key: cord-0941567-bn76yto1 authors: Machovec, Kelly A.; Ames, Warwick A. title: Recycle: Do it For the Kids date: 2020-07-15 journal: J Cardiothorac Vasc Anesth DOI: 10.1053/j.jvca.2020.07.030 sha: 2498fbe9274adb0db928773b07da58e8710f9d93 doc_id: 941567 cord_uid: bn76yto1 nan At this time of COVID-19, where government agencies, medical professionals and the general public are calling for an effective treatment, expectations of the pharmaceutical industry are high. Unveiling of a new cure-all magic bullet is, unfortunately, an unrealistic proposition. Vaccines aside, the time and expense of bringing new drugs to market for this specific indication is too great to meet current needs. It is hardly surprising that attention has been drawn to existing drugs, in the hope of finding a cure. Hydroxychloroquine and chloroquine enjoyed a brief departure from roles in malarial and rheumatic disease management to emerge as the darlings of COVID-19 treatment. In late March of 2020, the United States Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) allowing physicians the ability to prescribe these medications to patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This was largely based on data from 2005, when researchers discovered that chloroquine is a potent inhibitor of the SARS coronavirus in in vitro primate cell cultures 1 . Hydroxychloroquine quickly gained international attention during the current epidemic, despite evidence from human trials; incredibly, some people started consuming hydroxychloroquine as a prophylactic against SARS-CoV-2 infection. Only weeks later, the United States National Institutes of Health warned against this treatment, citing insufficient clinical data to recommend this class of drugs for the treatment of COVID-19, as well as concern over significant and potentially fatal side effects (prolonged QTc interval being the most noteworthy). Investigators have now turned their attention to a host of other anti-tumor, anti-malarial, anti-bacterial, and anti-retroviral medications with activity against SARS-CoV-2 infection, hoping for an effective therapy. Although this hydroxychloroquine episode has been an unfortunate distraction, "repurposing" of existing drugs for new medical indications is a successful strategy that has gained popularity in recent years. Examples abound in the medical literature. Propranolol, developed as an anti-hypertensive agent, is also a useful treatment for pediatric hemangiomas and a wide range of malignancies, including angiosarcoma. Thalidomide, withdrawn from clinical use as an antiemetic for pregnancy-related morning sickness, is effective in treating complications of leprosy, and is most recently being used to treat multiple myeloma. Flumazenil, used for treatment of benzodiazepine over dose, is used for hypersomnia and emergence delirium in children 2 . Dexamethasone, a long-utilized steroid, is also an effective anti-emetic but may also play a role in treatment of current SARS-CoV-2 infection. Given the opportunity, the advantages of repurposing drugs are obvious. Existing drugs that have survived the FDA approval process, have known pharmacokinetic and safety profiles. This allows any newly identified use of a previously approved drug to be readily evaluated in phase 2 clinical trials; it also may allow a measure of confidence in using a drug for an "off-label" indication. This is particularly important as research and development costs for pharmaceutical companies are rapidly expanding. The process of screening new therapeutic molecules, conducting preclinical in vitro trials, and then confirming with clinical trials in humans takes an average of 15 years and US$800 millionall to bring only a single drug to market 3 . Moreover, the current pharmaceutical research and development business model is threatened by poor transparency, questions of integrity and ethical practice, constricted health care budgets, loss of revenue due to rise in availability of generic medications, and a lack of novel therapeutic agents, all leading to fewer new drugs coming to market for clinical use 4, 5 . A medication with a long history of use in adults, with known safety, efficacy and tolerability data, may be used in children with a greater degree of comfort, especially if toxicity studies in pediatric populations are not yet conducted [6] [7] [8] . Such drugs also have efficacy in "off-label" use. Off-label drug use is common in pediatrics, as the vigorous studies needed to obtain FDA approval are not conducted in children; case reports and case series of off-label use aid physicians in increasing the number of pharmacologic therapies in the armamentarium. Drug repurposing therefore is one solution to the "productivity gap" that plagues the pharmaceutical industry. In this issue of Journal of Cardiothoracic and Vascular Anesthesia, Charlton, Ladd, Friesen and Friesen describe the use of labetalol in the management of paradoxical hypertension following aortic coarctation repair in children 9 . Labetalol is not a new medication; it was discovered in 1966 and first licensed for medical practice in 1977. Although safety and efficacy studies for labetalol have not been performed in pediatric patients, this drug has been and is used successfully in this population. Its use in the management of paradoxical hypertension was initially described 1988, but other, newer drugs eventually surpassed labetalol in clinical use. Notably nitroprusside and angiotensinconverting enzyme inhibitors, particularly for immediate blood pressure control following coarctation repair 10 11 . More recently, dexmedetomidine, a wonder drug of pediatric anesthesiology that seems to fix everything, has too been cited as an adjunct to assist in paradoxical hypertension 12 . When considering the anesthesia required for repair of complex congenital heart defects, providing anesthesia for repair of aortic coarctation seems much simpler. However, anesthesiologists have a critical role in establishing early control of post-operative hypertension in this population. Adequate treatment of hypertension and selection of appropriate agents following coarctation repair is important to prevent stroke, hemorrhage, and mesenteric arteritis, among other complications 13 . The authors of this study of labetalol provide an opportunity for us to reconsider paradoxical hypertension after coarctation repair, an important clinical issue that all pediatric cardiac anesthesiologists and intensivists encounter at some point. Indeed, anesthesiologists are familiar with immediate hypertension that occurs upon repair of the coarctation, even in the absence of a residual gradient across the aortic arch. However, this hypertension persists up to several days post-coarctation repair. The mechanism of action for post-operative paradoxical hypertension is two-pronged. The initial elevation is due to higher baroreceptor set pointsbaroreceptors sense relative "hypotension" after relief of the obstruction, and instigate increase in norepinephrine levels to restore blood pressure. The second phase of hypertension is due to renin-angiotensin-aldosterone system activation with elevated plasma renin activity (PRA) in the first postoperative week 11 . Beta-adrenergic antagonists are effective to decrease PRA, but may require concomitant use of vasodilators to achieve blood pressure goals. It is here that labetalol enjoys an advantageas both an alpha-and beta-adrenergic antagonist, it decreases norepinephrine concentrations and activation of the renin-angiotensin-aldosterone system 9 . Charlton et al acknowledge that some children in their study required nitroprusside in addition to labetalol, but hypothesize that higher doses of labetalol may have eliminated this need. Charlton et al have brought back into focus an old medication, labetalol, that is uniquely situated to manage paradoxical hypertension; their study also confirms increased renin activity as a cause of persistent hypertension following repair of aortic coarctation. The use of an older drug with activity against both alpha-and beta-adrenergic receptors highlights that repurposing drugs is particularly helpful for pediatric use. In summary, this serves as a reminder that old medications can still be highly effective and perfect for the problem at hand. When thoughtfully studied and used for the intended purpose and or repurposed for a new indication, medicines that have long been in our pharmaceutical armory can continue to be useful. Kelly A Machovec: conceptualization, writing and editing; Warwick A. Ames: con conceptualization, writing and editing. 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