Cost Analysis - Paper Answers

CharlesRiver xBiohuntressReportJune262020_1 xBiohuntressReportJune262020 x

I have done literature review on anticancer drugs ( blood cancer research cells ). Now my part is to do cost analysis of each models (zebrafish and mouse models) like 1. how many animals required to do research 2. long term/short term testing 3. how much cost 4. how much time (timeline) 5. what experiments to be done to check Bioavailability , toxicity and efficacy of these models the basic concept is this report going to help to my professor the estimation of his research basically NOTE: Please have a look into

https://www.cyprotex.com/admepk/in-vitro-permeability/caco-2-permeability/

https://www.altasciences.com/clinical-research-services/bioavailability

Bio-Analytical

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Charles River Laboratories | Every Step of the Way. Please follow instructions and consult all the attached materials

What Charles River is doing to Validate Anti-cancer Drugs

a) CRO, an acronym of contract research organizations

A syndicate that offers sustenance to the medical device, pharmaceuticals as well as for biotechnology industries via a mode of research services that gets outsourced on a contract mode.

b) What can be done through a CRO like Charles River to validate an anti-cancer drug (Bio Huntress) in their mouse myeloma/lymphoma/leukemia model?

1. The Charles River laboratory goes to the extent of acquiring contest that costs up to $38 million.

2. The laboratory acquires the Germany contest that specializes mostly in offering innovative services for oncology to create a peak tier oncology assortment for validating therapies resulting from new cancer.

3. Charles River lab attempts to carry out oncology as well as the immune-oncology cell that is based on assays.

4. The laboratory focuses on its oncology besieged compounds by testing the efficacy of its compound basing on its reliability, cost-effective means besides rapid in vitro.

5. The laboratories range of immune-oncology as well as oncology cells centred assays are inclusive of:

i). The role of PDX and TME

a. To make sure therapies test any effect on the actual patient materials

b. Therapies too test the interaction with human immunity

6. The laboratory carries out translational Patient-derived xenograft assays

Description of the experiment

7. Charles River laboratory adopts the strategy of creating a translation podium specifically for Immuno oncology.

a) Available Patented cell lines include pairs that are matched like;

i. Cell lines

ii. Corresponding PDX

8. Due to the difficulty resulting from the tumour microenvironment, the Charles River laboratory needs to come up with in vitro assays

9. Investigating through a multicellular phenotypic assessment facilitates a proper way to examine the way the element responses with the platform application

10. The company’s advantage to have a wide variety of malignant tumour lines facilitates with a broad range that can test fit alternatives.

11. The laboratory evaluates the classical xenograft assortment regularly to access gain a better response on the care standards to facilitate permutation of studies mode.

12. The company’s experience with the discovery of the oncology drug distances all the levels from the objective identification to the studies of IND.

13. Charles River laboratory tries to use the most operational mixture of tools accessible to detect the promising components.

14. The company combines effort with other partners to come up with studies via the method of selection from a wide variety of tumour prototypes that are well characterized.

15. Charles River company plays a crucial role in profiling the agent in a range of tumour categories

16. The company provides with a wide variety of histotypes which is inclusive of;

a) Cancer of the breast

b) Colon cancer

c) Cancer of the lungs

d) Non little cell cancer of the lungs

e) Tumor models that have a high medical requirement like;

i. Cancer of the ovary

ii. Leukemia cancer

iii. Prostate cancer

iv. Lymphoma cancer

17. An expert team from the Charles River Company attempts to magnify data in the tumour prototype essence as well as presenting a robust portfolio at the industry symposium.

18. The company’s compendium offers access to a more all-inclusive assortment of tumour models that are well established to use in the initial stages of oncology research

The type of animal is a AML mouse

19. The company carries out the development of dispersed AML mouse prototype to evaluate therapeutic processes of immune spot check inhibitors employing bioluminescence imaging.

20. Researchers have gone to the extent of developing a dispersed AML syndrome model to examine responses that result from the immune turnpike inhibitors like

i. PD-1

ii. PD-L1

iii. CTLA-4

21. Charles River expertise team of researchers attempts to monitor oncometabolite as well as immunomodulators in a direct means in the micro tumour surrounding.

22. Scientists, as well as researchers, work diligently towards hastening the research of cancer as well as accelerating efforts towards achieving anticancer drug progress.

