Therapeutic drug monitoring van adalimumab bij reumatologische patiënten

\u3cp\u3eOBJECTIVE and DESIGN Adalimumab (ADA) is effective in the treatment of rheumatoid arthritis IRA), ankylosing spondylitis (ASI and psoriatic arthritis (PsA). Despite suggestions that therapeutic drug monitoring (TDM) of ADA can optimize treatment of this population, it is not routinely implemented in clinical practice. We therefore carried out a prospective observational cohort study by measuring ADA levels in a population of patients with rheumatic diseases and related those levels to disease activity. METHODS Patient demographics were collected from the electronic hospital information system. Blood drawn before the regular outpatient visit was used for determination of ADA trough levels and antibodies against ADA (ATA). Objectified disease activity measurements were obtained at the appointment: DAS28 for RA, ASDAS for AS, and clinical assessment for SpA. RESULTS A total of 17A patients was included. ADA levels varied from less than 0.1 to 22.0 mg/L. The mean ADA level was 6.8 mg/L (standard deviation = 4.2). 5 patients (2,9%) developed ATA. The ADA level was significantly associated with remission (P = 0.002). The mean ADA level was 7.6 mg/L in patients in remission and 5.1 mg/L in patients with active disease. Use of immunosuppressants, frequency of administration, and body mass index were identified as significant covariates. CONCLUSION TDM of ADA demonstrated large interindividual differences in ADA levels. ADA trough levels were significantly associated with disease activity. TDM has the potential to individualize treatment and further research needs to show if it increases cost-effectiveness of this expensive therapy.\u3c/p\u3

Therapeutic drug monitoring van adalimumab bij patiënten met inflammatoire darmziekten

\u3cbr/\u3e\u3cbr/\u3e \u3cp\u3eOBJECTIVE: Adalimumab (ADA) trough levels correlate with clinical remission. Despite suggestions that therapeutic drug monitoring of ADA can optimize treatment in this population, it is not yet implemented in clinical practice. This study was conducted to provide more insight in ADA trough levels and antibodies to adalimumab (ATA) in an inflammatory bowel disease (IBD) population already treated with adalimumab. DESIGN: We carried out a prospective cohort study in IBD outpatients already treated with adalimumab. METHODS: Patient demographics were collected from the electronic hospital information system. Blood was drawn for determination of ADA trough levels and ATAs. Disease activity indices for Crohn's disease and ulcerative colitis and quality of life scores were obtained by a questionnaire. RESULTS: A total of 92 patients was included. ADA levels varied from < 0.1 to 20.2 mg/L. Mean ADA level was 7.7 mg/L (SD = 4.5), 4 patients developed ATAs. ADA levels ≤ 5 mg/L were demonstrated in 27 patients (29%). The ADA level was not significantly associated with remission [P = 0.391). Quality of life score correlated with ADA level (P = 0.031). CONCLUSION: Therapeutic drug monitoring in inflammatory bowel disease outpatients revealed large interindividual differences in adalimumab trough levels. These levels were subtherapeutic in nearly a third of patients. We think, despite no significant correlation was found between adalimumab trough level and disease activity, therapeutic drug monitoring has the potential to individualize treatment in inflammatory bowel disease patients using adalimumab.\u3c/p\u3

A value proposition for trough level-based anti-TNFα drug dosing

\u3cp\u3eTreatment of inflammatory bowel diseases and rheumatic disorders with anti-tumor necrosis factor alpha (TNFα) drugs is expensive, while a significant proportion of patients does not show adequate clinical response. Therapeutic drug monitoring (TDM) enables patient-specific anti-TNFα therapy. The role of laboratory tests in clinical care has recently been described in a value proposition framework. It describes care processes, stakeholders, costs, risks, benefits and patient outcomes based on the use of a laboratory test in a clinical care pathway. We have applied this concept to the use of TDM for anti-TNFα drugs, describing evidence that supports the intervention and its cost effectiveness, steps that need to be adjusted in the care pathway, possible treatment algorithms and measures to assess adoption of this framework into clinical practice. For effective TDM, an assay for measurement of drug levels together with appropriate target ranges and an anti-drug-antibody assay have to be implemented. Also, instead of only reporting the drug concentration, laboratorians, pharmacists and clinicians should deliver added value by introducing a TDM-based treatment algorithm into clinical practice. Thus, to maximize effectiveness of TDM of anti-TNFα therapy in routine care, adjustment of current care pathways and cooperation of many stakeholders are needed.\u3c/p\u3

