Inhibition of post-lanosterol biosynthesis by fentanyl: potential implications for Fetal Fentanyl Syndrome (FFS).

A recent study discovered a novel, complex developmental disability syndrome, most likely caused by maternal fentanyl use disorder. This Fetal Fentanyl Syndrome (FFS) is biochemically characterized by elevated 7-dehydrocholesterol (7-DHC) levels in neonates, raising the question if fentanyl inhibition of the dehydrocholesterol reductase 7 (DHCR7) enzyme is causal for the emergence of the pathophysiology and phenotypic features of FFS. To test this hypothesis, we undertook a series of experiments on Neuro2a cells, primary mouse neuronal and astrocytic cultures, and human dermal fibroblasts (HDFs) with DHCR7+/+ and DHCR7+/- genotype. Our results revealed that in vitro exposure to fentanyl disrupted sterol biosynthesis across all four in vitro models. The sterol biosynthesis disruption by fentanyl was complex, and encompassed the majority of post-lanosterol intermediates, including elevated 7-DHC and decreased desmosterol (DES) levels across all investigated models. The overall findings suggested that maternal fentanyl use in the context of an opioid use disorder leads to FFS in the developing fetus through a strong disruption of the whole post-lanosterol pathway that is more complex than a simple DHCR7 inhibition. In follow-up experiments we found that heterozygous DHCR7+/- HDFs were significantly more susceptible to the sterol biosynthesis inhibitory effects of fentanyl than wild-type DHCR7+/+ fibroblasts. These data suggest that DHCR7+/- heterozygosity of mother and/or developing child (and potentially other sterol biosynthesis genes), when combined with maternal fentanyl use disorder, might be a significant contributory factor to the emergence of FFS in the exposed offspring. In a broader context, we believe that evaluation of new and existing medications for their effects on sterol biosynthesis should be an essential consideration during drug safety determinations, especially in pregnancy.

Effects of Psychotropic Medication on Somatic Sterol Biosynthesis of Adult Mice.

Polypharmacy is commonly used to treat psychiatric disorders. These combinations often include drugs with sterol biosynthesis inhibiting side effects, including the antipsychotic aripiprazole (ARI), and antidepressant trazodone (TRZ). As the effects of psychotropic medications are poorly understood across the various tissue types to date, we investigated the effects of ARI, TRZ, and ARI + TRZ polypharmacy on the post-lanosterol biosynthesis in three cell lines (Neuro2a, HepG2, and human dermal fibroblasts) and seven peripheral tissues of an adult mouse model. We found that both ARI and TRZ strongly interfere with the function of 7-dehydrocholesterol reductase enzyme (DHCR7) and lead to robust elevation in 7-dehydrocholesterol levels (7-DHC) and reduction in desmosterol (DES) across all cell lines and somatic tissues. ARI + TRZ co-administration resulted in summative or synergistic effects across the utilized in vitro and in vivo models. These findings suggest that at least some of the side effects of ARI and TRZ are not receptor mediated but arise from inhibiting DHCR7 enzyme activity. We propose that interference with sterol biosynthesis, particularly in the case of simultaneous utilization of medications with such side effects, can potentially interfere with functioning or development of multiple organ systems, warranting further investigation.

The Effect of Nebulizer Position on Aerosolized Epoprostenol Delivery in an Adult Lung Model.

BACKGROUND: Aerosolized epoprostenol is an alternative for inhaled nitric oxide in the management of pulmonary arterial hypertension and possibly acute hypoxemia. Our objective was to determine differences in drug deposition based on different nebulizer positions in the ventilator circuit, using a vibrating mesh nebulizer. METHODS: An 8.0-mm inner diameter endotracheal tube (ETT) was connected to a training test lung, compliance of 30 mL/cm H2O, with a collecting filter placed at the ETT-test lung junction. A mechanical ventilator, heated wire circuit, and pass-over humidifier were utilized. A syringe pump continuously instilled a 15,000-ng/mL epoprostenol solution at 30, 50, and 70 ng/kg/min into the vibrating mesh nebulizer at all 4 positions. Tidal volumes (VT) were set at 4, 6, and 8 mL/kg for a 70-kg patient with breathing frequencies of 25, 16, and 12 breaths/min, respectively. Epoprostenol was eluted from the filters (no. = 180) and analyzed with ultraviolet-visible spectrophotometry at 205 nm to estimate drug deposition. RESULTS: Epoprostenol deposition increased significantly (P = .02) as the dosage increased from 30 ng/kg/min (median 4,520.0 ng, interquartile range [IQR] 2,285.0-6,712.2 ng) to 50 ng/kg/min (median 6,065.0 ng, IQR 3,220.0-13,002.5 ng) and 70 ng/kg/min (median 9,890.0 ng, IQR 6,270.0-16,140.0 ng). No significant difference was found between variations in ventilator settings. No difference in deposition was found between the humidifier inlet and outlet, but these positions resulted in greater deposition compared with the inspiratory limb and between the ETT and Y-piece. CONCLUSIONS: The greatest amount of mean epoprostenol deposition resulted with the nebulizer placed at the humidifier inlet or outlet in a ventilator with bias flow.

Mapping of Health Communication and Education Strategies Addressing the Public Health Dangers of Illicit Online Pharmacies.

Illicit online pharmacies are a growing global public health concern. Stakeholders have started to engage in health promotion activities to educate the public, yet their scope and impact has not been examined. We wished to identify health promotion activities focused on consumer awareness regarding the risks of illicit online pharmacies. Organizations engaged on the issue were first identified using a set of engagement criteria. We then reviewed these organizations for health promotion programs, educational components, public service announcements, and social media engagement. Our review identified 13 organizations across a wide spectrum of stakeholders. Of these organizations, 69.2% (n = 9) had at least one type of health promotion activity targeting consumers. Although the vast majority of these organizations were active on Facebook or Twitter, many did not have dedicated content regarding online pharmacies (Facebook: 45.5%, Twitter: 58.3%). An online survey administered to 6 respondents employed by organizations identified in this study found that all organizations had dedicated programs on the issue, but only half had media planning strategies in place to measure the effectiveness of their programs. Overall, our results indicate that though some organizations are actively engaged on the issue, communication and education initiatives have had questionable effectiveness in reaching the public. We note that only a few organizations offered comprehensive and dedicated content to raise awareness on the issue and were effective in social media communications. In response, more robust collaborative efforts between stakeholders are needed to educate and protect the consumer about this public health and patient safety danger.