Action of fragments of the cocaine molecule on the CNS

Zakusov, V. V.; Kostochka, L. M.; Сколдинов, А. П.

doi:10.1007/bf00800448

Cited by 7 publications

(3 citation statements)

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“…Some older literature has suggested that EME does affect blood vessel smooth muscle (Zakusov et al, 1978;Kurth et al, 1993), but we recently found no transient blood pressure changes after cocaine doses up to 80 mg/kg i.v. in mice pretreated with CocH vector (Murthy et al, 2015).…”

Section: Discussionmentioning

confidence: 51%

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Murthy

Reyes

Geng

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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Cocaine addiction is associated with devastating medical consequences, including cardiotoxicity and risk-conferring prolongation of the QT interval. Viral gene transfer of cocaine hydrolase engineered from butyrylcholinesterase offers therapeutic promise for treatment-seeking drug users. Although previous preclinical studies have demonstrated benefits of this strategy without signs of toxicity, the specific cardiac safety and efficacy of engineered butyrylcholinesterase viral delivery remains unknown. Here, telemetric recording of electrocardiograms from awake, unrestrained mice receiving a course of moderately large cocaine doses (30 mg/kg, twice daily for 3 weeks) revealed protection against a 2-fold prolongation of the QT interval conferred by pretreatment with cocaine hydrolase vector. By itself, this prophylactic treatment did not affect QT interval duration or cardiac structure, demonstrating that viral delivery of cocaine hydrolase has no intrinsic cardiac toxicity and, on the contrary, actively protects against cocaine-induced QT prolongation.

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Section: Discussionmentioning

confidence: 51%

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Murthy

Reyes

Geng

et al. 2015

Journal of Pharmacology and Experimental Therapeutics

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“…However, the potential desterification of Ibutropin to tropine ( Supplementary Figure S1 ) by nonspecific carboxyesterases within blood plasma ( Butterworth et al, 1993 ; Nishida et al, 1996 ; Hemmings and Egan, 2018 ) may be a factor in the ability of Ibutropin to exert its potent effects against opioid-induced respiratory depression (OIRD) ( Getsy et al, 2024 ). This is especially possible because tropine exerts the same behavioral profile as cocaine upon central administration to rats ( Zakusov et al, 1978 ). As such, the objectives of this study were to determine the effects an injection of tropine (200 μmol/kg, IV) has on the deleterious actions of fentanyl (75 μg/kg, IV) on breathing by looking at changes in ventilatory parameters, A-a gradient, ABG chemistry, antinociception and sedation (i.e., righting reflex) in freely-moving (unanesthetized) adult male Sprague Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats

Getsy,

May,

Young

et al. 2024

Front. Pharmacol.

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Our lab is investigating the efficacy profiles of tropine analogs against opioid-induced respiratory depression. The companion manuscript reports that the cell-permeant tropeine, tropine ester (Ibutropin), produces a rapid and sustained reversal of the deleterious actions of fentanyl on breathing, alveolar-arterial (A-a) gradient (i.e., index of alveolar gas exchange), and arterial blood-gas (ABG) chemistry in freely-moving male Sprague Dawley rats, while not compromising fentanyl analgesia. We report here that in contrast to Ibutropin, the injection of the parent molecule, tropine (200 μmol/kg, IV), worsens the adverse actions of fentanyl (75 μg/kg, IV) on ventilatory parameters (e.g., frequency of breathing, tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives), A-a gradient, ABG chemistry (e.g., pH, pCO2, pO2, and sO2), and sedation (i.e., the righting reflex), while not affecting fentanyl antinociception (i.e., the tail-flick latency) in freely-moving male Sprague Dawley rats. These data suggest that tropine augments opioid receptor-induced signaling events that mediate the actions of fentanyl on breathing and alveolar gas exchange. The opposite effects of Ibutropin and tropine may result from the ability of Ibutropin to readily enter peripheral and central cells. Of direct relevance is that tropine, resulting from the hydrolysis of Ibutropin, would combat the Ibutropin-induced reversal of the adverse effects of fentanyl. Because numerous drug classes, such as cocaine, atropine, and neuromuscular blocking drugs contain a tropine moiety, it is possible that their hydrolysis to tropine has unexpected/unintended consequences. Indeed, others have found that tropine exerts the same behavioral profile as cocaine upon central administration. Together, these data add valuable information about the pharmacological properties of tropine.

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“…However, the potential desterification of Ibutropin to tropine (Supplementary Figure S1) by nonspecific carboxyesterases within blood plasma (Butterworth et al, 1993;Nishida et al, 1996;Hemmings and Egan, 2018) may be a factor in the ability of Ibutropin to exert its potent effects against opioid-induced respiratory depression (OIRD) (Getsy et al, 2024). This is especially possible because tropine exerts the same behavioral profile as cocaine upon central administration to rats (Zakusov et al, 1978). As such, the objectives of this study were to determine the effects an injection of tropine (200 μmol/kg, IV) has on the deleterious actions of fentanyl (75 μg/kg, IV) on breathing by looking at changes in ventilatory parameters, A-a gradient, ABG chemistry, antinociception and sedation (i.e., righting reflex) in freelymoving (unanesthetized) adult male Sprague Dawley rats.…”

Section: Introductionmentioning

confidence: 99%

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Action of fragments of the cocaine molecule on the CNS

Cited by 7 publications

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Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Cocaine Hydrolase Gene Transfer Demonstrates Cardiac Safety and Efficacy against Cocaine-Induced QT Prolongation in Mice

Tropine exacerbates the ventilatory depressant actions of fentanyl in freely-moving rats

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