Oxytocin levels in the saliva of preterm infant twins during Kangaroo care

\u3cp\u3eBackground and purpose: To investigate whether Kangaroo care (KC) influences the salivary oxytocin (OT) concentration in preterm infants, and which correlates affect the OT response. Methods: Eleven twin pairs participated in a study in which we collected saliva using cotton swabs twice a day, once during KC and once during baseline conditions (lying in bed or incubator). The total study duration was five days. The saliva of twin siblings were pooled to obtain vials with sufficient volumes of either saliva collected during KC or at baseline. OT levels were measured using a radio-immuno assay. The infants’ state of comfort and parent-infant interaction were examined using previously developed Likert-scales, amongst other correlates such as the KC duration, gestational age and birth weight. Results: During KC, OT was lower compared to baseline (mean 1.39 pg/ml (SD 0.58 pg/ml) versus 2.40 pg/ml (SD 1.64 pg/ml), p = 0.03). Comfort at baseline and parent-infant interaction seemed to influence OT responses. Conclusion: The OT concentration in the pooled saliva of preterm infant twins decreased during KC. This response of the OT system might be explained by stress during baseline.\u3c/p\u3

Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients:results of a 12-month observational prospective cohort study

\u3cp\u3eThe objective of this study is to apply therapeutic drug monitoring (TDM) as an objective tool to monitor the switch from infliximab innovator (INX) to infliximab biosimilar (INB) in our diverse rheumatic cohort in daily clinical practice. All rheumatic patients on INX treatment (Remicade®) and ≥18 years were switched to INB (Inflectra®) as part of routine care, but in a controlled setting. Patients were monitored by taking blood samples just before the first infusion of INB (T1), and after the second (T2), fourth (T3), and seventh (T4) infusion of INB. T4 reflects the patients’ status after ∼12 months. Infliximab trough levels, antibodies-to-infliximab (ATI), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and validated disease activity scores (if possible) were measured. Our population consisted of 27 patients with seven different rheumatic diseases who had received INX for 143 (58–161) months (median (IQR)). Half of the patients (52%) received concomitant immunosuppressives. We found widely varying infliximab levels, with only 56% within the proposed therapeutic range of 1–5 μg/mL. One patient had very high ATI levels (>880 au/mL), and two had low ATI levels (≤30 au/mL). After switching to INB, seven patients (26%) discontinued the therapy, partially due to subjective reasons. No difference in infliximab levels, CRP levels, and disease activity scores was found between the four time points (p ≥ 0.2460). In conclusion, no pharmacokinetic or clinical differences were found between INX and INB in our diverse rheumatic cohort. TDM is a helpful tool to monitor patients switching from INX to INB.\u3c/p\u3

Chiral amplification in columns of self-assembled N,N′,N″-Tris((S)-3,7-dimethyloctyl)benzene-1,3,5-tricarboxamide in dilute solution

Remarkable control of chirality within a long and stable columnar self-assembly of N,N',N¿-Tris((S)-3,7-dimethyloctyl)benzene-1,3,5-tricarboxamide in dilute solution is achieved by strong, unidirectional hydrogen bonding and cooperative side-chain interactions; IR and CD-spectroscopy have been used to elucidate these features

Biologicals en biosimilars : de rol van spiegelbepalingen in therapieoptimalisering en kostenbesparingen

