Review on Non-Clinical Studies

Abstract

Non-Clinical testing is done throughout all phases of the drug development in order to survey the safety profile, pharmacokinetic and toxicokinetic (PK/TK) characteristics of therapeutic substances. If the Non-Clinical and Pre-clinical studies improvement is performed well, it can enhance the chances of success in the clinical development phases. Techniques for the Non-Clinical advancement of products follow general regulatory guidelines, but are also designed on a case-by-case premise as per the specific medication.

Pre-clinical studies, carcinogenicity, Genotoxicity, Pharmacology, Local tolerance

Introduction

Pre-clinical trials and clinical trials are the techniques carried out by researchers to examine drugs and medical devices of their safety and efficacy. Pre-clinical trial is a laboratory test of a new drug or a new device that is typically done on animal subjects to check, if the expected treatment practically works and if it is safe to test on humans [1-26].

Steps Involved in the Pre-Clinical Trial Process

1. Get an idea for drug target.
2. Bioassay has to be developed. A Bioassay is a live system that can be used to measure the drug effect. It might be a culture of cells or organs or an animal.
3. Assay method carried out on particular drug and screening the results safely.
4. Effective doses and toxic doses should be established.
5. Application is made to the Food and Drug Administration (FDA) as an Investigational New Drug (IND) [25-46].

Reasons behind the Non-Clinical Studies in Animals before Administrated to Man

1. To check the pharmacological effects are same in man as in animal.
2. Toxic effects in species will predict adverse effects in man.
3. Giving high doses in animals improve predictability to man.
4. Risk assessment can be made by differentiation of toxic doses in test species with predicted therapeutic dose in man [47-62].

Reasons behind the Non-Clinical Studies in Animals before Administrated to Man

1. To check the pharmacological effects are same in man as in animal.
2. Toxic effects in species will predict adverse effects in man.
3. Giving high doses in animals improve predictability to man.
4. Risk assessment can be made by differentiation of toxic doses in test species with predicted therapeutic dose in man [47-62].

According to Good Laboratory Practices and Non Clinical Studies explain about

1. Safety Pharmacology
2. Pharmacokinetics
3. Pharmacodynamics
4. General Toxicology
5. Local Tolerance
6. Genotoxicity
7. Carcinogenicity
8. Reproductive Toxicology

Safety Pharmacology

Safety pharmacology study uses the basic principles of pharmacology in a regulatory-driven process to find out the risk/benefit assessment. Safety pharmacology mainly plays an important role in pharmacodynamic/pharmacokinetic relationship of a drug’s adverse effects [63-79]. These methods are used for the detection of an adverse effect liability, projection of the information into safety margin computation and finally clinical safety monitoring. Safety pharmacology is the discipline that looks to anticipate, whether a therapeutic substance (in the most sense of the word) if administered to human (or animal) populations is liable to be discovered dangerous and its professional mandate is to prevent such an occurrence.

Safety Pharmacology provides early information to clinicians regarding risk assessment in terms of product viability. A Therapeutic window for acute dosing in man and a set of anticipated side-effects for the clinicians involved in Phase I design. Safety pharmacology study embraces the principles of physiology, pharmacology and toxicology.

Pharmacokinetics

Pharmacokinetic evaluation in Non-Clinical studies should be comprehensive enough to ensure that compounds do not fail in the clinic.

Pharmacodynamics

Pre-clinical pharmacodynamics and safety studies are important to improve drug development outcomes and to predict human responses for that particular drug. These studies are helpful to predict the safety and efficacy of the drug [80-87].

General Toxicology

Pharmaceutical and biopharmaceutical companies use Pre-clinical toxicology studies to evaluate the safety of new medication applicants. The pressure to finish these studies accurately, quickly, furthermore, financially, while holding fast to FDA and universal regulatory requirement is more prominent than ever [85-93]. With the developing diversity of products in development, assessing the safety of a compound has turned out to be progressively.

Local Tolerance

The estimation of local tolerance must be conducted in laboratory studies prior to human exposure to drug substance or product. The main purpose of these studies is to discover about the medical products i.e., both active substance and placebo are tolerated at sites in the body, which may interact with the drug as a result of its administration in clinical use. The testing procedure ought to be such that any mechanical effects of administration or purely physico chemical activities of the drug can be distinguished from toxicological or pharmacodynamic studies [94].

Tests Involved in Local Tolerance Study are

1. Tolerance testing at the site of administration
2. Systemic toxicity testing

Genotoxicity

Genotoxicity is the assessment of the harmful impacts of chemical or physical agents on the hereditary material and related genetic processes of living cells. Genotoxicity provides the nature of chemical substances that damage to collapse the genetic information within a cell which leads to mutations and then causes cancer [95,96]. Genotoxin is a chemical substance that can cause DNA/RNA or chromosomal damage and finally malignant transformation i.e., cancer.

