Determination of Benznidazole in Human Dried Blood Spots by Liquid Chromatography-Mass Spectrometry to Monitor Adherence to Trypanosoma cruzi Infection Treatment in Infants and Children.

Medication adherence is critical to the effectiveness of benznidazole (BZ) therapy for the treatment of Chagas disease. Assessing BZ adherence using traditional plasma sampling methods presents numerous challenges in resource-limited settings. Dried blood spot (DBS) sampling of BZ can be used to overcome logistical barriers and provides a less invasive method for assessing BZ levels. A BZ DBS assay using liquid chromatography-tandem mass spectrometry was developed and applied to a clinical study of infants and children being treated with BZ for Trypanosoma cruzi infection in Argentina. The assay was validated over a concentration range of 9.8-5,000 ng/mL. Inter-assay and intra-assay measures ranged from -2.9% to 2.7% and 0.5% to 8.3% for accuracy and from 3.5% to 12% and 1.6% to 13.6% for precision, respectively. The mean recovery of BZ was greater than 91%. Partitioning ratios for DBSs/plasma ranged from 0.95 to 1.02. A cohort of 10 infants and six children with T. cruzi infection being treated with BZ had median BZ concentrations of 1.2 (IQR 0.29, 2.14) µg/mL with seven of 65 (11%) samples above the BZ treatment goal of 3 µg/mL for adults. The reported DBS assay is a simple and accurate method for the quantitative measurement of BZ that can be applied to facilitate urgently needed clinical studies of BZ for the treatment of Chagas disease and assess BZ adherence in resource-limited settings.

Marijuana Use by Breastfeeding Mothers and Cannabinoid Concentrations in Breast Milk.

: media-1vid110.1542/5799877373001PEDS-VA_2018-1076Video Abstract BACKGROUND AND OBJECTIVE: Marijuana is the most commonly used recreational drug among breastfeeding women. With legalization of marijuana in several US states and a 1990 study in which authors documented psychomotor deficits in infants breastfed by mothers using marijuana, there is a need for information on potential exposure to the breastfed infant. Our objective with this study was to quantify cannabinoids in human milk after maternal marijuana use. METHODS: Between 2014 and 2017, 50 breastfeeding women who reported marijuana use provided 54 breast milk samples to a research repository, Mommy's Milk. Concentrations of Δ-9-tetrahydrocannabinol (∆9-THC), 11-hydroxy-Δ-9-tetrahydrocannabinol, cannabidiol, and cannabinol were measured by using liquid chromatography mass spectrometry electrospray ionization. RESULTS: ∆9-THC was detectable in 34 (63%) of the 54 samples up to ∼6 days after last reported use; the median concentration of ∆9-THC was 9.47 ng/mL (range: 1.01-323.00). Five samples had detectable levels of 11-hydroxy-Δ-9-tetrahydrocannabinol (range: 1.33-12.80 ng/mL) or cannabidiol (range: 1.32-8.56 ng/mL). The sample with the highest concentration of cannabidiol (8.56 ng/mL) did not have measurable ∆9-THC. Cannabinol was not detected in any samples. The number of hours since last use was a significant predictor of log ∆9-THC concentrations (-0.03; 95% confidence interval [CI] -0.04 to -0.01; P = .005). Adjusted for time since last use, the number of daily uses and time from sample collection to analysis were also significant predictors of log ∆9-THC concentrations (0.51; 95% CI 0.03 to 0.99; P = .039; 0.08; 95% CI 0.00 to 0.15; P = .038, respectively). CONCLUSIONS: ∆9-THC was measurable in a majority of breast milk samples up to ∼6 days after maternal marijuana use.

Modeling nikkomycin Z dosing and pharmacology in murine pulmonary coccidioidomycosis preparatory to phase 2 clinical trials.

Nikkomycin Z (NikZ) is a chitin synthase inhibitor with activity against Coccidioides species that is being developed as a first-in-class orphan product for treatment of coccidioidomycosis. It has previously been shown to reduce lethal respiratory infections in mice to undetectable levels when treatment is begun 48 hours after infection. The studies described here focus on bracketing NikZ doses for phase 2 and 3 clinical trials, using an established mouse respiratory infection as a model and starting treatment 120 hours after infection. A dose of 80 mg/kg/day, divided into 2 doses, nearly eradicated infection, and larger doses did not improve fungal clearance. Increasing the duration of treatment from 1 week to 3 weeks resulted in a greater percentage of culture-negative mice. Comparative data show that plasma levels of NikZ that nearly eradicate Coccidioides in mice are achievable in patients and provide a plausibly effective dose range for initial phase 2 clinical studies.

Synthesis, characterization and sol-gel entrapment of a crown ether-styryl fluoroionophore.

The synthesis and initial evaluation of a new dye-functionalized crown-ether, 2-[2-(2,3,5,6,8,9,11,12,14,15-decahydro-1,4,7,10,13,16-benzohexaoxacyclooctadecin)ethenyl]-3-methyl benzothiazolium iodide (denoted BSD), are reported. This molecule contains a benzyl 18-crown-6 moiety as the ionophore and a benzothiazolium to spectrally transduce ion binding. Binding of K(+) to BSD in methanol causes shifts in the both absorbance and fluorescence emission maxima, as well as changes in the molar absorptivity and the emission intensity. Apparent dissociation constants (K(d)) in the range 30-65 microm were measured. In water and neutral buffer, K(d) values were approximately 1 mm. BSD was entrapped in sol-gel films composed of methyltriethoxysilane (MTES) and tetraethylorthosilicate (TEOS) with retention of its spectral properties and minimal leaching. K(+) binding to BSD in sol-gel films immersed in pH 7.4 buffer causes significant fluorescence quenching, with an apparent response time of approximately 2 min and an apparent K(d) of 1.5 mm.