Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in a rat model

Abstract

Background: We hypothesised that Calabadion 1, an acyclic cucurbit [n]uril molecular container, reverses fentanylinduced respiratory depression and dysfunction of the CNS. Methods: Experiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 mg kg À1 over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5e200 mg kg À1 ) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG). Results: Calabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and PaCO 2 (P¼0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min À1 ; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P¼0.005), and hypercarbia (PaCO 2 43.4 [1.6] vs 63.4 [8.1] mm Hg; P¼0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50 Res and ED90 Res ) were 1.7 and 15.6 mg kg À1 , respectively. Higher effective doses were needed for recovery of righting reflex (ED50 CNS : 9.6 mg kg À1 ; ED90 CNS : 86.1 mg kg À1 ), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity. Conclusions: Calabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.

Supramolecular hosts as in vivo sequestration agents for pharmaceuticals and toxins

“…38 Most recently, we showed that M1 could reverse the respiratory depression and central nervous system effects of rats dosed with fentanyl. 39 In combination, the results described above suggest the great potential of acyclic CB[n]-type receptors as in vivo sequestration agents for drugs of abuse, especially methamphetamine for which no pharmacotherapies are currently available in the clinic.…”

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

“…The container molecule calabadion 1 is an acyclic cucurbit[ n ]uril that selectively encapsulates ammonium cations, such as the phenylammonium ion moiety of fentanyl. 67 In awake and isoflurane-anesthetized rats, calabadion 1 is able to dose-dependently reverse fentanyl-induced respiratory depression and muscle rigidity with correction of impaired blood gasses. 67 The calabadion–fentanyl complexes are rapidly eliminated via renal clearance, avoiding the risk of renarcotization.…”

From breathtaking to encapsulation: a novel approach to reverse respiratory depression from opioid overdosing

“…Consequently, CLB1 does not affect opioids from the 'morphine' class of opioid analgesics. 9 This is an important observation that is relevant to clinical practice. When patients at the end of surgery are antagonised with CLB1, just the fentanyl effect is reversed and the analgesic and respiratory effects of morphine, given during surgery or during recovery, will not be affected.…”

“…Their method is radically different from earlier methods: they describe a technique to lower the free (unbound) opioid concentration in plasma rather than targeting the opioid receptor with an antagonist or overcoming respiratory depression using a respiratory stimulant. Thevathasan and colleagues 9 studied the ability of calabadion 1 (CLB1) to restore breathing to acceptable levels after administration of fentanyl in a rat model of respiratory depression. CLB1 is a container molecule that is able to selectively encapsulate ammonium cations such as fentanyl, a popular opioid in anaesthesia and chronic pain management.…”

“…10 Thevathasan and colleagues convincingly show that CLB1 reverses fentanylinduced respiratory depression, reduces muscle rigidity, another possible cause of respiratory impairment, and accelerates motor function recovery after isoflurane anaesthesia. 9 Importantly, the affinity of CLB1 for morphine and hydromorphone is 100-fold less than its affinity for fentanyl. Consequently, CLB1 does not affect opioids from the 'morphine' class of opioid analgesics.…”