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BACKGROUND: Preterm white matter injury (PWMI) is the most common cause of brain injury in premature neonates. PWMI involves a differentiation arrest of oligodendrocytes, the myelinating cells of the central nervous system. Clemastine was previously shown to induce oligodendrocyte differentiation and myelination in mouse models of PWMI at a dose of 10 mg/kg/day. The minimum effective dose (MED) of clemastine is unknown. Identification of the MED is essential for maximizing safety and efficacy in neonatal clinical trials. We hypothesized that the MED in neonatal mice is lower than 10 mg/kg/day. METHODS: Mouse pups were exposed to normoxia or hypoxia (10% FiO2) from postnatal day 3 (P3) through P10. Vehicle or clemastine at one of four doses (0.5, 2, 7.5 or 10 mg/kg/day) was given to hypoxia-exposed pups. Myelination was assessed at age P14 and 10 weeks to determine the MED. Clemastine pharmacokinetics were evaluated at steady-state on day 8 of treatment. RESULTS: Clemastine rescued hypoxia-induced hypomyelination with a MED of 7.5 mg/kg/day. Pharmacokinetic analysis of the MED revealed Cmax 44.0 ng/mL, t1/2 4.6 h, and AUC24 280.1 ng*hr/mL. CONCLUSIONS: Based on these results, myelination-promoting exposures should be achievable with oral doses of clemastine in neonates with PWMI. IMPACT: Preterm white matter injury (PWMI) is the most common cause of brain injury and cerebral palsy in premature neonates. Clemastine, an FDA-approved antihistamine, was recently identified to strongly promote myelination in a mouse model of PWMI and is a possible treatment. The minimum effective dose in neonatal rodents is unknown and is critical for guiding dose selection and balancing efficacy with toxicity in future clinical trials. We identified the minimum effective dose of clemastine and the associated pharmacokinetics in a murine chronic hypoxia model of PWMI, paving the way for a future clinical trial in human neonates.

In recent years, potential therapeutic applications of several different cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC), its isomer Δ8-THC and Δ9-tetrahydrocannabivarin (Δ9-THCV), have been investigated. Nevertheless, to establish dose–effect relationship and to gain knowledge of their pharmacokinetics and metabolism, sensitive and specific analytical assays are needed to measure these compounds in patients. For this reason, we developed and validated an online extraction high-performance liquid/liquid chromatography–tandem mass spectrometry (LC/LC–MS-MS) method for the simultaneous quantification of 13 cannabinoids and metabolites including the Δ8 and Δ9 isomers of THC, THCV and those of their major metabolites in human plasma. Plasma was fortified with cannabinoids at varying concentrations within the working range of the respective compound and 200 µL was extracted using a simple one-step protein precipitation procedure. The extracts were analyzed using online trapping LC/LC–atmospheric pressure chemical ionization–MS-MS running in the positive multiple reaction monitoring mode. The lower limit of quantification ranged from 0.5 to 2.5 ng/mL, and the upper limit of quantification was 400 ng/mL for all analytes. Inter-day analytical accuracy and imprecision ranged from 82.9% to 109% and 4.3% to 20.3% (coefficient of variance), respectively. Of 534 plasma samples following controlled oral administration of Δ8-THCV, 236 were positive for Δ8-THCV (median; interquartile ranges: 3.5 ng/mL; 1.8–11.9 ng/mL), 383 for the major metabolite (−)-11-nor-9-carboxy-Δ8-tetrahydrocannabivarin (Δ8-THCV-COOH) (95.4 ng/mL; 20.7–328 ng/mL), 260 for (−)-11-nor-9-carboxy-Δ9-tetrahydrocannabivarin (Δ9-THCV-COOH) (5.8 ng/mL; 2.5–16.1 ng/mL), 157 for (−)-11-hydroxy-Δ8-tetrahydrocannabivarin (11-OH-Δ8-THCV) (1.7 ng/mL; 1.0–3.7 ng/mL), 49 for Δ8-THC-COOH (1.7 ng/mL; 1.4–2.3 ng/mL) and 42 for Δ9-THCV (1.3 ng/mL; 0.8–1.6 ng/mL). We developed and validated the first LC/LC–MS-MS assay for the specific quantification of Δ8-THC, Δ9-THC and THCV isomers and their respective metabolites in human plasma. Δ8-THCV-COOH, 11-hydroxy-Δ8-THCV and Δ9-THCV-COOH were the major Δ8-THCV metabolites in human plasma after oral administration of 98.6% pure Δ8-THCV. [ABSTRACT FROM AUTHOR]

