD membrane was strong (RRvt,AMI = 4.4%, RRvt,Naf = 1.5%) but unspecific adsorption to cOFM was negligibly small (RRvt,AMI = 98% and RRvt,Naf = 98%). CONCLUSIONS: cOFM showed better performance when sampling AMI and its metabolites, Naf and D2O, and had an about two times higher RRvv,D2O than MD. MD did not detect HYA, NOR, ANO and Naf, most likely due to membrane adsorption.

Development of a Protocol for Automated Glucose Measurement Transmission Used in Clinical Decision Support Systems Based on the Continua Design Guidelines.

BACKGROUND: A fast and accurate data transmission from glucose meter to clinical decision support systems (CDSSs) is crucial for the management of type 2 diabetes mellitus since almost all therapeutic interventions are derived from glucose measurements. OBJECTIVES: Aim was to develop a prototype of an automated glucose measurement transmission protocol based on the Continua Design Guidelines and to embed the protocol into a CDSS used by healthcare professionals. METHODS: A literature and market research was performed to analyze the state-of-the-art and thereupon develop, integrate and validate an automated glucose measurement transmission protocol in an iterative process. RESULTS: Findings from literature and market research guided towards the development of a standardized glucose measurement transmission protocol using a middleware. The interface description to communicate with the glucose meter was illustrated and embedded into a CDSS. CONCLUSION: A prototype of an interoperable transmission of glucose measurements was developed and implemented in a CDSS presenting a promising way to reduce medication errors and improve user satisfaction.