Gas Biology Research in Clinical Practice. Группа авторов

Omori-Nishi, Ota-Ku

      Tokyo, 143-8541 (Japan)

       Tel. [phone], Fax [phone], E- Mail [email protected]

       General

      Yoshikawa T, Naito Y (eds): Gas Biology Research in Clinical Practice.

       Basel, Karger, 2011, pp 15–23

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Therapeutic Medical Gas

      Atsunori Nakao

      Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa., USA

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      Abstract

      Therapeutic medical gas is pharmaceutical gaseous molecules which offer solutions to medical needs. In addition to traditional medical gases including oxygen and nitrous oxide, a number of medical gases have been recently discovered to play protective roles in various disease conditions. In particular, nitric oxide, carbon monoxide and hydrogen sulfide are found to be endogenously generated in the human body and mediate signaling pathways as biological messengers, and are shown to have potent cytoprotective effects. Herein, we summarize the recent advances of therapeutic medical gas research and discuss their clinical feasibility, typically such as nitric oxide, carbon monoxide, hydrogen sulfide, hydrogen, xenon, helium and ozone. A recent increase in publications in the medical gas field clearly indicates that there are significant opportunities for the use of medical gases as therapeutic tools. It would be necessary to identify safety concerns when using therapeutic gases along with potential side effects and toxicity. Although further investigations are required, medical gas may provide a huge impact as a novel and innovative therapeutic tool for unmet medical needs with considerable health burdens.

      Copyright © 2011 S. Karger AG, Basel

      What Is ‘Therapeutic Medical Gas’?

The definition of ‘therapeutic medical gas’ is the pharmaceutical gaseous molecules which are applied to the human body for the purpose of a variety of medical conditions and producing other desirable effects. It is no doubt that oxygen therapy to increase tissue oxygenation has been a mainstream in critical care medicine. However, recent observations in experimental and clinical studies clearly revealed the needs to provide additional supplemental gases to patients with many etiologies. The list of therapeutic medical gases has been growing continuously (table 1). Herein, we discuss the recent advances in medical gas research and delivery mechanisms including clinical application for special gases with recently discovered roles as protective properties.

Table 1. List of recent therapeutic medical gases

      Advantage of Medical Gas Therapy

Gas therapy has distinct advantages over pharmaceutical drugs; it easily penetrates biomembranes and diffuses into the cytosol, mitochondria and nucleus to reach target tissues. Therefore, therapeutic medical gases may be used for a variety of disorders in various clinical settings [1]. Medical gases can be administered in a straightforward way simply by providing the gas for the patients to inhale using a ventilator circuit, facemask, or nasal cannula. In most cases, administration of medical gas by inhalation may not complicate the current existing therapeutic strategies by simply adding the gas in the conventional delivery mechanism. The ability to administer medical gas inhalationally makes it extremely attractive from a feasibility standpoint for translation into a human clinical setting. Some gases such as supplemental oxygen may be administered in the patient’s home or in a medical setting. However, safety warrants uses of other therapeutic gases are given under the direct care of a physician and supervision of trained medical staff.

      Handling and Delivery of Therapeutic Medical Gases

      As these medical gases may be toxic, hazardous or poisonous at a higher concentration, methods and devices for the delivery of therapeutic gases must be carefully examined. The standard yoking system with compressed gas cylinder valve outlet and inlet connections with specific regulators will help avoid improper gas therapy delivery. The best delivered system will be through a closed system in which the delivery mechanism is not prone to problematic leaks or air entrainment. All techniques using gas therapy have the obligation to identify by label the different available therapy gases before administration, and provide safe gas delivery and precision gas analysis or monitoring.

In addition to the development of safe devices for inhaled medical gas, potential clinical application may include a parenteral injectable or a drug containing a gasreleasing moiety. Emerging evidence reveals the efficacies of a novel class of substance, CO-releasing molecules (CORMs), which are capable of exerting a variety of pharmacological activities via the liberation of controlled amounts of CO in biological systems [2]. Recent studies show that nitrate and nitrite, contained in green vegetables, can be recycled in vivo to form NO, representing an important alternative source of NO to the classical L-arginine-NO-synthase pathway, in particular in hypoxic states [3]. It is noteworthy that the enterobacterial flora is an important source of hydrogen and hydrogen sulphide. Experimental study has demonstrated that when hydrogen is released by intestinal bacteria systemic antibiotics may affect the stable levels of these gases along with suppression of commensal bacteria, which may influence to host’s resistance and innate immunity [4].

      Application of Medical Gas for Disease

Medical research must be ultimately conducted for human health benefits. Possible therapeutic opportunities for medical gases are shown in table 1. Although every experimental success might not be transferable to standard clinical practice in the near future, the sophisticated experimental concepts of gas inhalation therapy for a medical condition can be considered to be an important step toward clinical application. The medical gas research is relatively unexplored with a short history. Appropriately designed randomized controlled trials with patient-important outcomes, such as improvement of functions of target organs, decreased intensive care unit and hospital days, and decreased cost of therapy, are sorely needed to establish the role of medical gas therapy in patients with disease, associated with the benefits over preexisting standard therapy. At this moment, INOmax^®, NO gas for inhalation therapy, is a United States Food and Drug Administration (FDA)-approved drug for the treatment of hypoxic respiratory failure in term and near-term newborns. The drug is also approved by regulatory authorities and used in the clinical setting in Europe, Australia, Asia and Latin America. A European clinical study revealed that inhalation of 100-125 ppm CO by patients with chronic obstructive pulmonary disease in a stable phase was feasible and led to trends in reduction of sputum eosinophils and improvement of responsiveness to methacholine [5]. In the USA, a single-blind, placebo-controlled, dose-escalating phase 2 study of inhaled CO in patients receiving renal transplants is currently conducted using Covox^®, a device for CO inhalation. The primary endpoint of the study is to evaluate the safety and tolerability of increasing CO dose levels when administered as an inhaled gas to kidney transplant patients over the course of 1 h in an acute