RATIONAL OF ANIMALS USE IN DRUG DISCOVERY

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4.3. Respiratory Disorders: The respiratory system acts as a portal into the human body for airborne materials, which may gain access via the administration of medicines or inadvertently during inhalation of ambient air (e.g. air pollution). Due to increased rate of death from respiratory disease than from coronary heart disease or non-respiratory cancer experiment on animal is gaining momentum for understanding the mechanisms of human lung biology, especially in injury and repair events. It is now a principal focus within the field of respiratory medicine (Berube,2011).The methyl-CpG binding protein 2 (Mecp2)genesencodes a nuclear transcriptional modulator highly expressed in post-mitotic neurons. Mutations of this gene cause a large spectrum of neurological disorders in humans. A set of sensorimotor tests and respiratory metabolism measurements was done in a longitudinal study of the Mecp2-null male mice. Motor functions and respiratory metabolism was found to be severally impaired. A detailed description of these gradual defects may help to identify their neuronal origin and to elaborate novel therapeutic strategies (Pratte et al., 2011).Rett syndrome is a neurological disorder caused by mutation of the X-linked MECP2 gene. Mice lacking functional Mecp2 show a spectrum of Rett syndrome-like signs, including disturbances in motor function and abnormal patterns of breathing, accompanied by structural defects in central motor areas and the brainstem. The absence of Mecp2 during brain development does not irreversibly compromise brain function.So MeCP2 does not play a pivotal role in brain development, but may instead be required to maintain full neurological function once development is complete (Robinson et al.,2012).For better understanding and progression of lung cancer an experiment was done on mice with knockout (KO) of G-protein coupled receptor 5A(Gprc 5a). It was found that lung tumor genesis in the Gprc5a-KO mouse model is augmented by NNK and gene expression changes induced by tobacco carcinogen(s) may be conserved between mouse and human lung epithelial cells (Fujimoto et al., 2010).New surface-active agents in waterproofing sprays were tested for acute inhalation toxicity using isolated perfused lung of rat. This pre-test prevented many deathsdue lung infection (Fischer et al., 2012)

4.4. Acquired Immunodeficiency Syndrome (AIDS): Patients with AIDS often develop cognitive and motor dysfunction that results from damage to synapses and death of neurons in brain regions such as the hippocampus and basal ganglia. This brain syndrome is called AIDS dementia or HIV encephalitis. Two neurotoxic HIV-1 proteins have been identified, the viral coat protein gp120 and the transcription regulator Tat. Each of these proteins can induce apoptosis of cultured neurons and can render neurons vulnerable to excitotoxicity and oxidative stress. Gp120 and Tat also cause neuronal dysfunction and death in rodentsin-vivo. Both gp120 and Tat disrupt neuronal calcium homeostasis. A better understanding of how gp120 and Tat disrupt neuronal calcium homeostasis may lead to the development of novel treatments for AIDS patients(Haughey and Mattson, 2002). At least in some neuronal cell types, gp120-induced neurotoxicity can be prevented by antagonists of L-type voltage-dependent calcium channels or by antagonists of N-methyl-D-aspartate (NMDA, a subtype of glutamate receptor). Degradation of endogenous glutamate also protects neurons from gp120-related neuronal injury, suggesting that gp120 and glutamate are both necessary for neuronal cell death as synergistic effectors(Lipton,1991). Clinically tolerated calcium channel antagonists and NMDA antagonists have potential for trials in humans with AIDS dementia in the near future(Lipton, 1994). Recent experimental evidence suggests that disturbance by HIV-1 results not only in neuronal injury and death but also in impairment of neurogenesis.Various methods are used to assess HIV burden in CNS (Kaul, 2008;Wiley et al., 1994). Various in-vivo and cell culture studies indicate that cells of neuroectodermal origin, particularly astrocytes, may also be infected by HIV-1. These cells restrict virus production and serve as reservoirs for HIV-1. Entry of HIV-1 into neuroectodermalcells is independent of the CD4 receptor, and a number of different cell-surface molecules have been implicated as alternate receptors of HIV-1. Future challenges will be to develop strategies to prevent HIV-1 spread in the brain, bolster intrinsic defense mechanisms of the brain and to elucidate the impact of long-term persistence of HIV-1 on CNS functions in individuals without AIDS(Kramer-Hammerleet al., 2005). In a prospectively clinically characterized population of acquired immunodeficiency syndrome (AIDS) patients we investigated the relationship between the clinical syndrome of HIV-associated dementia and the presence and relative quantity of immunocytochemical markers for HIV-1 (gp41 antibody), and for macrophages and microglia (HAM-56 antibody). Several nondemented patients showed abundant gp41 immunoreactivity, and some severely demented showed little to no gp41 immunoreactivity(Glasset al., 1995).