23. Charles River laboratory initiates a tumour prototype anthology that eases up oncology research.

24. The company carries on within Vivo cancer models which are inclusive of;

i. Cachexia prototype

ii. Syngeneic model

iii. Solo mouse tribunals

iv. Orthotopic prototype

v. PDX model

vi. Cell line xenograft prototype applying to both rats as well as rats

25. Charles River laboratory adopts an advanced strategy of the innovative Zebrafish PDX also known as ZTX tm model that makes it possible to trajectory metastasis found in vivo

i. Zebrafish PDX model attempts to match the mouse PDX prototype by making it possible to examine responses resulting from drugs in a more nonrodent in vivo strategy together with dispatch time besides in vitro

Amount of drug commonly usually

26. Researchers from Charles River Company attempt to report any resulting evidence of ZTX tm models correctness when it comes to predicting anti-tumour reactions to most non-cell lung cancer drugs.

i). ZTX tm prototype offers a subtle strategy when determining the risks that result from metastatic as well as the anti-metastatic effectiveness of non-small cell lung cancer significant drugs.

Running Head: IN VIVO MODELS FOR DEVELOPING ANTICANCER DRUGS

IN VIVO MODELS FOR DEVELOPING ANTICANCER DRUGS 2

INVIVO MODELS FOR DEVELOPING ANTICANCER DRUGS

RELEVANCE AND COST EFFECTIVENESS

Cancer has increasingly become a troublesome disease and many people and countries have suffered as a result of this disease. To a great extent, rodent animal models have been used to offer an understanding of the developmental biology of cancer cells and how hosts respond to the transformed cells. Unfortunately, rodent animal models have not helped develop treatments as cancer continues to cause a high rate of death in the western hemisphere (MacRae & Peterson, 2015, p.723, para.5). The effects of the diseases not only affect the diseased individual but also their friends and family since they have to offer emotional support to the individual and also help in their activities of daily living when one becomes weak during the last stages of cancer.

There is also a financial impact that comes with the disease since treatment is costly and people in poor economies are overwhelmed to the point it leaves them poorer. Due to these effects, great investment has been put in developing anticancer drugs as well as the best treatment approaches to handle the disease. Cancer researchers spent a great time studying how this dreadful disease develops in the human body and how it affects the immune system in efforts to discover treatment techniques.

To discover drugs and improve diagnosis and cellular therapy, cancer researchers use both in vitro and in vivo models where the former takes outside the living organism and the latter occurs within the body of the organism. In vivo models are preferred since they offer a more detailed and practical understanding. Rodent animal models have been in great use in helping to understand the developmental biology of carcinogenesis. However, the disease continues to be a threat and there is a need to understand the disease better and this has necessitated the rise in the use of zebrafish models to develop anticancer drugs due to their increased features and benefits compared to murine models. This essay will focus on in vivo models of developing anticancer drugs with a key focus on blood cancers.

1. Blood Cancers.

Blood cancers affect how blood cells are produced and how they function and limit them from performing their functions at optimal levels. most blood cancers emanate from the bone marrow which is where the production of blood takes place. The spongy tissue inside the bones is greatly affected by cancer and this leads to the production of abnormal blood cells which then grow out of control (Zhao et al., 2015, p.8, para.4). Blood cancers as suggested by the name refers to types of cancers that affect the blood, lymphatic system, and bone marrow. Blood cancers are also known as hematologic cancers and are characterized by abnormal blood cells that grow out of control and affect the normal functioning of the white blood cells responsible for fighting infections.

Symptoms of blood cancer depend on the type of cancer by the general symptoms include recurring infection due to low immunity, fatigue caused by low hemoglobin, increased weight loss, backache, swollen nodes, itchy skin, and bone pain (Davis et al., 2014, p. 731, para.1). Some of the causes of blood cancer include human T-virus, radiation, myelodysplastic syndrome, genetics, and chemical contact. The cure rate in blood cancer is high where a patient can become from the disease through the right medication and treatment. The cure rate however depends on the type of cancer. The known and leading blood cancers are leukemia (blood), lymphoma (lymphatic system), and myeloma (bone marrow).

a. Leukemia.

Leukemia is common in adults and children and develops when the cell regulatory processes considered normal lead to uncontrolled proliferation of hematopoietic stem cells found within the bone marrow. Leukemia occurs in the bone marrow and blood and is characterized by the production of many abnormal white blood cells which cannot fight infection and reduces the ability of the bone marrow to produce platelets and red blood cells. The known types of leukemia mostly encountered by primary care physicians include chronic myelogenous, acute myelogenous, acute lymphoblastic, and chronic lymphocytic (Davis et al., 2014, p. 731, para.2). In the United States, the age-adjusted incidence rate of leukemia is 12.8 percent per 100,000 people every year where the most affected people are white males, and the risk of getting the disease increases with age (Davis et al., 2014, p. 731, para.2). Numerous genetic syndromes such as neurofibromatosis and Down’s syndrome are pointed as the leading causes of acute myelogenous and acute lymphoblastic in children.

