Reversing anesthesia with Caffeine

 描述(申请人提供)：这项研究的目的是确定咖啡因是否能逆转人类的麻醉。全身麻醉药导致类昏迷状态；从麻醉中恢复是被动的，是由于麻醉剂的停止。问题是，从麻醉中恢复在某种程度上是随机的，取决于临床医生无法控制的各种因素，如年龄或遗传。虽然从麻醉中“苏醒”的速度相对较快，但认知能力会持续数小时。此外，有些病人的“苏醒”速度很慢。能够以可重复的方式对麻醉恢复进行计时并使恢复完成将是非常有益的。我们在培养的PC12细胞和海马神经元上进行的初步结果表明，全麻药抑制神经递质的释放。我们假设，抑制神经递质释放在麻醉剂在动物和人类中产生麻醉的方式中发挥关键作用。此外，我们假设，逆转麻醉剂对释放机制的抑制作用的药物应该逆转麻醉。从历史上看，cAMP信号在突触功能和可塑性中起着关键作用。升高cAMP有助于神经递质的释放。我们推测，升高细胞内cAMP可能通过恢复神经递质的释放来改变麻醉作用。三种升高[cAMP]i水平的药物被测试；在体外研究中，这些药物被发现完全逆转麻醉药对神经递质释放的抑制作用。当测试时，这些升高cAMP的药物极大地加快了大鼠从麻醉中恢复的速度。测试中最有效的药物是咖啡因，在相对适中的浓度下，咖啡因可以极大地加速麻醉(异氟醚和异丙酚)的恢复。除了升高[cAMP]i，咖啡因还抑制腺苷受体。A2a受体介导咖啡因的唤醒作用，因为敲除或阻断这一受体在药理上会抑制咖啡因介导的唤醒作用。咖啡因抑制腺苷受体的能力可能有助于其逆转麻醉。这项应用的目标是：1)小鼠和大鼠的盲法行为研究-a)确定A2A受体是否在逆转麻醉中发挥作用。B)确定咖啡因是否对所有麻醉剂有效。C)确定麻醉逆转的最佳咖啡因时机。2)人类志愿者的盲法研究-a)确定咖啡因是否加速麻醉恢复，以及它是否加速认知能力的恢复。B)确定麻醉逆转的最佳咖啡因浓度和时机。C)确定咖啡因是否对所有麻醉剂有效。如果咖啡因能加速从麻醉中恢复并恢复认知能力，那么它可能会在短时间内以积极的方式影响医学。

 DESCRIPTION (provided by applicant): The objective of this research is to determine whether caffeine reverses anesthesia in humans. General anesthetics induce a coma-like state; recovery from anesthesia is passive and is due to the discontinuation of anesthetic. Problematically, recovery from anesthesia is somewhat random, dependent upon a variety of factors like age or genetics that are beyond the clinician's control. Although "waking" from anesthesia can be relatively rapid, cognitive abilities are depressed for hours. In addition, some patients "wake" very slowly. It would be extremely beneficial to be able to time recovery from anesthesia in a reproducible manner and to have that recovery be complete. Our preliminary results, carried out in cultured PC12 cells and hippocampal neurons, suggested that general anesthetics inhibit neurotransmitter release. We hypothesized that inhibition of neurotransmitter release plays a key role in how anesthetics produce anesthesia in animals and humans. Furthermore we hypothesized that drugs that reverse the inhibitory effects of anesthetics on the release machinery should reverse anesthesia. Historically, cAMP signaling has been shown to play a key role in synaptic function and plasticity. Elevating cAMP facilitates neurotransmitter release. We posited that elevating intracellular cAMP might alter anesthetic action by restoring neurotransmitter release. Three drugs that elevate [cAMP]i levels, were tested; these drugs were found to completely reverse the inhibitory effects of anesthetics on neurotransmitter release in in vitro studies. When tested, these same cAMP elevating drugs dramatically accelerated recovery from anesthesia in rats. The most effective drug tested was caffeine which dramatically accelerated recovery from anesthesia (isoflurane and propofol) at relatively modest concentrations. In addition to elevating [cAMP]i, caffeine also inhibits adenosine receptors. A2A receptors mediate caffeine's arousal effects since knocking out this receptor or blocking it pharmacologically suppresses caffeine mediated arousal. It is possible that caffeine's ability to inhibit adenosine receptors helps it to reverse anesthesia. The goals of this application are: 1) Blinded Behavioral Studies in Mice and Rats - a) Determine whether A2A receptors play a role in reversing anesthesia. b) Determine whether caffeine works for all anesthetics. c) Determine optimal caffeine timing for anesthesia reversal. 2) Blinded Studies in Human Volunteers - a) Determine whether caffeine accelerates recovery from anesthesia and whether it accelerates recovery of cognitive abilities. b) Determine the optimal caffeine concentration and timing for anesthesia reversal. c) Determine whether caffeine is effective for all anesthetics. If caffeine accelerates recovery from anesthesia and restore cognitive abilities, then it may have the potential to impact medicine in a positive manner and in a brief time frame.