Pharmacologic Characterization of Substituted Nitazenes at µ, κ, and Δ Opioid Receptors Suggests High Potential for Toxicity.

The benzimidazole opioids (substituted nitazenes) are highly potent µ opiod receptor (MOR) agonists with heroin- or fentanyl-like effects. These compounds have caused hospitalizations and fatal overdoses. We characterized the in vitro pharmacology and structure-activity relationships of 19 nitazenes with substitutions at three positions of the benzimidazole core. Affinities were assessed using agonist radioligand binding assays at human µ, κ, and Δ opioid receptors (MOR, KOR, and DOR, respectively) heterologously expressed in CHO cells. Notably, for MOR binding, nine substituted nitazenes had significantly higher affinities than fentanyl including N-pyrrolidino etonitazene, N-pyrrilidino isonitazene, and N-desethyl isotonitazene; 13 had subnanomolar affinities. Only metodesnitazene and flunitazene had significantly lower affinities than fentanyl. Affinities for the substituted nitazenes at KOR and DOR relative to MOR were 46- to 2580-fold and 180- to 1280-fold lower, respectively. Functional activities were assessed using [35S]GTPγS binding assays. Four nitazenes had subnanomolar potencies at MOR: N-pyrrolidino etonitazene, N-pyrrilidino isonitazene, N-pyrrilidino protonitazene and N-desethyl isotonitazene. Ten substituted nitazenes had significantly higher potencies than fentanyl. All tested nitazenes were full MOR agonists. Potencies at KOR and DOR relative to MOR were 7.3- to 7920-fold and 24- to 9400-fold lower, respectively. Thus, many of these compounds are high affinity/high potency MOR agonists with elevated potential to elicit toxicity and overdose at low doses. SIGNIFICANCE STATEMENT: Substituted nitazenes are a growing public health threat. Although the 19 nitazenes tested vary in their opioid receptor pharmacology, a number are very high affinity, high potency, and high efficacy compounds- higher than fentanyl. Their pharmacology suggests high potential for harm.

Measuring glucose at the site of insulin delivery with a redox-mediated sensor.

Automated insulin delivery systems for people with type 1 diabetes rely on an accurate subcutaneous glucose sensor and an infusion cannula that delivers insulin in response to measured glucose. Integrating the sensor with the infusion cannula would provide substantial benefit by reducing the number of devices inserted into subcutaneous tissue. We describe the sensor chemistry and a calibration algorithm to minimize impact of insulin delivery artifacts in a new glucose sensing cannula. Seven people with type 1 diabetes undergoing automated insulin delivery used two sensing cannulae whereby one delivered a rapidly-acting insulin analog and the other delivered a control phosphate buffered saline (PBS) solution with no insulin. While there was a small artifact in both conditions that increased for larger volumes, there was no difference between the artifacts in the sensing cannula delivering insulin compared with the sensing cannula delivering PBS as determined by integrating the area-under-the-curve of the sensor values following delivery of larger amounts of fluid (P = 0.7). The time for the sensor to recover from the artifact was found to be longer for larger fluid amounts compared with smaller fluid amounts (10.3 ± 8.5 min vs. 41.2 ± 78.3 s, P < 0.05). Using a smart-sampling Kalman filtering smoothing algorithm improved sensor accuracy. When using an all-point calibration on all sensors, the smart-sampling Kalman filter reduced the mean absolute relative difference from 10.9% to 9.5% and resulted in 96.7% of the data points falling within the A and B regions of the Clarke error grid. Despite a small artifact, which is likely due to dilution by fluid delivery, it is possible to continuously measure glucose in a cannula that simultaneously delivers insulin.

An Amperometric Glucose Sensor Integrated into an Insulin Delivery Cannula: In Vitro and In Vivo Evaluation.

BACKGROUND: Labeling prohibits delivery of insulin at the site of subcutaneous continuous glucose monitoring (CGM). Integration of the sensing and insulin delivery functions into a single device would likely increase the usage of CGM in persons with type 1 diabetes. METHODS: To understand the nature of such interference, we measured glucose at the site of bolus insulin delivery in swine using a flexible electrode strip that was laminated to the outer wall of an insulin delivery cannula. In terms of sensing design, we compared H2O2-measuring sensors biased at 600 mV with redox mediator-type sensors biased at 175 mV. RESULTS: In H2O2-measuring sensors, but not in sensors with redox-mediated chemistry, a spurious rise in current was seen after insulin lis-pro boluses. This prolonged artifact was accompanied by electrode poisoning. In redox-mediated sensors, the patterns of sensor signals acquired during delivery of saline and without any liquid delivery were similar to those acquired during insulin delivery. CONCLUSION: Considering in vitro and in vivo findings together, it became clear that the mechanism of interference is the oxidation, at high bias potentials, of phenolic preservatives present in insulin formulations. This effect can be avoided by the use of redox mediator chemistry using a low bias potential.