Exposure to ionizing radiation is also a risk factor for leukemia especially when people are exposed to medical radiation and atomic bombs. Environmental and occupational exposure to benzene, a chemical released during the combustion of coal and petrol and in plastics and paints is also a risk factor for acute myelogenous leukemia (Davis et al., 2014, p. 731, para.3).

Acute myelogenous leukemia in adults accounts for 80 percent of acute leukemia cases. On the other hand, cases of chronic leukemia subtypes occur majorly in adults where half of the patients with chronic lymphocytic leukemia get the diagnosis with leukocytosis (Davis et al., 2014, p. 732, para.4). Diagnosis of leukemia starts with a blood count where patients with chronic myelogenous leukemia have a higher white blood cells count in comparison to those with acute lymphoblastic leukemia or acute myelogenous leukemia. Diagnosis may also include the measuring of liver function tests, creatinine levels, coagulation studies, and serum electrolytes (Davis et al., 2014, p. 733, para.4).

The clonal expansion of lymphocytes in the peripheral blood is a characteristic of chronic lymphocytic leukemia, and this can be confirmed through immunophenotyping. The diagnosis of leukemia is confirmed by a hematologist-oncologist and any positive response leads to the commencement of treatment which may include monoclonal antibodies, radiation, chemotherapy, or hematopoietic stem cell transplantation (Davis et al., 2014, p. 735, para.5). The subtype of leukemia is what determines the treatment to be used as well as comorbid conditions, age of the patient, and molecular and cytogenetic findings. A patient is described to be in the active stage when conditions of progressive lymphadenopathy, anemia, thrombocytopenia, thrombocytosis, and splenomegaly get worse.

Leukemias are classified according to the cell of origin and the rate in which they grow. Therefore, the leukemias can be lymphoblastic or lymphocytic (Lymphoid origin), myeloid or myelogenous (myeloid origin), chronic, or acute (Baeten & Jong, 2018, p.1, para.1). Zebrafish model is being increasingly used to study the development of leukemia and possible development of anticancer drugs due to their numerous advantages which include ease of transgenesis, specialized lines which allow transplantation into immunodeficient and syngeneic animals, precise imaging, rapid fecundity and development, genome editing, and genomic similarity to humans (Baeten & Jong, 2018, p.1, para.2). There are a large number of knockouts, inbred, transgenic, and other specialized lines in the zebrafish community over the years to be applied in various conditions. Leukemia models are of several lines and allow tumors to be transplanted without it being necessary to pre-transplant immune ablation.

Zebrafish leukemia models of lymphoid origin are B-Cell Acute lymphoblastic leukemia (B-ALL), and T-Cell lymphoblastic leukemia (T-AL). the oncogene c-Myc is the most affected gene pathways and associated with most cancers related to lymphoid leukemia (Baeten & Jong, 2018, p.3, para.5). The first T-ALL model was analyzed, and it was confirmed that tumor cells obtained from clonal expansion of transformed T lymphocyte precursors had their origin in the thymus. B-ALL was discovered in the rag2: cMyc fish which provided a chance to study B-ALL in an accessible model (Baeten & Jong, 2018, p.6, para.1). Acute myeloid leukemia (AML) and myeloproliferative neoplasms were developed following the success of zebrafish ALL models. This was done through the creation of transgenic lines that could express oncogenic fusion mutations and genes found in patients with myeloproliferative neoplasms and acute myeloid leukemia.

b. Multiple Myeloma.

Multiple myeloma causes interference of the plasma cells in the blood and reduces the ability of antibodies to protect the body from being attacked by pathogens, resulting in a weak body. Myeloma (Multiple Myeloma, MM) affects the plasma cells of the blood and affects how antibodies necessary to keep the body’s immune system from being produced normally, making the body weak and easy to be infected (Letrado et al., 2018, p.6050, para.2). Multiple myeloma is described as a systemic malignant disease. Nonfunctional intact immunoglobulin chains are a characteristic of multiple myeloma due to the uncontrolled proliferation of monoclonal plasma cells (Gerecke et al., 2016, p.470, para.1). Globally, multiple myeloma forms 1 percent of all cancers and more than 10 percent of hematological neoplasms. Smoldering (asymptomatic) myeloma is a transitional phase that leads to symptomatic multiple myeloma and is common with monoclonal gammopathy of uncertain significance (MGUS). There is no need for treatment of smoldering myeloma although therapeutic measures are necessary in case of certain risk factors (Gerecke et al., 2016, p.471, para.1). Systemic therapy is offered for patients who have clonal plasma cell damage or where any organ in their body is threatened.

