BioEssays, Journal Year: 2022, Volume and Issue: 44(7)
Published: May 22, 2022
The author has stock and works closely with Atelerix Life Sciences, a company that aims to develop D-Cysteine Ethyl Ester into drug reverse opioid induced respiratory depression. Data sharing not applicable this article as no datasets were generated or analyzed during the current study.
Language: Английский
Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2023, Volume and Issue: 385(2), P. 117 - 134
Published: Feb. 24, 2023
The opioid overdose death toll in the United States is an ongoing public health crisis. We characterized magnitude and duration of respiratory depression, leading cause cases, induced by heroin or fentanyl development tolerance male female rats. used whole-body plethysmography to first establish dose-response curves recording breathing for 60 minutes post-intravenous injection. then tested acute over several weeks chronic with challenge. Heroin each provoked dose-dependent depression. caused prolonged (45–60 minute) depression rats, decreased frequency, tidal volume, minute ventilation increased inspiratory time apneic pause. Fentanyl produced similar changes a shorter (10–15 minutes). High-dose robust that was slightly more severe females and, when given intermittently (acute doses 2 3 apart), did not lead tolerance. In contrast, delivered osmotic minipump resulted heroin, This effect persisted during withdrawal males only. Our model experimental design will allow investigation neurobiology opioid-induced testing potential therapeutics reverse stimulate breathing.
Language: Английский
Citations
31
Peptides, Journal Year: 2023, Volume and Issue: 169, P. 171095 - 171095
Published: Sept. 12, 2023
Language: Английский
Citations
13
Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15
Published: April 18, 2024
Fentanyl elicits profound disturbances in ventilatory control processes humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on frequency of breathing (Freq), tidal volume (TV), minute ventilation (MV = Freq × TV) are resolved, then no longer a concern. results present study challenge this concept findings, as they reveal while apparent inhibitory fentanyl (75 μg/kg, IV) Freq, TV, MV adult male rats were fully resolved within 15 min, many other responses full effect, including opposing timing parameters. For example, although at inspiratory duration (Ti) end pause (EIP) elevated, whereas expiratory (Te) (EEP) diminished. Since TV had subsided it would be expected administration an opioid receptor (OR) antagonist have minimal if parameters resolved. We now report intravenous injection 1.0 mg/kg dose peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes MV, Te, EEP pronounced Ti EIP. In contrast, 2.5 NLXmi dramatic variables, which associated increases non-apneic events such apneas. two compelling conclusions from follows: 1) blockade central ORs produced by apparently 2) induced activation systems counter-balancing TV: one being system non-OR excitatory system.
Language: Английский
Citations
4
Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 183, P. 117847 - 117847
Published: Jan. 24, 2025
Language: Английский
Citations
0
Neuropharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 110479 - 110479
Published: April 1, 2025
Language: Английский
Citations
0
Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 153, P. 113277 - 113277
Published: June 17, 2022
There is an urgent need for development of drugs that are able to reverse the adverse effects opioids on breathing and arterial blood-gas (ABG) chemistry while preserving opioid analgesia. The present study describes bolus injections N-acetyl-L-cysteine (L-NAC, 500 μmol/kg, IV) ventilatory parameters, ABG chemistry, Alveolar-arterial (A-a) gradient, sedation (righting reflex) analgesia status (tail-flick latency assay) in unanesthetized adult male Sprague Dawley rats receiving a continuous infusion fentanyl (1 μg/kg/min, IV). Fentanyl elicited pronounced disturbances (1) parameters (e.g., decreases frequency breathing, tidal volume minute ventilation), (2) (decreases pH, pO
Language: Английский
Citations
16
Frontiers in Pharmacology, Journal Year: 2022, Volume and Issue: 13
Published: Sept. 28, 2022
We are developing a series of thiolesters that produce an immediate and sustained reversal the deleterious effects opioids, such as morphine fentanyl, on ventilation without diminishing antinociceptive these opioids. report here systemic injections L-cysteine methyl ester (L-CYSme) morphine-induced changes in ventilatory parameters, arterial-blood gas (ABG) chemistry (pH, pCO2, pO2, sO2), Alveolar-arterial (A-a) gradient (i.e., index alveolar gas-exchange within lungs), antinociception unanesthetized Sprague Dawley rats. The administration (10 mg/kg, IV) produced including decreases tidal volume, minute ventilation, inspiratory drive peak flow were accompanied by increase end pause. A single injection L-CYSme (500 μmol/kg, rapid long-lasting second elicited pronounced increases to values well above pre-morphine levels. (250 or 500 also arterial blood pH, sO2 A-a gradient, whereas itself was inactive. did not appear modulate sedative measured righting reflex times, but diminish duration, however, magnitude actions (5 10 determined tail-flick latency hindpaw-withdrawal assays. These findings provide evidence can powerfully overcome breathing rats while affecting early stage opioid. mechanisms which interferes with OR-induced signaling pathways mediate performance, diminishes late action remain be determined.
