Toxicology Evaluation of Drugs Administered via Uncommon Routes: Intranasal, Intraocular, Intrathecal/Intraspinal, and Intra-Articular.

As the need for nasal, ocular, spinal, and articular therapeutic compounds increases, toxicology assessments of drugs administered via these routes play an important role in human safety. This symposium outlined the local and systemic evaluation to support safety during the development of these drugs in nonclinical models with some case studies. Discussions included selection of appropriate species for the intended route; conducting nonclinical studies that closely mimic the intended use with adequate duration; functional assessment, if deemed necessary; evaluation of local tissues with special histological staining procedure; and evaluations of safety margins based on local and systemic toxicity.

Target engagement and histopathology of neuraxial resiniferatoxin in dog.

OBJECTIVE: To evaluate target engagement of intracisternally (IC) delivered TRPV1 agonist, resiniferatoxin (RTX), as measured by primary afferent and dorsal horn substance P immunoreactivity (sP-IR), histopathology and thermal escape latencies in dogs. STUDY DESIGN: Prospective experimental trial. ANIMALS: Fourteen adult male Beagle dogs, weighing 10.3-13.2 kg; 11 dogs surviving to scheduled euthanasia. METHODS: Anesthetized dogs were randomly assigned to be administered IC RTX (3.6 µg, 0.1 mL kg-1) in a hyperbaric (hRTX, n = 6), normobaric (nRTX, n = 4) vehicle or a hyperbaric vehicle (hVehicle, n = 4). Over 16 days, animals were examined for thoracic and pelvic limb paw thermal withdrawal latencies and neurologic function. Spinal cords, trigeminal ganglia and dorsal root ganglia (DRGs) were assessed for morphologic changes and sP-IR. RESULTS: IC RTX in anesthetized dogs resulted in a < 1 hour increase in blood pressure. Acute reactions leading to euthanasia within 8 hours occurred in three dogs (two hRTX, one nRTX). All other animals recovered with normal neurologic, bowel and bladder function. Final groups were: vehicle n = 4, hRTX n = 4 and nRTX n = 3. Animals in nRTX and hRTX showed increases in escape latencies in thoracic paws and, to a lesser extent, in pelvic paws, correlating to a loss of sP-IR in cervical cord with smaller reductions in thoracic and lumbar cord. In animals surviving to euthanasia, thickening of the arachnoid membrane (predominantly in the cervical region) was the most consistent change. This change, present in controls, was interpreted to be vehicle related. There was no evidence of structural changes in brain and spinal cord. CONCLUSIONS AND CLINICAL RELEVANCE: IC RTX produced localized loss of spinal and DRG sP with a corresponding thermal analgesia, absent motor impairment or spinal pathology. Loss of three animals emphasizes the need to refine the use of this promising therapeutic modality in managing companion animal pain.

Changes in blood volume indicators and dynamic indicators measured with transpulmonary ultrasound velocity during blood depletion and repletion in a neonatal swine model.

BACKGROUND: Dynamic indicators such as pulse pressure and stroke volume variations can be measured to track changes in preload during hemorrhage, and evaluate fluid therapy. However, these dynamic indicators require mechanical ventilation, and might be affected by cardiac dysrhythmias and changes in vascular tone. Blood volume indicators may offer alternatives for assessing changes in volume status. AIMS: The aims of this study were to measure changes in blood volume indicators and dynamic indicators during removal of blood in two stages and subsequent blood replacement in anesthetized, mechanically ventilated, neonatal pigs. METHODS: In eight anesthetized, mechanically ventilated piglets (5-6 weeks old), cardiac index, stroke volume index, total end-diastolic volume, central blood volume, active circulating volume, pulse pressure variation, and stroke volume variation were measured during blood removal in two stages (15 mL kg-1 each stage) and blood replacement (30 mL kg-1 ). Values after each intervention were measured for each parameter. RESULTS: All indicators differed from baseline after removal of 15 mL kg-1 of blood, except for stroke volume variation. Differences between both stages of hemorrhage were only observed for indexed stroke volume, total end-diastolic volume, central blood volume, and pulse pressure variation. CONCLUSION: Total end-diastolic volume and central blood volume changed during blood depletion and repletion, and differed between stages of hemorrhage. These indicators might be useful for assessing volume status instead of, or in addition to cardiac index and dynamic indicators.