Randomized controlled trials using modern therapy have shown that the median survival rate in multiple myeloma is estimated to be six years. The treatment of multiple myeloma takes place in 3-4 cycles of induction therapy before the harvest of stem cell which is followed by induction therapy to delay autologous stem cell transplantation (ASCT) or frontline ASCT (Rajkumar, 2018, p.1096, para.1). Other treatments for multiple myeloma are lenalidomide-low dose dexamethasone, bortezomib-containing regimens, and carfilzomib-lenalidomide-dexamethasone (Rajkumar, 2018, p.1096). The chances of relapsing for patients with multiple myeloma are high and the treatment of the relapse is affected by the aggressiveness of the relapse, timing of the relapse, performance status, and response to past therapy.

The 5T model has been a great achievement in understanding the pathogenesis of multiple myeloma, although there have been efforts to overcome the limitations presented by genetically murine myeloma. The specific effect of a specific drug is determined by mouse survival and tumor volume (Rossi et al., 2018, p.20120, para.2). In the SCID-hu model, the recipient mouse is implanted with a human fetal bone chip. In the SCID-rab model, rabbit bones replace the human fetal bone where the human disease is produced once the multiple myeloma cells and engrafted into the rabbit (Rossi et al., 2018, p.20122, para.3). Xenograft models of human myeloma in mice, genetically engineered models, and immunodeficient and immunocompetent mouse myeloma models are used as preclinical murine models of multiple myeloma (Lwin et al., 2016, p.5, para.1).

c. Lymphoma.

This type of cancer affects the lymphatic system in humans and hinders the system from making immunity cells and the removal of excess fluids. During lymphoma, there is abnormal production of lymphocytes which turns them into lymphoma cells that are incapable of fighting infections. The fourth most common hematologic malignancy in man is the B-cell lymphomas as well as the common Hodgkin’s lymphoma. The follicular lymphoma, Burkitt’s lymphoma, diffuse large B-cell lymphoma, and marginal zone lymphoma are the most common types of B-cell lymphomas (Kohnken et la., 2017, p.8, para.1). Through murine models, it has been possible to study tumor microenvironment, biology, response mechanisms to therapy. Follicular lymphoma grows slowly with generally favorable response to therapy but there is increased resistance. Peripheral T-cell lymphoma is an aggressive and rare non-Hodgkin lymphoma and has a poor response to chemotherapeutic treatment. Cutaneous lymphocytes are heterogeneous and majorly damage the skin (Kohnken et la., 2017, p.8, para.6). Lymphoma affects the body’s lymphatic system and prevents how this system makes immune cells and emitting excess fluids. Lymphoma causes the production of abnormal lymphocytes, turning them into lymphoma cells that cannot fight infection (Katt et al., 2016, p.6). According to the Leukemia and Lymphoma Society, it is estimated that more than I million people in the United States are living with or are in remission from Myeloma, Lymphoma, or leukemia.

2. Current Treatments Available.

The treatment of blood cancers is a process that needs physicians and doctors to be cautious to ensure that the causing factors are identified and eliminated to lower the chances of cancer recurring. The current treatments available have not managed to completely eradicate the various cancers and result in managing the symptoms to increase the survival rate of patients. Treatments in the present that are considered in treating cancer include biological therapy, chemotherapy, blood transfusion, radiation therapy, and bone marrow transplantation (Blackburn & Langenau, 2014, p. 759, para.1). Bone marrow transplantation and blood transfusion aim to replace the affected bone marrow and blood with another that is healthy but faces the danger of rejection by the recipient’s body which could put them at great health risk (Blackburn & Langenau, 2014, p.757, para.2). Chemotherapy as a cancer treatment involves administering medication to reduce the impact of cancer cells, but this is at the expense of the patient’s health since the medication is too strong and may cause other problems. Zebrafish have a great potential to be used in the future to address the problems of chemotherapy medication since it is suitable for various pharmacological techniques (Langheinrich, 2003, p.911, para.11).

