Vitamin D oral intermittent treatment (DO IT) study, a randomized clinical trial with individual loading regimen.

Comparison of several regimens of oral vitamin D including an individually calculated loading regimen with the aim of achieving serum values > 75 nmol/l. Interventional, randomized, 3-arm study in vitamin D-deficient outpatients. Participants were allocated to supplementation of 24,000 IU vitamin D monthly over three months, using either a monthly drinking solution (Vi-De 3) or capsule (D3 VitaCaps), or an individualized loading regimen with the capsules taken weekly. For the loading regimen, the cumulative dose was calculated according to baseline 25-hydroxy-vitamin D (25(OH)D) serum value and body weight. Main inclusion criteria were age ≥ 18 years and 25(OH)D serum concentration < 50 nmol/l. The primary outcome was 25(OH)D serum concentration one week after treatment termination. Secondary endpoints were patient's preferences and adverse events. Full datasets were obtained from 52 patients. Mean 25(OH)D values were statistically significant higher after a loading regimen compared to a monthly administration of 24,000 IU vitamin D (76.4 ± 15.8 vs 61.4 ± 10.8 nmol/l; p < 0.01). All patients treated with the loading regimen reached sufficient 25(OH)D values > 50 nmol/l. Serum 25(OH)D values > 75 nmol/l were observed more frequently in patients taking the loading regimen (47% vs 11% drinking solution vs 12% capsules). Vitamin D-related adverse effects did not occur in any treatment groups. Capsules were preferred by 88.5% of the patients. Compared to treatments with monthly intake of 24,000 IU vitamin D, the intake of an individually calculated weekly loading regimen was able to raise serum concentrations > 50 nmol/l in all cases within a safe range.

Identification of Patients with Cobalamin Deficiency Crucially Depends on the Diagnostic Strategy.

BACKGROUND: Our goal was to determine vitamin B12 (cobalamin) deficiency with different diagnostic strategies, to propose the best possible laboratory strategy, and to synthesize the relevance of biomarkers in the diagnosis of a cobalamin deficiency. METHODS: We performed a secondary data analysis. The testing strategies were (i) vitamin B12 solely, (ii) holotranscobolamin solely, (iii) vitamin B12 and holotranscobolamin, and (iv) reflex testing of holotranscobalamin in samples with vitamin B12 < 300 pmol. A set of 3,044 laboratory samples with vitamin B12 and holotranscobalamin serum values from unselected in- and outpatients from a secondary care hospital. A sample was classified as cobalamin deficient when low values of vitamin B12 < 137 pmol/L or holotranscobalamin ≤ 37 pmol/L were measured. RESULTS: Low cobalamin values were identified in 591 (19.4%) samples either according to low vitamin B12 values (305; 10.0%) or low holotranscobalamin values (436; 14.3%). For 2,404 values with vitamin B12 < 300 pmol/L, the additional measurement of holotranscobalamin (reflex-testing) enabled the detection of an additional 278 (9.1%) deficiencies. When the grey zone was decreased to 138 - 219 pmol/L, the reflex testing of an additional 1,240 samples identified a total of 511 (16.8%) samples as cobalamin deficient. CONCLUSIONS: The identification of cobalamin deficiency or sufficiency highly depends on the diagnostic strategy. A reflex testing with a grey zone for vitamin B12 < 220 pmol/L identifies cobalamin deficiency cost efficiently in 86.5% cases (511 out of 591). Physicians should apply a uniform strategy on how to address the diagnosis of cobalamin deficiency and indication for treatment. In-hospital guidelines, which describe methodology and sensitivity of the locally used assays for vitamin B12 and holotranscobalamin could guide them.

Oral intermittent vitamin D substitution: influence of pharmaceutical form and dosage frequency on medication adherence: a randomized clinical trial.

