Synthetic cannabinoids (SCBs), designer drugs marketed as legal alternatives to marijuana, act as ligands to cannabinoid receptors; however, they have increased binding affinity and potency, resulting in toxicity symptoms such as cardiovascular incidents, seizures, and potentially death. N‐(adamantan‐1‐yl)‐1‐(5‐fluoropentyl)‐1H‐indole‐3‐carboxamide (STS‐135) is a third generation SCB. When incubated with hepatocytes, it undergoes oxidation, hydrolysis, and glucuronidation, resulting in 29 metabolites, with monohydroxy STS‐135 (M25) and dihydroxy STS‐135 (M21) being the predominant metabolites. The enzymes responsible for this oxidative metabolism were unknown. Thus, the aim of this study was to identify the cytochrome P450 (P450s or CYPs) enzymes involved in the oxidative metabolism of STS‐135. In this study, STS‐135 was incubated with liver, intestinal, and brain microsomes and recombinant P450s to determine the enzymes involved in its metabolism. Metabolite quantification was carried out using ultra‐performance liquid chromatography. STS‐135 was extensively metabolized in HLMs and HIMs. Screening assays indicated CYP3A4 and CYP3A5 could be responsible for STS‐135’s oxidation. Through incubations with genotyped HLMs, CYP3A4 was identified as the primary oxidative enzyme. Interestingly, CYP2J2, a P450 isoform expressed in cardiovascular tissues, showed high activity towards the formation of M25 with a Km value of 11.4 μmol/L. Thus, it was concluded that STS‐135 was primarily metabolized by CYP3A4 but may have extrahepatic metabolic pathways as well. Upon exposure to STS‐135, individuals with low CYP3A4 activity could retain elevated blood concentration, resulting in toxicity. Additionally, CYP2J2 may aid in protecting against STS‐135‐induced cardiovascular toxicity.

RATIONALE: To investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT). METHODS: After a baseline oral food challenge (OFC) of up to 2gm (median tolerated dose 46mg), 40 subjects, aged 12-37 (median 15) years, were randomized 1:1 across 5 sites to receive daily peanut (escalating from .00017mcg to 1386mcg) or placebo SLIT. A 5gm OFC was performed after 44 weeks. Placebo subjects then crossed-over to peanut SLIT to a maximum of 3696mcg, followed by a week-44 5gm OFC. Week-44 OFC was compared to baseline OFC; subjects successfully consuming 5gm or at least 10-fold more peanut than baseline OFC threshold were considered ''responders.'' RESULTS: 14/20 (70%) subjects receiving peanut SLIT were responders compared to 3/20 (15%) receiving placebo (p50.001). In peanut-SLIT responders, median successfully consumed dose increased from 3.5mg to 496mg; none tolerated the entire 5gm OFC. Of 10,701 peanut doses through week-44 OFCs, 61.6% were symptom-free; excluding oral/pharyngeal symptoms, 95.2% were symptom-free. Basophil activation did not decline significantly from baseline to 44 weeks; median peanut-IgE levels significantly declined from weeks 29 to 44 in the peanut group compared to placebo (p50.01). 6/15 crossover subjects with week-44 OFC assessment to date were responders; median successfully consumed dose increased from 11mg to 496mg. Three subjects (2 peanut,1 placebo) withdrew during the blinded phase prior to week-44 OFCs; 9 subsequently withdrew (3 peanut,6 original placebo). CONCLUSIONS: Initial results demonstrate that peanut SLIT can safely induce significant, low-level desensitization in a majority of subjects. Maintenance dosing is ongoing for 3 years to determine further efficacy.

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