Enika, Nagababu, M.S., Ph.D.

Education

M.S., Mysore University, Mysore, India

Ph.D., National Institute of Nutrition/Osmania University, Hyderabad, India

Dr. Enika’s laboratory focuses on developing innovative inhaled nitric oxide (iNO) generation and delivery technologies to expand access to pulmonary hypertension treatment for a broader global patient population. The lab is also developing low-molecular-weight S-nitrosothiols as nitric oxide donor compounds to lower systemic blood pressure and improve the treatment and management of acute and chronic cardiovascular diseases.

Contact

Office Location: PBMR, 326 and 352

Email: nenika@uabmc.edu

Phone: 205-934-7707

Active Research Projects

Developing Novel inhaled Nitric oxide Delivery systems

Objective: Inhaled nitric oxide (iNO) has been approved by FDA to treat pulmonary hypertension. The current iNO has significant limitations that restrict its broader global use and clinical applications. Our goal is to empower physicians to explore iNO therapy for additional clinical indications while making it accessible to a broader patient population whenever and wherever it is needed. The currently available NO delivery systems are highly expensive and complex, which has largely limited their use to hypoxic respiratory failure in neonates and cardiac surgery applications in adults, while also restricting the feasibility of conducting clinical studies for other indications. Our objective is to simplify both nitric oxide synthesis and delivery systems.

Rationale: Conventional NO production involves multiple complex steps, including synthesis, purification, dilution with nitrogen, storage in large compressed gas cylinders, and hospital distribution, all of which contribute substantially to the high cost of therapy. The NO delivery system also complex and bulky to expand the therapy to homecare, emergency situations and ambulatory patients.

Novel procedures: Developed a single-step chemical process capable of generating medical-grade nitric oxide gas at high concentration (~95% or 950,000 ppm) without requiring further purification. This NO can be stored in compact 1–2-pound canisters for convenient shipping and hospital use, significantly reducing both cost and logistical challenges. The next major challenge is to safely mix highly concentrated NO directly with inspired oxygen to achieve therapeutic doses while maintaining toxic nitrogen dioxide (NO₂) levels below 1 ppm. The current technologies rely on highly diluted NO mixtures (0.08%) to minimize the rate of NO reaction with oxygen to generate NO₂. In contrast, we developed a revolutionary technology to mix undiluted or highly concentrated NO while minimizing NO₂ generation to FDA safety levels. Another critical challenge is achieving precise NO delivery of extremely as low as (5 µL/min) volumes for neonatal applications.

Impact on human health: These novel technologies for NO synthesis, oxygen mixing, and precision dosing across a broad therapeutic range of 0.5 ppm to 250 ppm at inspired gas flow rates ranging from 2 L/min to 100 L/min, offers several important advantages, including substantially lower cost, device miniaturization, simplified transport, longer dosing duration without cartridge replacement, and compatibility with a broad range of NO doses and carrier gas flow rates. These innovations could expand the use of exogenous NO therapy for pulmonary hypertension, high-altitude hypoxia, respiratory infections, and wound healing in both hospital and non-hospital settings.

Developing Nitric Oxide Donor Compounds

Objective: Decreased bioavailability of endogenous nitric oxide (NO) and subsequent dysregulation of NO signaling are major contributors to endothelial dysfunction, vascular stiffness, hypertension, and the development of cardiovascular disease (CVD). Although the pathways of NO synthesis and signaling are well established, effective therapies to restore NO bioavailability remain limited to century-old organic nitrates (ONs) and phosphodiesterase (PDE) inhibitors such as sildenafil. A major limitation of ONs is the rapid development of tolerance and unsuitable for long-term use. S-nitrosothiols (RSNOs) release NO spontaneously and induce vasodilation through both NO-dependent mechanisms and NO-independent protein S-nitrosylation pathways. However, their instability after preparation has limited their therapeutic applications. More recently, inorganic nitrite has emerged as a potential hypoxic vasodilator, but clinical studies suggest that relatively high doses are required to achieve meaningful reductions in systemic blood pressure. The objective is to solve the problems associated with these three promising NO donors.

Novel approach: S-nitroso-N-acetylcysteine (RSNO) generated in situ by reacting sodium nitrite with N-acetylcysteine (NAC) in the sublingual saliva and/or gastric acid, so that it readily diffuses across mucosal and intestinal tissues into the systemic circulation, serving as an effective NO reservoir. A key advantage of this approach is that a substantial portion of nitrite converts into RSNO that immediately diffuse into systemic circulation. Unlike ONs, RSNO does not need to be enzymatically bioactivated to develop tolerance.

Preclinical Studies: The hypothesis was evaluated in normotensive and hypertensive animal models using acute and chronic sublingual or oral administration of the nitrite-NAC combination. Plasma RSNO levels and systemic blood pressure were measured. The results demonstrated significant increases in circulating RSNOs and rapid reductions in blood pressure, supporting potential applications in both acute cardiovascular emergencies and chronic CVD management.

Clinical Studies: While preclinical findings do not always translate directly to humans, preliminary studies in healthy volunteers have demonstrated successful translation of these findings. Further clinical investigations are planned to evaluate efficacy in patient populations and to assess additional hemodynamic outcomes.

Clinical Relevance: Drugs that lower systemic blood pressure can provide therapeutic benefit in acute and chronic angina, congestive heart failure, and hypertensive crises by reducing cardiac preload and afterload while improving coronary perfusion. Our RSNO-based approach fulfills these requirements without the development of tolerance observed with nitroglycerin (NTG). Furthermore, RSNOs may be administered continuously to restore NO bioavailability, unlike organic nitrates, which often require intermittent dosing to prevent tolerance.

Patent Publications

Inventors: Nagababu Enika and Dan Berkowitz

1. Generation of nitric oxide and delivery systems. International publication number: WO 2022/040696 A1 (2022)

2. Chemical-based nitric oxide gas-generating drug device for delivery to patient: International publication number. WO 2023/154970 A2 (2023)

3. Generation of S-nitrosoacetylcysteine. United States Publication number, US 2024/0382443 A1

Grants support: NIH/NHLBI, sponsored Small Business Technology Transfer, phase 1 and 2