Language: Английский
Citations
15
Frontiers in Pharmacology, Journal Year: 2023, Volume and Issue: 14
Published: Sept. 19, 2023
Introduction: Despite their inclination to induce tolerance, addictive states, and respiratory depression, synthetic opioids are among the most effective clinically administered drugs treat severe acute/chronic pain surgical anesthesia. Current medical interventions for opioid-induced depression (OIRD), wooden chest syndrome, opioid use disorder (OUD) show limited efficacy marked by low success in face of highly potent such as fentanyl. D-Cysteine ethylester (D-CYSee) prevents OIRD post-treatment withdrawal male/female rats mice with minimal effect on analgesic status. However, potential aversive or rewarding effects D-CYSee have yet be fully characterized its could compromised interactions opioid-reward pathology. Methods: Using a model fentanyl-induced conditioned place preference (CPP), this study evaluated 1) dose sex dependent fentanyl 2) extent which alters affective state acquisition seeking behaviors. Results: Fentanyl reward-related were found dependent. Male exhibited range-bound response centered at 5 µg/kg. Female CPP only 50 This was 25% females remaining 75% showing no significant any dose. Pretreatment 100 mg/kg, but not 10 prevented males while both doses preventing females. Discussion: These findings suggest that is an co-treatment prescribed reduce development OUD.
Language: Английский
Citations
7
Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 14
Published: April 5, 2024
We examined whether co-injections of the cell-permeant D-cysteine analogues, ethyl ester (D-CYSee) and amide (D-CYSea), prevent acquisition physical dependence induced by twice-daily injections fentanyl, reverse acquired to these in freely-moving male Sprague Dawley rats. Injection opioid receptor antagonist, naloxone HCl (NLX, 1.5 mg/kg, IV), elicited a series withdrawal phenomena that included cardiorespiratory behavioral responses, falls body weight temperature, rats received 5 or 10 fentanyl (125 μg/kg, same number vehicle co-injections. Regarding development dependence, NLX-precipitated were markedly reduced fentanyl-injected had D-CYSee (250 μmol/kg, IV) D-CYSea (100 but not IV). reversal established was starting with injection 6 fentanyl. This study provides evidence The lack effect suggests enhanced cell-penetrability into cells, particularly within brain, is key their ability interact intracellular signaling events involved
Language: Английский
Citations
2
Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15
Published: June 24, 2024
Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that cell-permeant tropeine, ester (Ibutropin), produces a rapid and sustained reversal deleterious actions fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index alveolar gas exchange), arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising analgesia. We report here contrast to Ibutropin, injection parent molecule, (200 μmol/kg, IV), worsens adverse (75 μg/kg, IV) ventilatory parameters (e.g., frequency tidal volume, minute ventilation, peak inspiratory expiratory flows, drives), A-a gradient, ABG pH, pCO 2 , pO sO ), sedation righting reflex), affecting antinociception tail-flick latency) rats. These data suggest augments opioid receptor-induced signaling events mediate breathing exchange. opposite effects Ibutropin may result from ability readily enter peripheral central cells. Of direct relevance tropine, resulting hydrolysis would combat Ibutropin-induced fentanyl. Because numerous drug classes, such as cocaine, atropine, neuromuscular blocking drugs contain moiety, it possible their has unexpected/unintended consequences. Indeed, others have found exerts same behavioral profile cocaine upon administration. Together, these add valuable information about pharmacological properties tropine.
Language: Английский
Citations
2