Genotoxicity screening tests carried out on molecular level, gene level and chromosomal level.

Carcinogenicity

As per the regulatory approval process, all the new drugs should be tested for their carcinogenic potential. The safety testing for the carcinogenetic potential of a pharmaceutical substance is the two years rodent bioassay in rats and mice. Carcinogenic agents may include Chemical (mutagenic compounds), physical (radiation, asbestos) and biological (oncogenic viruses like human T-leukemia virus) [97].

Carcinogenicity studies should be performed for all medications that are required to be clinically utilized for over six months and in addition medications [98,99].

Reproductive Toxicology

Reproductive toxicology study explains with the effects of chemicals on reproductive and neuroendocrine systems.

References

1. Jain A. Curcumin Inhibit PhIP-Induced Carcinogenicity by Regulating Expression of Nrf2 and FOXO Targets, and BRCA-1 and P16 Expression in Breast Epithelial Cells. J Carcinog Mutagen. 2015;6:236.
2. Kakehashi A, et al.Threshold in Carcinogenicity of Genotoxic Carcinogens. J Carcinog Mutagen.2014;S3:006.
3. Johnson DE. Estimating Human Cancer Risk from Rodent Carcinogenicity Studies: The Changing Paradigm for Pharmaceuticals. J Drug Metab Toxicol.2012;3:e114.
4. Vasyunina Ye A, et al. Estimation of Toxicity and Genotoxicity of Water, Bottom Sediments and Submerged Macrophyte Elodea canadensis of the Yenisei River in the Presence or Absence of Americium-241. J Environ Anal Toxicol.2016;6:389.
5. Bakare AA, et al. Genotoxicity of Titanium Dioxide Nanoparticles using the Mouse Bone Marrow Micronucleus and Sperm Morphology Assays. J PollutEff Cont.2016;4:156.
6. Dar AM, et al. DNA Binding, Cleavage Activity, Molecular Docking, Cytotoxicity and Genotoxicity Studies of Newly Synthesized Copper Based Metal Complexes. Pharm Anal Acta.2016;7:464.
7. Araujo SD, et al. Genotoxicity and Mutagenicity Assays for Selection of Chemical Compounds with Therapeutic Potential: A Short Commentary. Biochem Anal Biochem.2016;4:208.
8. Girgis SM, et al. Potential Protective Effect of Costusspeciosus or its Nanoparticles on Streptozotocin-induced Genotoxicity and Histopathological Alterations in Rats. J Nutr Food Sci.2015;S3:002.
9. Starodub NF. Genotoxicity: Modern Instrumental Approaches for its Control in Environmental Objects. J BiosensBioelectron.2015;6:169.
10. Yadav AS andJaggi S.Buccal Micronucleus Cytome Assay- A Biomarker of Genotoxicity. J MolBiomarkDiagn.2015;6:236.
11. Osborne AE, et al. Palm Fruit Juice Mitigates AZT Mitochondrial Genotoxicity and Dose-Dependent Cytotoxicity. J AIDS Clin Res.2014;5:400.
12. Ghosh I, et al. Evaluation of the Protective Effect of Hibiscus sabdariffa L. Calyx (Malvaceae) Extract on Arsenic Induced Genotoxicity in Mice and Analysis of its Antioxidant Properties. Biol Med (Aligarh).2014;6:218.
13. Larramendy ML, et al. Genotoxicity and Cytotoxicity Exerted by Pesticides in Different Biotic Matrices-An Overview of More Than a Decade of Experimental Evaluation. J Environ Anal Toxicol.2014;4:225.
14. Lapchak PA, et al. J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox™ Safety and Genotoxicity Analysis. J NeurolNeurophysiol.2013;4:158.
15. Mishra RP and Mishra S. In Vitro Assessment of Genotoxicity of Some Ayurvedic Drugs in Human Lymphocytes by Using Single Cell Gel Electrophoresis. J Drug Metab Toxicol.2013;4:139.
16. Diab KAE, et al. Assessment of Genotoxicity and Histopathological Changes Induced by Polyethylene Glycol (PEG6000) in Male Mice. J CytolHistol.2013;3:153.
17. Hassan GM andMazher KHM. Genotoxicity and Histopathological Studies on the Liver, Kidney and Lymphocytes of Male Rats Fed on Diet Containing Waste Fat Released from Chicken During Grilling Process. J CytolHistol.2011;2:111.
