Impaired Driving Associated with the Synthetic Cannabinoid 5f-Adb.

Synthetic marijuana compounds are more potent than Δ9-tetrahydrocannabinol (∆9-THC) and are known to produce a wide variety of clinical symptoms including cardiac toxicity, seizures, and death. Erratic driving by a 45 y/o male was witnessed in the fall of 2017 and roadside evaluation of the driver by the responding law enforcement officer concluded that the driver was intoxicated. Comprehensive analysis of the cigarettes by gas chromatography-mass spectrometry detected the synthetic cannabinoid 5-fluoro-ADB (5F-ADB or 5F-MDMB-PINACA). Validated forensic liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to detect the 5-fluoro ADB metabolite 7 (26.37 ng/mL) in the driver's blood sample. No other drugs were detected. This case report is one of the first to conclusively show that designer synthetic cannabinoids, commonly referred to as "K2" and "Spice", can significantly impair driving at relatively low concentrations.

Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate.

BACKGROUND: Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells. METHODS: Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells. RESULTS: Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients. CONCLUSIONS: Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.

Enhanced evaluation of selective androgen receptor modulators in vivo.

Selective androgen receptor modulators (SARMs) are a class of drugs that control the activity of the androgen receptor (AR), which mediates the response to androgens, in a tissue-selective fashion. They are specifically designed to reduce the possible complications that result from the systemic inhibition or activation of AR in patients with diseases that involve androgen signalling. However, there are no ideal in vivo models for evaluating candidate SARMs. Therefore, we created a panel of androgen-responsive genes in clinically relevant AR expressing tissues including prostate, skin, bone, fat, muscle, brain and kidney. We used select genes from this panel to compare transcriptional changes in response to the full agonist dihydrotestosterone (DHT) and the SARM bolandiol at 16 h and 6 weeks. We identified several genes in each tissue whose expression at each of these time points correlates with the known tissue-specific effects of these compounds. For example, in the prostate we found four genes whose expression was much lower in animals treated with bolandiol compared with animals treated with DHT for 6 weeks, which correlated well with differences in prostate weight. We demonstrate that adding molecular measurements (androgen-regulated gene expression) to the traditional physiological measurements (tissue weights, etc.) makes the evaluation of potential SARMs more accurate, thorough and perhaps more rapid by allowing measurement of selectivity after only 16 h of drug treatment.