Evaluating the reliability of hair analysis in monitoring the compliance of ADHD patients under treatment with Lisdexamphetamine.

Considering the high clinical and forensic relevance of pharmaco-adherence during lisdexamphetamine (LDX) treatment for attention-deficit/hyperactivity disorder (ADHD), the aim here was to evaluate hair analysis as a tool for monitoring compliance in patients currently undergoing long term treatment with LDX, by detecting possible interruptions of medication intake or changes in dosage. For this purpose, a total of 24 patients from an outpatient clinic for ADHD were recruited. Hair and urine samples were taken after three consecutive therapy sessions over a 7-month period and analyzed for amphetamine (AMP) enantiomers and other drugs, using chiral and achiral liquid chromatography-tandem mass spectrometry (LC-MS/MS). Participants also provided information on the condition of their hair, the consumption of illegal psychotropic substances and the regularity of taking LDX. Two participants withdrew from the study early. Urine analyses were positive for D-AMP in all urine samples and therapy sessions, except in two patients who did not take LDX on a daily basis. D-AMP was detected in all hair samples; however, no correlation was found between prescribed dose/day and D-AMP concentrations in proximal hair segments. Qualitative interpretation of hair analysis showed that 18 of the 22 study completers were compliant concerning the intake of LDX without additional consumption of illegal D,L-AMP. Analysis of urine taken during the therapy sessions showed no correlation between D-AMP concentrations and prescribed dosage, with or without normalization for creatinine. In conclusion, chiral LC-MS/MS hair analysis might represent a non-invasive way to confirm LDX use within the approximate period covered by the hair segment tested, but it does not allow for quantitative therapeutic drug monitoring because of interindividual variability of concentrations in hair. Drug concentrations in hair at different stages of long-term treatment should thus be interpreted with caution by clinicians and forensic experts alike when making assessments of treatment adherence.

Development of a dynamic delivery method for in vitro bioassays.

Measuring the biological activity of hydrophobic chemicals using in vitro assays is challenging because their aqueous solubility is low and the high density of bio-suspensions strongly decreases the bioavailability of hydrophobic pollutants. Dynamic dosing by partitioning from a stable polymer has a potential to overcome these limitations. Poly(dimethylsiloxane) (PDMS) was chosen due to its documented bio-compatibility and excellent partitioning properties. PDMS sheets were loaded with five polycyclic aromatic hydrocarbons (PAHs) and then immersed in model bio-suspensions composed of membrane vesicles ("chromatophores", composed of 30% lipids and 70% proteins) isolated from the photosynthetic bacterium Rhodobacter sphaeroides or phospholipid bilayer vesicles (liposomes) composed of palmitoyl-oleoyl phosphatidylcholine (POPC). Method development included the determination of partition coefficients between chromatophores or liposomes and water, desorption rate constants from PDMS to bio-suspensions, and diffusion resistances in both PDMS and bio-suspensions. The release of the PAHs from the PDMS into the bio-suspensions was measured and modeled as a combination of diffusion in pure water and diffusion in a completely mixed solvent composed of water and bio-suspensions. The mass transfer resistance for the release was lower in the PDMS than in the tested solutions, which demonstrates that PDMS can efficiently deliver PAHs even to dense biosuspensions. The contribution of aqueous diffusion to the mass transfer decreased with increasing hydrophobicity of the PAHs indicating that hydrophobic chemicals are efficiently transported with suspended biomaterial. The passive dosing system is versatile and offers a number of applications. Promising are tests with instantaneous response, where the time-dependent effect can be translated to concentration-effect curves but the system is also applicable for assuring constant dosing for longer-term testing.

Dynamic permeation method to determine partition coefficients of highly hydrophobic chemicals between poly(dimethylsiloxane) and water.

Measurement of partition coefficients between poly(dimethylsiloxane) (PDMS) and water (KPDMSw) becomes more and more difficult as the hydrophobicity of the compound increases. Experimental challenges include long extraction times, sorption to various surfaces and materials, and incomplete dissolution of the compound in the aqueous phase. In order to avoid these artifacts and to shorten experimental time, a dynamic permeation method was developed. According to steady-state diffusion theory, KPDMSw is inversely proportional to the permeation rate through the aqueous boundary layer (ABL) from the donor PDMS to the acceptor PDMS. A simple ABL permeation reactor can thus be applied to determine KPDMSw values of hydrophobic chemicals within a few days. The obtained values were in good agreement with those obtained using a conventional shaking method and the partition controlled delivery system. A good linear correlation was obtained between the logarithm of the 1-octanol/water partition coefficient (log Kow) from the literature and log KPDMSw over 6 orders of magnitude.