18. Stephen BD and Gareth H. An Inductive Approximation to the Solution of Systems of Nonlinear Ordinary Differential Equations in Pharmacokinetics-Pharmacodynamics. J TheorComput Sci.2014;1:119.
19. Connors KP, et al. Optimizing Antibiotic Pharmacodynamics for Clinical Practice.Pharmaceut Anal Acta.2013;4:214.
20. Slaughter RL. Welcome to the Special Edition of Recent Advances in Pharmacokinetics and Pharmacodynamics. AdvPharmacoepidem Drug Safety.2013;S1:008.
21. Cadwell JJS. The Hollow Fiber Infection Model for Antimicrobial Pharmacodynamics and Pharmacokinetics. AdvPharmacoepidem Drug Safety.2013;S1:007.
22. Alice Nichols I, et al. Pharmacokinetics, Pharmacodynamics, and Safety of Desvenlafaxine, a Serotonin-Norepinephrine Reuptake Inhibitor. J BioequivAvailab.2013;5:022-030.
23. Cha R, et al. Antimicrobial Pharmacokinetics and Pharmacodynamics in the Treatment of Nosocomial Gram-negative Infections. AdvPharmacoepidem Drug Safety.2012;S1:005.
24. Sunkara G, et al. Assessment of Ethnic Differences in the Pharmacokinetics and Pharmacodynamics of Valsartan. J BioequivAvailab.2010;2:120-124.
25. Stauber AJ, et al.Non-Clinical Safety Evaluation of a Transforming Growth Factor ß Receptor I Kinase Inhibitor in Fischer 344 Rats and Beagle Dogs. J Clin Pract.2014;4:196.
26. Schattner A. Are Physicians' Decisions Affected by Multiple Non-Clinical Factors?. Intern Med.2014;4:152.
27. Whitmire M, et al. LC-MS/ MS Bioanalysis Method Development, Validation, and Sample Analysis: Points to Consider When Conducting Non-Clinical and Clinical Studies in Accordance with Current Regulatory Guidances. J Anal Bioanal Tech.2011;S4:001.
28. Michael Conn P. et al. G protein-coupled receptor trafficking in health and Disease: lessons learned to prepare for therapeutic mutant rescue in vivo. Pharmacol Rev. 2007;59:225–250.
29. Dagmar Ringe and Gregory A Petsko. What are pharmacological chaperones and why are they interesting? Journal of Biology. 2009;8:80.
30. Ulloa-Aguirre A. et al. Pharmacoperones: Targeting Therapeutics Toward Diseases Caused by Protein Misfolding. Rev InvesClin. 2015;67:15-9.
31. Michael Conn P, et al. “Pharmacoperone”: What’s in a word? Pharmacol Res 2014;83:1–2.
32. UlloaAA and Michael CP. Pharmacoperones: a new therapeutic approach for diseases caused by misfolded G protein-coupled receptors. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery. 2011;5:13-24.
33. Soto C, et al. ß-Sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis: implication for Alzheimer therapy. Nat Med. 1998;4:822–826.
34. Sigurdsson EM, et al. In vivo reversal of amyloid-lesions in rat brain. J NeuropatholExp Neurol.2000;59: 11–17.
35. Fan JQ, et al. Accelerated transport and maturation of lysosomal -1 galactosidaseA in Fabrylymphoblasts by an enzyme inhibitor. Nat Med. 1999;5:112–115.
36. Parenti G, et al. New strategies for the treatment of lysosomal storage diseases (review). Int J Mol Med. 2013;31:11-20.
37. Parenti G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol Med. 2009;1:268-79.
38. Bernier V. et al. Pharmacologic chaperones as a potential treatment for X-linked nephrogenic diabetes insipidus. J Am SocNephrol. 2006;17:232-43.
39. Neelima N and Sudhakar M. Phytochemical investigation and evaluation of Nephroprotective activity of aerial parts of Bauhinia purpurea. Int J Appl Basic Med Res. 2012;1:97-102.
40. Gupta D, et al. In vitro Antidiabetic activity of stem bark of Bauhinia purpurea Linn. Der Pharmacia Lettre. 2012;4:614-619.
41. Sharma S and Kumar A. Tribal uses of medicinal plants of rajashthan:Kachnar. Int. J. Life Sc. Pharma. Res. 2012;2:2250-0480.
42. Kar A and Panda S.Ayurvedic therapies for thyroid dysfunctions in Mishra LC Scientific Basis for Ayurvedic Therapies. CRC Press, Boca Raton, FL, London.2004.
43. Tahiliani P and Kar A. The combined effects of Trigonella and Allium extracts in the regulation of hyperthyroidism in rats. Phytomedicine. 2003;10:665–668.