Therapieoptimalisering van anti-TNFα biologicals kan efficiënt gedaan worden met behulp van het meten van geneesmiddelspiegels,\u3cbr/\u3egevolgd door dosisadvies op maat ofwel therapeutic drug monitoring. Om spiegelmetingen in de klinische praktijk te bevorderen heeft\u3cbr/\u3ehet kenniscentrum klinische chemie een infliximab test gevalideerd en in gebruik genomen in nauwe samenwerking met de\u3cbr/\u3eziekenhuisapotheek. Bij het meten van infliximabspiegels in ons ziekenhuis vonden we zeer grote verschillen tussen patiënten, waarbij\u3cbr/\u3eeen significant deel buiten het therapeutisch bereik zat. Hieruit blijkt dat er mogelijk nog winst valt te behalen bij het instellen van\u3cbr/\u3epatiënten op deze zeer kostbare therapie. Met deze test kunnen ook de nieuw verschenen infliximab biosimilars gemeten worden, zodat\u3cbr/\u3ede overstap van geneesmiddelen (originator naar biosimilar) in een gecontroleerde setting, waarbij geneesmiddelspiegels gemeten\u3cbr/\u3eworden, kan plaatsvinden. Therapieoptimalisering van anti-TNFα biologicals kan efficiënt gedaan worden met behulp van het meten van geneesmiddelspiegels,\u3cbr/\u3egevolgd door dosisadvies op maat ofwel therapeutic drug monitoring. Om spiegelmetingen in de klinische praktijk te bevorderen heeft\u3cbr/\u3ehet kenniscentrum klinische chemie een infliximab test gevalideerd en in gebruik genomen in nauwe samenwerking met de\u3cbr/\u3eziekenhuisapotheek. Bij het meten van infliximabspiegels in ons ziekenhuis vonden we zeer grote verschillen tussen patiënten, waarbij\u3cbr/\u3eeen significant deel buiten het therapeutisch bereik zat. Hieruit blijkt dat er mogelijk nog winst valt te behalen bij het instellen van\u3cbr/\u3epatiënten op deze zeer kostbare therapie. Met deze test kunnen ook de nieuw verschenen infliximab biosimilars gemeten worden, zodat\u3cbr/\u3ede overstap van geneesmiddelen (originator naar biosimilar) in een gecontroleerde setting, waarbij geneesmiddelspiegels gemeten\u3cbr/\u3eworden, kan plaatsvinden

Self-assembly of soft nanoparticles with tunable patchiness

Details of the forces between nanoparticles determine the waysin which the nanoparticles can self-assemble into larger structures.The use of directed interactions has led to new conceptsin self-assembly such as asymmetric dendrons1,2, Janus particles3,patchy colloids46 and colloidal molecules7. Recentmodels that include attractive regions or patches on thesurface of the nanoparticles predict a wealth of intricatemodes of assembly812. Interactions between such particlesare also important in a range of phenomena including proteinaggregation13,14 and crystallization15, re-entrant phase transitions1618, assembly of nanoemulsions19 and the organizationof nanoparticles into nanowires20. Here, we report the synthesisof 6-nm nanoparticles with dynamic hydrophobicpatches and show that they can form reversible self-assembledstructures in aqueous solution that become topologically moreconnected upon dilution. The organization is based onguesthost supramolecular chemistry with the nanoparticlescomposed of a hydrophobic dendrimer host molecule andwater-soluble hydrophilic guest molecules. The work demonstratesthat subtle changes in hierarchal composition and/orconcentration can dramatically change mesoscopic ordering

Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease:A 12-month multicentre observational prospective cohort study

\u3cp\u3eBackground: Infliximab biosimilars have become available for treatment of inflammatory bowel disease (IBD). However, data showing long-term safety and effectiveness of biosimilars in IBD patients are limited. Aim: To study prospectively the switch from infliximab innovator to biosimilar in an IBD cohort with 12 months follow-up to evaluate safety and effectiveness. Methods: Adult IBD patients from two hospitals treated with infliximab innovator (Remicade; Janssen Biotech, Horsham , Pennsylvania, USA) were switched to infliximab biosimilar (Inflectra; Hospira, Lake Forest, Illinois, USA) as part of routine care, but in a controlled setting. Blood samples were taken just before the first, second, fourth and seventh infusion of biosimilar. Infliximab trough levels, antibodies-to-infliximab (ATI), CRP and ESR were measured and disease activity scores were calculated. Results: Our cohort consisted of 133 IBD patients (64% CD, 36% UC). Before switching we found widely varying infliximab levels (median 3.5 μg/mL). ATI were detected in eight patients (6%). Most patients were in remission or had mild disease (CD: 82% UC: 90%). After switching to biosimilar, 35 patients (26%) discontinued therapy within 12 months, mostly due to subjective higher disease activity (9%) and adverse events (AE, 9.8%). AE included general malaise/fatigue (n = 7), arthralgia (n = 2), skin problems (n = 2) and infusion reactions (n = 2). No differences in IFX levels, CRP, and disease activity scores were found between the four time points (P ≥ .0917). Conclusions: We found no differences in drug levels and disease activity between infliximab innovator and biosimilar in our IBD cohort, indicating that biosimilars are safe and effective. The high proportions of discontinuers were mostly due to elective withdrawal or subjective disease worsening.\u3c/p\u3