BACKGROUND: To assess adherence to and preference for vitamin D substitution with different pharmaceutical forms and frequencies of administration. METHODS: A focus group of stakeholders aimed at preparing the design of an interventional, randomized, cross-over study with 2 × 2 groups obtaining monthly or weekly vitamin D products in liquid or solid form for 3 months each. Dosage corresponds to cumulated amount of recommended 800 IU daily (5.600 IU weekly / 24.000 IU monthly). Main inclusion criteria were a vitamin D serum value < 50 nmol/l and age ≥ 18 years. Primary endpoint was adherence, secondary endpoints were preferences and vitamin D serum levels. RESULTS: The focus group reached consensus for preference of a monthly administration of solid forms to adults. Full datasets were obtained from 97 participants. Adherence was significantly higher with monthly (79.5-100.0%) than weekly (66.4-98.1%) administration. Vitamin D levels increased significantly (p < 0.001) in all participants. An optimal value of > 75 nmol/l was achieved by 32% after 3 months and by 50% after 6 months. Preferred formulation was solid form (tablets, capsules) for 71% of participants, and preferred dosage frequency was monthly for 39% of participants. CONCLUSIONS: Monthly oral vitamin D in solid form lead to the highest adherence, and is preferred by the participants. However, only one third of study participants achieved values in the optimal range of > 75 nmol/l cholecalciferol using weekly or monthly administration providing an average daily cholecalciferol dose of 800 IU. TRIAL REGISTRATION: NCT03121593 | SNCTP000002251 . Registered 30. May 2017,. Prospectively registered.

Impact of type 2 Diabetes and Metformin use on Vitamin B12 Associated Biomarkers - an Observational Study.

AIMS: Assessment of the impact of type 2 diabetes (T2DM) and metformin use on vitamin B12 (VB12) associated biomarkers and their suitability to represent VB12 supply. METHODS: Differences of VB12, holotranscobalamine (HoloTc), the biologically active fraction (%AB12)=HoloTc/VB12*100 and homocystein (Hcy) were analysed i) among diabetic outpatients with (DMMet+ ) and without metformin use (DMMet-) and ii) in comparison to an external non-diabetic reference group with low VB12 (<200 pmol/L). RESULTS: VB12 associated biomarkers were distributed equally between DMMet+ (n=29, 58%) and DMMet- (n=21, 42%). Significant differences in %AB12 in diabetic patients with low VB12 (n=19) compared to the non-diabetic reference group (n=31) were found. Higher %AB12 was associated with diabetes. Hcy levels were significantly associated with age, folic acid level, renal function and HoloTc but not with VB12. CONCLUSIONS: In T2DM patients with low VB12, %AB12 was confirmed as being higher in comparison to nondiabetic patients. The effect was not clearly attributable to metformin use. HoloTc was unaffected by the lowering of VB12 and significantly associated with the functional marker Hcy. Both findings support the use of HoloTc for the assessment of VB12 supply in diabetic patients.

The 8-item Morisky Medication Adherence Scale translated in German and validated against objective and subjective polypharmacy adherence measures in cardiovascular patients.

RATIONALE, AIMS AND OBJECTIVES: To translate in German the 8-item Morisky Medication Adherence Scale (MMAS-8D). To validate it against objective and subjective measures of adherence in cardiovascular patients with polypharmacy. METHODS: A standard forward-backward procedure was used to translate the MMAS-8 into German. Validation took place on a convenience sample of ambulatory patients on chronic antiplatelet therapy between June 2010 and June 2011. Objective adherence was obtained from electronically monitored multi-drug punch cards. Internal consistency was assessed using Cronbach's alpha coefficient, construct validity using exploratory factor analyses and correlations between MMAS-8D and related measures. Convergent validity was assessed with a subjective questionnaire about beliefs about medicines (BMQ Specific, two sub-scales). RESULTS: A total of 70 patients were included (mean age 65.7 ± 9.9 years; 31.4% women). The mean score of the MMAS-8D was 7.5 (SD 0.8; range 4.5-8). Moderate internal consistency (alpha = 0.31) was observed due to multidimensionality of the scale. Factor analysis yielded four components that accounted for 71.7% of the total variance. Convergent validity was supported by significant correlations with BMQ Necessity (r = 0.31, P < 0.01), BMQ Concerns (r = -0.16, P < 0.05) and with electronic adherence reports (U-values 44 and 471, P < 0.05). Platelet aggregation values were within therapeutic range for 80% of the patients. Blood values of the antiplatelet agent within therapeutic range were associated with a higher MMAS-8D score (U-value 125, P < 0.05). CONCLUSIONS: The German MMAS-8 appears to be a reliable instrument to catch medication adherence in cardiovascular patients. It may be useful in patients with chronic therapy for detecting non-adherence.