44. Kumar T and Chandrashekar KS. Bauhinia purpureaLinn:A Review of its Ethnobotany, Phytochemical and Pharmacological Profile. Research Journal of Medicinal Plants. 2011;5:420-431.
45. Panda S and Kar A. Withaniasomnifera and Bauhinia purpurea in the regulation of circulating thyroid hormone concentrations in female mice.J Ethnopharmacol. 1999;67:233–239.
46. Divakar MC. Plant drug evaluation: Aguide. CD remedies. 2002.
47. Ganong WF. The thyroid gland. In: Review of Medical Physiology, Appleton and Lange, East Norwalk (CT). 1995;90–305.
48. Nunes MT. Hormôniostiroideanos: Mecanismodeaçãoeimportânciabiológica. Arq Bras EndocrinolMetabol. 2003;47:639-643.
49. Shi YB, et al. Complex regulation of thyroid hormone action: Multiple opportunities for pharmacological intervention. Pharmacol Therap. 2002;94:235-251
50. RijnberkA, et al. Endocrine diseases in dogs and cats: similarities and differences with endocrine diseases in humans. Growth Horm IGF Res. 2003;13:S158-S164.
51. Ketzis JK, et al. Evaluation of efficacy expectations for novel and non-chemical helminth control strategies in ruminants. Veterinary Parasitology. 2006;139:321-335.
52. Koleckar V, et al. Condensed and hydrolysable tannins as antioxidants influencing the health. Mini Reviews in Medicinal Chemistry.2008;8:436-447.
53. Chung KT, et al. Tannins and human health: A review. CriticalReviewsinFood ScienceandNutrition. 1998;38:421-464.
54. Clauss M, et al. The influence of dietary tannin supplementation on digestive performance in captive black rhinoceros (Dicerosbicornis). J AnimPhysiolAnim Nutr. 2007;91:449-458.
55. Nyarko AA and Addy ME. Effects of aqueous extract of Adeniacissampeloides on blood pressure and serum analyte of hypertensive patients. Phytotherapy Research. 1990;4:25-28.
56. Okwu DE. Phytochemicals, vitamins and mineral contents of two Nigeria medicinal plants. International Int. J Mol Med Adv Sci. 2005;1:375-381.
57. Kam PCA and Liew S. Traditional Chinese herbal medicine and anaesthesia. Anaesthesia. 2002;57:1083-1089.
58. Stray F. The natural guide to medicinal herbs and plants. Tiger Books International, London. 1998.
59. Heinrich M, et al. Fundamentals of Pharmacognosy and Phytotherapy. Churchill Livingstone, Elsevier Science Limited, UK. 2004.
60. Gurib-Fakim A. Medicinal plants: Traditions of yesterday and drugs of tomorrow. Molecular Aspects of Medicine. 2006;26:1-93.
61. Kretovich VL. Principles of Plant Biochemistry. First English Edition, Pergamon Press, Oxford. 1966.
62. Dudani S and Ramachandra TV. Pteridophytes of Western Ghats. First Indian Biodiversity Congress. 2010.
63. Ballhorn DJ et al. Cyanogenesis of wild lima bean (Phaseoluslunatus L.) is an efficient direct defence in nature. Plant Signaling and Behavior 2009;4:735-745.
64. Schafer H and Wink M. Medicinally important secondary metabolites in recombinant microorganisms or plants: progress in alkaloid biosynthesis. Biotechnol J. 2009;4:1684-1703.
65. Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomorrow. Molecular Aspects of Medicine. 2006;27:1-93.
66. Hershberger JW. The purpose of ethnobotany. Botany Gazette. 1896;31:146-154.
67. Das S. Usefulness of pteridophytes in India with special reference to medicine and conservation. Journal of Economic and Taxonomic Botany. 2003;27:7-16.
68. Rout SD et al. Ethnomedicinal studies on some pteridophytes of Similipal Biosphere Reserve, Orissa, India. Int J Med Med Sci. 2009;1:192-197.
69. Singh HB. Potential medicinal pteridophytes of India and their chemical constituents. Journal of Economic and Taxonomic Botany 1999;23:63-77.
70. Dhawan BN, et al. Screening of Indian plants for biological activity.Indian J Exp Biol. 1977;15:208-219.
71. Kumar S, et al. Traditional medicinal plants curing diabetes: A promise for today and tomorrow. Asian JTra Med. 2012;7:178-188.
