Toxicology International (Formerly Indian Journal of Toxicology)

Open Access Open Access  Restricted Access Subscription Access
Open Access Open Access Open Access  Restricted Access Restricted Access Subscription Access

Sub-Acute Inhalation Toxicity Study of Submicronic Alpha-Ketoglutarate Respiratory Formulation


Affiliations
1 Department of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Delhi, India
2 Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi, India
     

   Subscribe/Renew Journal


Alpha Ketoglutaric Acid (AKG), one of two ketone derivatives of glutaric acid is an important biological compound that serves as a natural scavenger of ammonium ion, facilitating its conversion to amino acids and protein. AKG inhalation has potential therapeutic role against ammonia-induced structural and inflammatory changes in the lungs. In the present study sub-acute inhalation toxicity of a novel submicronic AKG respiratory formulation was evaluated in Sprague Dawley rats. Sub-acute inhalation toxicity study of novel AKG respiratory formulation at doses, 1, 3 and 5% was conducted as per Schedule-'Y' guidelines of ICMR, India. Hematological, serum biochemical and lung toxicity biomarkers in bronchoalveolar lavage (BAL) fluid were determined. Histopathological analysis of lung tissues and other vital organs was carried out to observe any microscopic changes. Hematology, serum biochemistry and lung toxicity biomarkers in BAL fluid revealed no adverse effects of AKG inhalation except for a slight increase in levels of BAL fluid protein. At autopsy, no histopathological changes in major vital organs, including the lungs were observed. The safety evaluation data suggest that aerosols of submicronic AKG respiratory formulation are safe for inhalation and could be developed as a potential therapeutic option against lung injuries induced through chemical toxicants such as ammonia.

Keywords

Industrial Chemicals, Alpha-Ketoglutaric Acid, Sub-Micronic Aerosols, Inhalation Toxicity, BAL Fluid Analysis.
User
Subscription Login to verify subscription
Notifications
Font Size

  • Tuorinsky SD, Sciuto AM. Toxic Inhalational Injury and Toxic Industrial Chemicals in Medical Aspects of Chemical Warfare. Defense Dept., Army, Office of the Surgeon General, Borden Institute 2009;Chapter 10:339-70.

  • Rodrigo GJ. Inhaled therapy for acute adult asthma. Curr Opin Allergy Clin Immuno 2003;3:169-75.

  • Iuchi T, Akaike M, Mitsui T et al. Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction. Circ Res 2003; 92:81-7.

  • Tang BMP, Craig JC, Eslick GD et al. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: a systematic review and meta-analysis. Crit Care Med 2009;37:1594-1603.

  • Filip R, Harrison AP, Stefan G et al. Effect of feed supplementation with phyto-haemagglutinin in combination with Alpha Ketoglutarate on growth and nitrogen elimination pathways in rats with acute renal failure induced by nephrectomy. Arch Med Sci 2008;4(2):122-8.

  • Mittal G, Singh T, Kumar N et al. Radiolabeling and dose-fixation study of oral alpha-ketoglutarate as a cyanide antidote in healthy human volunteers. Clin Toxicol 2010;48:509-15.

  • Baud FJ. Cyanide: critical issues in diagnosis and treatment. Hum Exp Toxicol 2007;26:191-201.

  • Ali R, Mittal G, Sultana S et al. Ameliorative potential of alpha ketoglutaric acid on acute lung injuries induced by ammonia inhalation in rats. Exp Lung Res 2012;38(9-10):435-44.

  • Ali R, Mittal G, Soni NL et al. Safety and efficacy study of sub-micronized aerosols of sodium nitrite respiratory fluid against smoke induced oxidative stress and lung injuries. Int J Drug Dev Res 2012;4(2):358-68.

  • Patton JS, Byron PR. Inhaling medicines: delivering drugs to the body through the lungs. Nat Rev Drug Discov 2007;6:67-74.

  • Sultana S, Singh T, Ahmad FJ et al. Development of nano alpha ketoglutarate nebulization formulation and its pharmacokinetic and safety evaluation in healthy human volunteers for cyanide poisoning. Environ Toxicol Pharmacol 2011;31:436-42.

  • Sultana S, Ali R, Talegaonkar S et al. In vivo lung deposition and sub-acute inhalation toxicity studies of nano-sized alendronate sodium as an antidote for inhaled toxic substances in Sprague Dawley rats. Environ Toxicol Pharmacol 2013;36(2):636-47.