4.5. Cancer:Chemopreventive potential of curcumin against skin cancer was experimentally found using mice(Philips, 2013).Bone marrow stromal cells, precoated on the implant, accelerate the formation of new sinusoidal blood vessels with vascular integrity at the micro capillary level that enhances the recruitment hematopoietic progenitor cells to the site. This implantable construct can serve as a tool enabling the study of hematopoiesis(Lee et al.,2012). An animal model system was used for evaluating targeted ultrasound (US) contrast agents binding using adenoviral (Ad) vectors to modulate cellular receptor expression. An Ad vector encoding an extracellular hemagglutinin (HA) epitope tag and a green fluorescent protein (GFP) reporter was used to regulate receptor expression. A low and high receptor density (in breast cancer tumor bearing mice) was achieved by varying the Ad dose with a low plaque forming unit (PFU) on day 1 and high PFU on day 2 of experimentation(Saini et al., 2013).Liver tumour was induced in male C3H mice using diethylnitrosamine(DEN). Micewere routinely scanned by noninvasive magnetic resonance imaging (MRI) using a T2-weighted 3D sequence on regular intervals. Liver tumors became detectable in both experiments when they exceeded a diameter of less than 1 mm. This led to early detection of tumour onset hence it can be cured easily (Schimd et al., 2012).

4.6. Diabetes: Interleukin-6 and several of its family members but not other well-recognized insulin sensitizing agents were identified as potent hypoglycemic factors.This experimental system servesas a powerful and flexible in-vivo screening platform for identifying genes that modulate complex behavioral and metabolic phenotypes(Chen et al., 2012). An inbred rat model of diabetic embryopathy, was developed in which the offspring displays skeletal malformations (agnathia or micrognathia) when the mother is diabetic, and no malformations when she is not diabetic. Genes controlling the embryonic maldevelopment in a diabetic environment was found. The fetal outcome in inbred Sprague-Dawley rats (20% skeletal malformations in diabetic pregnancy) with that of inbred Wistar Furth rats, no skeletal malformations in diabetic pregnancy) was compared.Final conclusion was that the genetic involvement in rodent diabetic embryopathy is polygenic and predisposing for congenital malformations(Nordquist et al., 2012). The relation of production ghrelin with hyperphagiain diabetic state was found using spontaneous Torii Rat(Mifuneet al., 2012). Diabetes mellitus is a metabolic disorder associated with structural and functional alterations of various organ systems including the central nervous system. AGM(Agmatine)posttreatment reduced cerebral infarct size and neurological deficit expression in diabetic rats subjected to MCAO. The reduced infarct size was associated with a decrease in apoptosis and NOS(Nitric oxide synthase) expression(Cui et al., 2012).Mouse model of heart failure are commonly used today to understand the cardiac biology and convert the specific advancement into new drug(Brekenridge, 2010).

4.7. Thyroid Disorders: Effects of methimazole (a major anti-thyroid drug) administration to rat dams on the development of cerebellum of their pups has been investigated with morphological, morphometrical and functional procedures (Hasebeet al., 2008)

5. CONCLUSION
The use of animals is the heart of scientific and medical research.Their contribution especially in the field of medicine is immeasurable. Legislative rules have been prepared to give ethical treatment to them. To the best regard of animals, their experimentation has been abolished from the undergraduate syllabus. Care is taken to provide better ambience and least possible pain during testing. Sacrifice of their life is generally compromised forthe benefit of human society. Nowadays in-vitro methods are mostly used for research purpose but life process can only be revealed using whole animal system.