Antiplatelet resistance in outpatients with monitored adherence.

Antiplatelet resistance with aspirin and clopidogrel has been associated with clinical, cellular and pharmacogenetic factors; and non-adherence has been considered as a major contributor to resistance in outpatients. We aimed at assessing factors to resistance when adherence to the antiplatelet drugs and all other oral solid drugs was controlled for. In a pilot study, we tested arachidonic acid and/or ADP-induced in vitro platelet aggregation of 82 outpatients with chronic aspirin and/or clopidogrel treatment before and after a one-week period of measuring the patient's adherence with the polymedication electronic monitoring system (POEMS). Resistance was found in 20% (aspirin; n = 69) and 25% (clopidogrel; n = 32) of the patients after monitored adherence. Mean platelet aggregation was not (aspirin) or non-significantly (clopidogrel) lowered when compared to baseline. Diabetes mellitus and inflammation were consistently associated with resistance to both drugs, but CYP2C19 polymorphisms could not be confirmed as predictors of clopidogrel response. Electronically compiled multidrug dosing histories allowed the concomitant intake of high-dose lipophilic statins to be identified as a risk factor of impaired response to clopidogrel and revealed that exposure to further potential drug-drug interactions (DDIs) was too low for analysis. Multidrug adherence monitoring allowed thus dismissing non-adherence as a major contributor to resistance and inter-individual response variability in an outpatient setting. Additionally, it allowed analysing the impact of DDIs according to the actual exposure to the potentially interfering drugs. Further studies based on this methodology are essential to prevent misleading results due to incomplete adherence and gain additional insight into the impact of timing adherence on antiplatelet drug response.

Polymedication Electronic Monitoring System (POEMS) - a new technology for measuring adherence.

INTRODUCTION: Reliable and precise measurement of patient adherence to medications is feasible by incorporating a microcircuitry into pharmaceutical packages of various designs, such that the maneuvers needed to remove a dose of drug are detected, time-stamped, and stored. The principle is called "electronic medication event monitoring" but is currently limited to the monitoring of a single drug therapy. AIM: Our aims were introducing a new technology; a clear, self-adhesive polymer film, with printed loops of conductive wires that can be affixed to multidrug punch cards for the electronic adherence monitoring of multiple medication regimens (Polymedication Electronic Monitoring System, POEMS), and illustrating potential benefits for patient care. We present a preliminary report with one patient experience. MATERIALS AND METHODS: Our illustrative case was supplied with a pre-filled 7-day multiple medication punch card with unit-of-use doses for specific times of the day (six pills in the morning cavity, two pills in the evening cavity, and one pill in case of insomnia in the bedtime cavity), with the new electronic film affixed on it. RESULTS: The intake times over 1 week were extremely skewed (median intake hours at 2:00 pm for the morning doses and at 6:40 pm for the evening doses). After an intervention aimed at optimizing the timing adherence, the morning and evening intake hours became more balanced, with 42.3% of correct dosing intervals (±3 h) for drugs with twice daily intake (vs. 0% before the intervention). DISCUSSION: The electronic monitoring of the entire therapy revealed an intake pattern that would have remained undiscovered with any other device and allowed a personalized intervention to correct an inadequate medication intake behavior. POEMS may guide health professionals when they need to optimize a pharmacotherapy because of suspected insufficient adherence. Further, knowing the intake pattern of the entire pharmacotherapy can elucidate unreached clinical outcome, drug-drug interactions, and drug resistance. In the near future, one could imagine that medication adherence data over the entire therapy plan would be available as soon as the electronic wires are activated, so that a failure to take medication could be detected immediately and intervention could be taken if appropriate.