Cannabichromene (CBC) is a minor cannabinoid within the array of over 120 cannabinoids identified in the Cannabis sativa plant. While CBC does not comprise a significant portion of whole plant material, it is available to the public in a purified and highly concentrated form. As minor cannabinoids become more popular due to their potential therapeutic properties, it becomes crucial to elucidate their metabolism in humans. Therefore, the goal of this was study to identify the major CBC phase I-oxidized metabolite generated in vitro following incubation with human liver microsomes. The novel metabolite structure was identified as 2′-hydroxycannabicitran using gas chromatography–mass spectrometry and nuclear magnetic resonance spectroscopy. Following the identification, in silico molecular modeling experiments were conducted and predicted 2′-hydroxycannabicitran to fit in the orthosteric site of both the CB1 and CB2 receptors. When tested in vitro utilizing a competitive binding assay, the metabolite did not show significant binding to either the CB1 or CB2 receptors. Further work necessitates the determination of potential activity of CBC and the here-identified phase I metabolite in other non-cannabinoid receptors. [ABSTRACT FROM AUTHOR]

Currently, there are no ex vivo systems that can model the motion of peripheral arteries and allow for the evaluation of pharmacokinetics (PK) of endovascular devices. The objective of this study was to develop a novel peripheral simulating bioreactor system to evaluate drug pharmacokinetics of stents. We utilized 3D-printed and off-the-shelf components to construct a peripheral-simulating bioreactor system capable of mimicking the motion of peripheral arteries. Servo motors were primarily used to shorten/elongate, twist, and bend explanted porcine carotid arteries. To evaluate the pharmacokinetics in the bioreactor, drug-eluting stents were deployed within explanted arteries and subjected to vascular motion along with pulsatile flow conditions. Following 30 min and 24 h, the arteries were removed, and paclitaxel levels were measured. Scanning electron microscopy was also performed to evaluate the stent surface. Arterial paclitaxel levels of the stent-treated arteries were found to be higher at 30 min than at 24 h following pulsatile and no vascular motion and even higher at 24 h following pulsatile flow and vascular motion. The residual drug on the stent significantly decreased from 30 min to 24 h. Scanning electron microscopy confirmed the loss of paclitaxel coating at 24 h and greater disturbance in stents under peripheral motion versus pulsatile only. This system represents the first ex vivo system to determine the PK of drug-eluting stents under physiological flow and vascular motion conditions. This work provides a novel system for a quick and inexpensive preclinical tool to study acute drug tissue concentration kinetics of drug-releasing interventional vascular devices designed for peripheral applications. [ABSTRACT FROM AUTHOR]

Solid organ transplantation in human immunodeficiency virus 1 (HIV)-infected individuals requiring the concomitant use of immunosuppressants (IS) [e.g. cyclosporine (CsA) or tacrolimus (TAC)] and antiretrovirals (ARVs) [e.g. protease inhibitors (PIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs)] is complicated by significant drug interactions. This paper describes the pharmacokinetics of CsA and TAC in 52 patients on both IS and NNRTIs, PIs or combined NNRTIs + PIs, in studies conducted at 2 weeks, 3, 6, 12 and 24 months after transplantation. Cyclosporine and TAC blood concentrations were measured by LC/MS/MS. This multisubject, varied ARV-IS drug combination, longitudinal observational patient study provided a unique opportunity to examine the effect of different ARV drugs on IS pharmacokinetics (PK) by comparing the ratios of parameters over time and between PK parameters. Subjects taking concomitant PIs exhibited increases in CsA and TAC exposure (AUC/dose) due to the increased apparent oral bioavailability and decreased apparent oral clearance. Those subjects taking CsA and concomitant efavirenz (EFV) showed time dependent increases in exposure due to ~30% increases in the apparent oral bioavailability over time as well as a decreased apparent oral clearance, while subjects on TAC and EFV showed time-dependent changes in all PK parameters. The increased bioavailability was not observed in patients on CsA and nevirapine (NVP). These differences between IS drugs and the changes in PK parameters are not easily predicted, illustrating the importance of continued therapeutic drug monitoring in patients on these complex medication regimens. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

Solid organ transplantation in human immunodeficiency virus 1 (HIV)-infected individuals requiring the concomitant use of immunosuppressants (IS) [e.g. cyclosporine (CsA) or tacrolimus (TAC)] and antiretrovirals (ARVs) [e.g. protease inhibitors (PIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs)] is complicated by significant drug interactions. This paper describes the pharmacokinetics of CsA and TAC in 52 patients on both IS and NNRTIs, PIs or combined NNRTIs + PIs, in studies conducted at 2 weeks, 3, 6, 12 and 24 months after transplantation. Cyclosporine and TAC blood concentrations were measured by LC/MS/MS. This multisubject, varied ARV-IS drug combination, longitudinal observational patient study provided a unique opportunity to examine the effect of different ARV drugs on IS pharmacokinetics (PK) by comparing the ratios of parameters over time and between PK parameters. Subjects taking concomitant PIs exhibited increases in CsA and TAC exposure (AUC/dose) due to the increased apparent oral bioavailability and decreased apparent oral clearance. Those subjects taking CsA and concomitant efavirenz (EFV) showed time dependent increases in exposure due to ~30% increases in the apparent oral bioavailability over time as well as a decreased apparent oral clearance, while subjects on TAC and EFV showed time-dependent changes in all PK parameters. The increased bioavailability was not observed in patients on CsA and nevirapine (NVP). These differences between IS drugs and the changes in PK parameters are not easily predicted, illustrating the importance of continued therapeutic drug monitoring in patients on these complex medication regimens. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.