Table 1: Advances in basic research that depended on animals

Pre 20th Century

• Malaria parasite lifecycle (cattle, birds)

• Vaccine for smallpox (cattle)

• Vaccine for anthrax (sheep)

•  Early anaesthetics (cats, rabbits, dogs)

• Rabies vaccine (rabbits, dogs)

• Typhoid, cholera and plague vaccines (mice, rats)

• Treatment for beriberi (chickens)

1900’s

• Treatment for rickets (dogs)

• Corneal transplants (rabbits)

• Local anaesthetics (rabbits, dogs)

• Discovery of Vitamin C (guinea pigs)

1910’s

• Blood transfusions (dogs, guinea pigs, rabbits)

1920’s

• Insulin (dogs, rabbits, mice)

• Canine distemper vaccine (dogs)

1930’s

• Modern anaesthetics (rats, rabbits, dogs, cats, monkeys)

• Tetanus vaccine (horses,  guinea pigs)

• Diphtheria vaccine (guinea pigs, rabbits, horses, monkeys)

• Anticoagulants (rabbits, guinea pigs, mice, dogs)

1940’s

• Penicillin and streptomycin (mice)

• Discovery of rhesus factor (monkeys)

• Kidney dialysis (guinea pigs, rabbits, dogs, monkeys)

• Whooping cough vaccine (mice, rabbits)

• Heart-lung machine for open heart surgery (dogs)

1950’s

• Polio vaccine (mice, monkeys)

• Hip replacement surgery (dogs, sheep, goats)

• Kidney transplants (dogs)

• Cardiac pacemakers (dogs)

• Medicines for high blood pressure (rats, mice, dogs)

• Replacement heart valves (dogs)

• Chlorpromazine and other psychiatric medicines (rats, rabbits, monkeys)

1960’s

• Heart transplants (dogs)

• Coronary bypass operations (dogs)

• German measles vaccine (monkeys)

• MMR vaccine (monkeys)

• Antidepressants and antipsychotics (rats, guinea pigs, rabbits)

1970’s

• CT scanning for improved diagnosis (pigs)

• Chemotherapy for leukaemia (mice)

• Medicines to treat ulcers (rats, dogs)

• Inhaled asthma medication (guinea pigs, rabbits)

1980’s

• MRI scanning for improved diagnosis (rabbits, pigs)

• Prenatal corticosteroids improving survival of premature babies (sheep, rabbits, cattle)

• Treatment for river blindness (rodents, cattle)

• Life support systems for premature babies (monkeys)

• Medicines to control transplant rejection (mice, rabbits, dogs, monkeys)

• Hepatitis B vaccines (monkeys)

• Medicines to treat viral diseases (many species)

• Treatment for leprosy (armadillos, monkeys)

1990’s

• Combined therapy for HIV infection (mice, monkeys)

• Meningitis vaccines (mice)

• Better medicines for depression (rats)

• Medicines for breast and prostate cancer (mice, rats, dogs)

• Medicines for type 2 diabetes (mice)

• New medicines for asthma (guinea pigs, monkeys)

•  Statins to lower cholesterol (rabbits)

2000’s

• Deep brain stimulation for Parkinson’s Disease (monkeys)

• Monoclonal antibodies for adult leukaemia, lymphoma (mice)

• Cervical cancer vaccine (rabbits, cattle)

• Clotting agent from milk (goats)

• Bird flu vaccine (chickens and ferrets)

2010’s

• Stem cells for spinal cord, heart repair (mice, rats)

• Oral or inhaled insulin for type 1diabetes (mice)

• Angiogenesis inhibitors for cancer, blindness (mice)

• Gene therapy for muscular dystrophy, cystic fibrosis, sickle cell disease (mice)

• Alzheimer’s vaccine (mice)

• Malaria vaccine (mice, monkeys)

Source: Research Defence Society & Coalition for Medical Progress, 2007.

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