Radiation therapy focuses on destroying cancer cells through radiation. Radiation therapy has the limitations of causing damage to surrounding tissues, failure to kill tumor cells not visible in imaging scans, and failure to kill cancer cells within tumors (Chakraborty & Rahman, 2012, p.2, para.3). There is a challenge in targeting cancer stem cells which would help to get rid of cancer cells and this is contributed to by the inadequate research in this area (Chakraborty & Rahman, 2012, p.2, para3). The problem with radiation is that it damages the neighboring tissues which may leave the patient suffering from injuries as well as challenges with killing tumor cells that may not be visible through imaging scans, and failure of radiation to kill cells within tumors.

These treatments are important in that they help the patients to manage pain as caused by cancer as well as other symptoms that reduce the quality of life of patients. Some of the treatments have side effects like diarrhea, loss of appetite, constipation, swelling, delirium, and thrombocytopenia that further increase the discomfort of the patients. The current treatments for cancer are invasive to the human body and also greatly affect the health of individuals who are already sick, making cancer a greatly dreaded disease (Mione & Trede, 2010, p.518, para.3). Also, the treatments are expensive for many people and quite often most families are drained financially, leading to poverty especially in developing countries. There is thus the need for new treatments which will be less invasive, less impact on health, and cheaper to allow affordability in treatment since cancer is a disease for both the poor and rich.

Such problems can be avoided through research since drugs have similar effects on zebrafish just as humans in terms of anemia, hematopoiesis, physiology, and cardiovascular disorders (Huiting et al., 2015. P.723, para.4). Also, such problems can be improved through the use of the zebrafish whose transparent nature allows a good angle to examine the responses of the host (Mione & Trede, 2010, p.518, para.4). Zebrafish remains to be an instrumental animal model which has been used in drug discovery as well as discovering new compounds, toxicity, and response (Letrado et al., 2018, p.6052, para.2).

3. Evaluating New Drugs.

The shortcomings of current treatments necessitate the need to develop new drugs that will be more efficient in dealing with cancer and yield better results. Cancer researchers are continuously researching new drugs for treating known blood cancers. In vitro tumor models have been used I cancer research and act as low-cost screening models for drug therapies, but cancer continues to recur due to unchecked metastasis. Cancer researchers have intensively used in vitro tumor models to perform research on cancer and have been considered as low-cost screening models to develop therapies.

The different in vitro models include tumor-micro vessel, spheroid-based, hybrid, and trans well-based models. The advantages of the trans well-based models are that they are applied in comparing the metastatic potential of cells, increased throughput, low-cost assays, and ease in implementation (Katt et al., 2016, p.2, para.5). The advantages of spheroid-based models are that there is the mass production of culture, increased throughput, more efficiency, the possibility of coculture with defined cell types, progressing perfusion, and speedy spheroid formation (MacRae & Peterson, 2015, p. 6). The advantages of hybrid tumor models include the possibility of tracking cells in real-time, outgrowth is mimicked in the surrounding tissues, tumor heterogeneity is maintained, and patient-specific assays are allowed (Katt et la., 2016, p.8). The demerits of in vitro models include failure in the control of uniformity concerning size and composition, a contradiction in data from migration assays and invasion, unpredictability, tumor complexity is absent, and issues in the collection cells for analysis (Mione & Trede, 2010, p.520, para.4).

The various in vitro models have disadvantages like conflicting data from invasion and migration assays, failure to control uniformity in terms of composition and size, problems in collecting cells to be analyzed, absence of tumor complexity, and unpredictability in random vessel network.

Source: Therasnotics

a. In vitro model

Such limitations create the need to use an animal model such as a mouse and zebrafish. Both mouse and zebrafish models allow in vivo research which makes research within an organism possible to help cancer researchers to observe the effects of cancer on animals. When compared in terms of efficiency, zebrafish is a better animal model since its transparency and rapid development allow researchers to make better observations. The zebrafish is able to enhance multiple myeloma cell growth and offer in-depth knowledge on cell microenvironment to understand treatment (Lin et al, 2016, p.252, para.3). There have been large-scale drug screens that have been completed in vitro using human cell lines, but in vivo studies have been considered an accurate representation of how drugs respond (Blackburn & Langenau, 2014, p.759, para.1).

