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Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson's disease (PD). Understanding the rate of progression in PD as measured by both motor and non-motor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson's Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I (non-motor aspects of experiences of daily living) in 158 PD participants who were carriers and 598 PD participants who were non-carriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in non-carriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is approximately 60% lower in carriers as compared to non-carriers of LRRK2 gene mutations.

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.

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 (Kd) in the range 30–65 µm were measured. In water and neutral buffer, Kd 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 Kd of 1.5 mm. Copyright © 2009 John Wiley & Sons, Ltd.

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.