An observational time-series study on the behavioral effects of adjunctive artisanal cannabidiol use by adults with treatment resistant epilepsies.

BACKGROUND: For approximately 30% of people with epilepsy, seizures are not well-controlled by anti-seizure medication (ASM). This condition, called treatment resistant epilepsy (TRE), is associated with increased morbidity and mortality, and substantially impacts the quality of life of both the individual and their family. Non-responsiveness to ASMs leads many people with TRE to seek alternative therapies, such as cannabinoid-based medication, particularly cannabidiol (CBD), with or without medical or professional advice. This is due in part to widespread reporting in the media about the benefits of CBD for seizures in some forms of epilepsy. METHODS: Adults with TRE, opting to add CBD to their existing treatment regime, completed this prospective, observational, longitudinal, quasi-experimental, time-series study. We hypothesized that adjunctive CBD use would positively impact participants' quality of life and psychological well-being in comparison to a baseline period without CBD use. Participants were followed for a period of approximately six months - for approximately one month of baseline prior to the initiation of CBD use and approximately five months after the initiation of CBD use. Participants provided urine samples and completed behavioral questionnaires that assessed quality of life, anxiety/depression, and adverse events during baseline and at two times during CBD use. RESULTS: Complete case analyses (n = 10) showed a statistically significant improvement in quality of life, a statistically significant decrease in anxiety symptoms, and a statistically significant decrease in the experience of adverse events over time (p < 0.05). Improvements noted in the experience of depression symptoms did not reach statistical significance. Urinalysis revealed the majority of participants had no CBD/metabolites in their system at the beginning of the study, and confirmed the presence of CBD/metabolites in participants' urine after CBD was added to their treatment regime. Analysis of missing data using multiple imputation supported the findings of the complete case analysis. INTERPRETATION: For a small group of individuals with TRE of varying etiologies, adjunctive use of artisanal CBD was associated with improvements in the behavioral and psychological symptoms of TRE, as well as improved medication tolerability.

Metabolic clearance of select opioids and opioid antagonists using hepatic spheroids and recombinant cytochrome P450 enzymes.

The opioid crisis is a pressing public health issue, exacerbated by the emergence of more potent synthetic opioids, particularly fentanyl and its analogs. While competitive antagonists exist, their efficacy against synthetic opioids is largely unknown. Furthermore, due to the short durations of action of current antagonists, renarcotization remains a concern. In this study, metabolic activity was characterized for fentanyl-class opioids and common opioid antagonists using multiple in vitro systems, namely, cytochrome P450 (CYP) enzymes and hepatic spheroids, after which an in vitro-in vivo correlation was applied to convert in vitro metabolic activity to predictive in vivo intrinsic clearance. For all substrates, intrinsic hepatic metabolism was higher than the composite of CYP activities, due to fundamental differences between whole cells and single enzymatic reactions. Of the CYP isozymes investigated, 3A4 yielded the highest absolute and relative metabolism across all substrates, with largely negligible contributions from 2D6 and 2C19. Comparative analysis highlighted elevated lipophilicity and diminished CYP3A4 activity as potential considerations for the development of more efficacious opioid antagonists. Finally, antagonists with a high degree of molecular similarity exhibited comparable clearance, providing a basis for structure-metabolism relationships. Together, these results provide multiple screening criteria for early stage drug discovery involving opioid countermeasures.

Dose-dependent emergence of acute and recurrent corneal lesions in sulfur mustard-exposed rabbit eyes.