72. Asolkar LV, etal. Glossary of Indian medicinal plants with active principles - Part I. CSIR, New Delhi. 1992.
73. Meyboom RH, et al. Pharmacovigilance in perspective. Drug Safety. 1999;2:429-447.
74. Kulkarni RD. Reporting system for rare side effects of non-narcotic analgesics in India: Problems and opportunities. Med Toxicol. 1986;1:110-113.
75. Protocol for National Pharmacovigilance Program. CDSCO, Ministry of Health and Family Welfare, Government of India. 2004.
76. PharmacovigilanceProgramme of India.Guidance Document for Spontaneous Adverse Drug Reaction Reporting. 2013;1:1-69.
77. Olsson S. Pharmacovigilance training with focus on India. Indian J Pharmacol. 2008;40:SS28-SS30.
78. Novotny J and Novotny M. Adverse drug reactions to antibiotics and major antibiotic drug interactions. Gen PhysiolBiophys. 1999;18:126-139.
79. Nair MD. Pharmacovigilance: the need for a formal system in India. 2001.
80. Pradhan A, et al. Suicide: Attempts Methods and Causes in Cases Brought for Autopsy in Bpkihs, Dharan. J Forensic Res.2013;3:166.
81. Heikal TM, et al. Protective Effect of a Synthetic Antioxidant “Acetyl Gallate Derivative” Against Dimethoate Induced DNA Damage and Oxidant/Antioxidant Status in Male Rats. J Environ Anal Toxicol.2012;2:155.
82. Coppola M andMondola R.Bromo-DragonFly: Chemistry, Pharmacology and Toxicology of a Benzodifuran Derivative Producing LSD-Like Effects. J Addict Res Ther.2012;3:133.
83. Shams N, et al. Metal-Induced Oxidative Stress in Egyptian Women with Breast Cancer. J Clinic Toxicol.2012;2:141.
84. Liu F andGuo L.Toxicogenomics in the Evolution of Toxicology. J Pharmacogenomics Pharmacoproteomics.2012;3: e123.
85. Ding WX. Autophagy in Toxicology: Defense against Xenobiotics. J Drug Metab Toxicol.2012;3:e108.
86. Brown K, et al. Aging: The Mitochondrial Connection. J Clin ExpPathol.2012;S4:003.
87. McIntyre IM and Anderson DT. Postmortem Fentanyl Concentrations: A Review. J Forensic Res.2012;3:157.
88. Niko B andSnezhana RB. Unique Case with Seizures after Prolonged Use of Camphor Crème in Elderly Patient. J Clinic Toxicol.2012;2:126.
89. Sánchez-Bayo F and Ortega R. Special issue on Toxicology of Pesticides. J Environ Anal Toxicol.2012;S4:e001.
90. Heikal TM, et al.Cyromazine and Chlorpyrifos Induced Renal Toxicity in Rats: The Ameliorating Effects of Green Tea Extract. J Environ Anal Toxicol.2012;2:146.
91. Tair-Abbaci K andGarric J. Histological Study of Gonadogenesis in Potamopyrgusantipodarum and Valvatapiscinalis. J CytolHistol.2012;3:140.
92. Deabes MM, et al. Protective Effects of Lactobacillus rhamnosus GG on Aflatoxins- Induced Toxicities in Male Albino Mice. J Environment Analytic Toxicol.2012;2:132.
93. El-Desouky TA, et al. Effect of Ozone Gas on Degradation of Aflatoxin B1 and AspergillusFlavus Fungal. J Environment Analytic Toxicol.2012;2:128.
94. Bugelski PJ, et al. Differential Effects of Long-lived Erythropoietin Receptor Agonists in Rats. Pharm Anal Acta.2012;2:133.
95. Manzetti S. Research and Environmental Protection of Norwegian fjords: A Standstill. J Marine Sci Res Development.2012;S2:001.
96. Jasmine G andYogeshwer S. Prognostic Factors of Male Breast Cancer: Proteomic Approaches for Early Detection and Treatment. J Proteomics Bioinform.2008;1:112-127.
97. Nicolson TJ, et al. Sex Differences in FDA Regulated Products: Research for the Future. J Drug Metab Toxicol.2010;1:103.
98. Malik P, et al. Biomedical Nanotoxicology and Concerns with Environment: A Prospective Approach for Merger with Green Chemistry Enabled Physicochemical Characterization. J MicrobBiochem Technol.2014;S9:001.
99. Abbassy A, et al. Impact of Oxidative Stress and Lipid Peroxidation Induced by Lambda-cyhalothrin on P450 in Male Rats: The Ameliorating Effect of Zinc. J Environ Anal Toxicol.2014;4:218.