Continuous minimally invasive cardiac output monitoring with the COstatus in a neonatal swine model: recalibration is necessary during vasoconstriction and vasodilation.

BACKGROUND: The COstatus monitor measures cardiac output via the transpulmonary ultrasound dilution method (COTPUD ) after injection of normal saline, and can calculate continuous cardiac output (CCO) from the arterial pressure waveform. The relationship between arterial waveform and COTPUD however, might be degraded during vasoconstriction/vasodilation. OBJECTIVES: To examine if recalibration of arterial waveform-derived CCO is required during mild vasoconstriction/vasodilation. METHODS: In 10 anesthetized piglets (6.6-10.1 kg), two COstatus monitors calculated the CCO from the same femoral arterial waveform before and during infusions of phenylephrine (PE; 1 or 3 mg·kg(-1) ·min(-1) ) and sodium nitroprusside (SNP; 1 or 5 mg·kg(-1) ·min(-1) ), administered in random order. One monitor was recalibrated (CCORecal ) after each intervention, while the other monitor was not (CCONon-Recal ). Recalibration was performed with COTPUD with 1 ml·kg(-1) normal saline as indicator. The effects of each infusion on hemodynamic parameters were compared with baseline using paired t-tests. The bias, limits of agreement (LOA), and percentage error between simultaneous measurements (CCORecal and CCONon-Recal ) were examined with Bland-Altman plots. RESULTS: Infusion of PE significantly increased COTPUD , heart rate (HR), and arterial pressures but not systemic vascular resistance (SVR). Infusion of SNP decreased arterial pressures without affecting COTPUD , HR, and SVR. There was no bias between CCORecal and CCONon-Recal at the baseline, but a small bias was observed during PE and SNP infusions. The LOA increased approximately 10 fold during vasoconstriction and vasodilation. The percentage error increased from ≤ 5% to 32% and 27% during PE and SNP infusions, respectively. CONCLUSION: Continuous cardiac output (CO) measured with the COstatus monitor requires recalibration during vasoconstriction and vasodilation, even if changes in COTPUD or SVR are not substantial.

Unintended consequences of COVID-19 safety measures on patients with chronic knee pain forced to defer joint replacement surgery.

In recent months, with the emergence of the COVID-19 pandemic, the American College of Surgeons and the U.S. Centers for Disease Control and Prevention officially recommended the delay of nonemergency procedures until the public health crisis is resolved. Deferring elective joint replacement surgeries for an unknown period is likely to decrease the incidence of infection with SARS-CoV-2 but is likely to have detrimental effects in individuals suffering from chronic knee pain. These detrimental effects extend beyond the discomfort of osteoarthritis (OA) and the inconvenience of rescheduling surgery. Disabling pain is a driving factor for individuals to seek medical intervention, including pharmacological palliative treatment and surgical procedures. The need for surgical intervention due to chronic pain as for knee and hip replacement is now put on hold indefinitely because access to surgical care has been limited. Although a moderate delay in surgical intervention may not produce a significant progression of OA within the knee, it could lead to muscle wasting due to immobility and exacerbate comorbidities, making rehabilitation more challenging. Importantly, it will have an impact on comorbidities driven by OA severity, notably decreased quality of life and depression. These patients with unremitting pain become increasingly susceptible to substance use disorders including opioids, alcohol, as well as prescription and illegal drugs. Appreciation of this downstream crisis created by delayed surgical correction requires aggressive consideration of nonsurgical, nonopiate supported interventions to reduce the morbidity associated with these delays brought upon by the currently restricted access to joint repair.