Sulfur mustard (SM) is a lipid soluble alkylating agent that causes genotoxic injury. The eye is highly sensitive to SM toxicity and exposures exceeding 400 mg min/m3 can elicit irreversible corneal pathophysiologies. Development of medical countermeasures for ocular SM exposure has been hindered by a limited understanding of dose-dependent effects of SM on corneal injury. Here, clinical, histological and ultrastructural analyses were used to characterize the effects of SM dose on corneal injury progression. Corneas were evaluated for up to 20 wk following exposure to saturated SM vapor for 30-150 s, which corresponds to 300-1,500 mg min/m3. In acute studies, a ceiling effect on corneal edema developed at doses associated with full-thickness corneal lesions, implicating endothelial toxicity in corneal swelling. Recurrent edematous lesions (RELs) transiently emerged after 2 wk in a dose-dependent fashion, followed by the development of secondary corneal pathophysiologies such as neovascularization, stromal scarring and endothelial abnormalities. RELs appeared in 96 % of corneas exposed for ≥ 90 s, 52 % of corneas exposed for 60 s and 0 % of corneas exposed for 30 s. While REL latency was variable in corneas exposed for 60 s, REL emergence was synchronized at exposures ≥ 90 s. Corneas did not exhibit more than one REL, suggesting RELs are part of a programmed pathophysiological response to severe alkylating lesions. In post-mortem studies at 12 wk, corneal edema was positively correlated to severity of endothelial pathologies, consistent with previous findings that endothelial toxicity influences long-term outcomes. These results provide novel insight into long-term corneal pathophysiological responses to acute toxicity and identify exposure conditions suitable for therapeutic testing.

Cannabis Contaminants Limit Pharmacological Use of Cannabidiol.

For nearly a century, Cannabis has been stigmatized and criminalized across the globe, but in recent years, there has been a growing interest in Cannabis due to the therapeutic potential of phytocannabinoids. With this emerging interest in Cannabis, concerns have arisen about the possible contaminations of hemp with pesticides, heavy metals, microbial pathogens, and carcinogenic compounds during the cultivation, manufacturing, and packaging processes. This is of particular concern for those turning to Cannabis for medicinal purposes, especially those with compromised immune systems. This review aims to provide types of contaminants and examples of Cannabis contamination using case studies that elucidate the medical consequences consumers risk when using adulterated Cannabis products. Thus, it is imperative to develop universal standards for cultivation and testing of products to protect those who consume Cannabis.

Camelid VHH Antibodies that Neutralize Botulinum Neurotoxin Serotype E Intoxication or Protease Function.

Botulinum neurotoxin (BoNT) serotype E is one of three serotypes that cause the preponderance of human botulism cases and is a Tier 1 Select Agent. BoNT/E is unusual among BoNT serotypes for its rapid onset and short duration of intoxication. Here we report two large panels of unique, unrelated camelid single-domain antibodies (VHHs) that were selected for their ability to bind to BoNT/E holotoxin and/or to the BoNT/E light chain protease domain (LC/E). The 19 VHHs which bind to BoNT/E were characterized for their subunit specificity and 8 VHHs displayed the ability to neutralize BoNT/E intoxication of neurons. Heterodimer antitoxins consisting of two BoNT/E-neutralizing VHHs, including one heterodimer designed using structural information for simultaneous binding, were shown to protect mice against co-administered toxin challenges of up to 500 MIPLD50. The 22 unique VHHs which bind to LC/E were characterized for their binding properties and 9 displayed the ability to inhibit LC/E protease activity. Surprisingly, VHHs selected on plastic-coated LC/E were virtually unable to recognize soluble or captured LC/E while VHHs selected on captured LC/E were poorly able to recognize LC/E coated to a plastic surface. This panel of anti-LC/E VHHs offer insight into BoNT/E function, and some may have value as components of therapeutic antidotes that reverse paralysis following BoNT/E exposures.

Cannabidiol Drugs Clinical Trial Outcomes and Adverse Effects.

This review aims to present completed clinical trial data surrounding the medicinal benefits and potential side effects of the increasingly popular cannabidiol (CBD)-based drug products, specifically Epidiolex. The article is divided into two sections based on if the ailment being treated by this cannabinoid is classified as either physiological or neurological conditions. In addition to describing the current status, we also examined the different primary and secondary outcomes recorded for each study, which varies greatly depending on the funding source of the clinical trial. With the recent FDA-approval of Epidiolex, this review mainly focused on trials involving this specific formulation since it is the only CBD-based drug currently available to clinicians, although all other clinically trialed CBD(A) drugs were also examined. We hope this review will help guide future research and clinical trials by providing the various outcomes measured in a single review.