  • Kumar N, Soni S, Singh T et al. Development and optimization of gastro-retentive controlled release tablet of calciumdisodium edentate and its in vivo gamma scintigraphic evaluation. AAPS PharmSci Tech 2015;16(6):1270-80.

  • Mittal G, Kumar N, Rawat H et al. Development and clinical study of submicronic-atropine sulphate respiratory fluid as a novel organophosphorous poisoning antidote. Drug Deliv 2015;14:1-7.

  • Singh T, Mittal G, Singh AK et al. A new method for radiolabeling of alendronate with Tc-99m for bone scintigraphy. Ind J Nucl Med 2007;22:41-6.

  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248-54.

  • Henderson RF, Scott GG, Waide JJ. Source of alkaline phosphatase activity in epithelial lining fluid of normal and injured F344 rat lungs. Toxicol Appl Pharmacol 1995;57:170-4.

  • Kornberg A. Lactic dehydrogenase of muscle, in: S.P. Colowick, N.O. Kaplan (Eds.), Methods in Enzymology, Academic Press, New York, 1995:441-3.

  • Marklund S, Marklund G. Involvement of superoxide anion radical in the autoxidation of pyrogallol and a convenient assay of superoxide dismutase. Eur J Biochem 1974;47:469-74.

  • Claiborne A. Catalase activity, in: R.A. Greenwald (Ed.), CRC Handbook of Methods for Oxygen Radical Research. CRC Press, Boca Raton, 1985;1:283-4.

  • Wright JR, Colby HD, Miles PR. Cytosolic factors which affect microsomal lipid peroxidation in lung and liver. Arch Biochem Biophy 1981;206:296-304.

  • Carlberg I, Mannervik B. Glutathione level in rat brain. J Biol Chem 1975;250:4480-4575.

  • Sole PD, Pagliari G, Napolitano M et al. Cell count in bronchoalveolar lavage fluid: comparison between counting chamber and two automatic cell counters. J Bronch Interven Pulmonol 1996;3:192-5.

  • Mittal G, Kumar N, Rawat H et al. A radiometric study of factors affecting drug output of jet nebulizers. Indian J Pharm Sci 2010;72(1):31-8.

  • Costabel U, Guzman J. Bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulm Med 2001;7:255-61.

  • Reynolds HY. Bronchoalveolar lavage: perspective from the 11th BAL Conference, Monaldi. Arch Chest Dis 2008;69:91-3.


Abstract Views: 540

PDF Views: 0




  • Sub-Acute Inhalation Toxicity Study of Submicronic Alpha-Ketoglutarate Respiratory Formulation

Abstract Views: 540  |  PDF Views: 0

Authors

Rashid Ali
Department of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Delhi, India
Shaheen Sultana
Department of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Delhi, India
Sarwat Sultana
Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi, India
Amit Kumar
Department of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Delhi, India
Aseem Bhatnagar
Department of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Delhi, India
Gaurav Mittal
Department of Nuclear Medicine, Institute of Nuclear Medicine and Allied Sciences, Defence R&D Organization, Delhi, India

Abstract


Alpha Ketoglutaric Acid (AKG), one of two ketone derivatives of glutaric acid is an important biological compound that serves as a natural scavenger of ammonium ion, facilitating its conversion to amino acids and protein. AKG inhalation has potential therapeutic role against ammonia-induced structural and inflammatory changes in the lungs. In the present study sub-acute inhalation toxicity of a novel submicronic AKG respiratory formulation was evaluated in Sprague Dawley rats. Sub-acute inhalation toxicity study of novel AKG respiratory formulation at doses, 1, 3 and 5% was conducted as per Schedule-'Y' guidelines of ICMR, India. Hematological, serum biochemical and lung toxicity biomarkers in bronchoalveolar lavage (BAL) fluid were determined. Histopathological analysis of lung tissues and other vital organs was carried out to observe any microscopic changes. Hematology, serum biochemistry and lung toxicity biomarkers in BAL fluid revealed no adverse effects of AKG inhalation except for a slight increase in levels of BAL fluid protein. At autopsy, no histopathological changes in major vital organs, including the lungs were observed. The safety evaluation data suggest that aerosols of submicronic AKG respiratory formulation are safe for inhalation and could be developed as a potential therapeutic option against lung injuries induced through chemical toxicants such as ammonia.

Keywords


Industrial Chemicals, Alpha-Ketoglutaric Acid, Sub-Micronic Aerosols, Inhalation Toxicity, BAL Fluid Analysis.

References





DOI: https://doi.org/10.22506/ti%2F2016%2Fv23%2Fi2%2F146687