4. Animal Models.

BioPharma needs to carry out animal experimentation to test a drug to a certain disease. Animal experimentation allows the research to make critical observations of the effect of the drug on the animal as well as the disease being tested. Animal experimentation allows the researcher to introduce cancerous tissue to the embryo of an animal and observe how cancer grows and its effect on the animal (Pringle et al., 2020). The fact that in vitro models do not allow cancer researchers to view cancer cells within an organism to better understand how they affect the body, it is vital that BioPharma conduct animal experimentation, hence the zebrafish and murine in vivo animal models.

Mouse models for lymphoma, leukemia, and myeloma have been extensively used to test how the various cancers affect living organisms. The benefits of mouse models include the easy availability of mice, they have a short generation period which allows the research to take less time, the low maintenance cost of the mice, and the possibility of easy genetic manipulation of the animals (Lin et al., 2016, p.252, para2). The limitations of mouse models include problems in collecting blood due to the small body size, difficulties in vivo imaging, and research mice could be inbred which fails to capture the right genetic variation in humans. Through in vivo animal models, the researchers manage to may incredible observations that allow them to understand how cancer affects the body as well as how the various anticancer drugs being tested attack the cancerous cells and the host’s body (Pringle et al., 2020, p.6).

Due to the challenges in the mouse models, there is a need for other models which necessitates the use of zebrafish. Zebrafish can be used to study leukemia, lymphoma, and myeloma just like mouse models (Langheinrich, 2003, p.907). The benefits of using zebrafish to develop anticancer drugs are due to their ability to recapitulate different human cancers to identify and validate drugs, the advantage of in vivo imaging, rapid development, high numbers of progeny, easy absorption of compounds, lower maintenance costs, increased sharing of genetic and molecular homologies with humans, fewer legal restrictions, and increased accessibility of zebrafish embryos (Huiting et al., 2015, p.2, para.2). Limitations in the use of zebrafish models are that their physiology is not identical to that of humans, most genes may occur in two copies causing problems in determining functional roles, and problems in drug diffusion.

Source: ScienceDirect.

b. In vivo animal model

Just like mice, zebrafish animal models can be used to perform research on myeloma, lymphoma, and leukemia. Zebrafish has increasingly been used as a model organism in various areas of developmental biology and molecular genetics of vertebrates (Langheinrich, 2003, p.904, para.2). There are numerous benefits to derive from the use of zebrafish in developing anticancer drugs due to their unique features of an increased number of progeny, the rapid rate of development, they are quick to absorb compounds, the possibility of in vivo imaging, zebrafish share more molecular and genetic homologies with man, cost of maintenance is low, easy accessibility of zebrafish, and less legal restrictions. Challenges in the use of zebrafish include difficulties in determining the roles of genes since they may occur in two copies, differences in physiology compared to humans, and drug diffusion is slower (Zhao et al., 2015, p.4). Regardless of the few challenges, zebrafish stand out as the best in the development of anticancer drugs.

Conclusion

The development of the right anticancer drugs is of great importance to ensure that patients will be able to receive the right care so they can go back to their normal lives. cancer researchers are continuously studying the various types of cancer to understand how they affect the human body as well as how they respond to treatment and therapy. Cancer continues to be a deadly disease in the world and many people lose their lives every year. The emotional and financial impact of cancer is immense considering the investments in research and receiving the care. Animal models offer a great chance through which anticancer drugs can be developed to increase the level of treatment. mouse models have been extensively used to understand tumor biology and microenvironment. In addition to murine models, zebrafish models have grown in popularity due to their critical features that promote in vivo research to enhance understanding of the disease with the living organism. More research should continue to be performed to increase the chances of success in defeating cancer.

5. Cost – Efficiency of Particular Model

a. Cost – efficiency of Zebrafish Model on Blood Cancer Research Cells

The Zebrafish are small and warm water pond fish. Mostly, they are popular in-home aquariums since they are easy to take care of. However, they are vertebrates with same organs that of humans. Besides, they have transparent embryos that establishes outside the womb (Aksoy et al, 2019). These Zebrafish are always popular when it comes to biomedical research model. Apart from of having the same immune system as that of human beings, these fish are also found in fresh water. It is an aspect which makes them relatively easy and cost – efficient to keep. In addition, they breed at higher rate an aspect which makes them to be ideal for the multi- national general research.

The advantages of Zebrafish over the other research model are as follows

· The maintenance costs are far much less than even 1/1000th maintenance cost of mice

· It is discovered that Zebrafish are social and small and can be contained 70 of them in a standard tank. It is vital economic aspect compared with only 5 mice in one cage.

· The Zebrafish are substantial less expensive as one goes for only 6.5 cents in one day. It is more economical compared to 90cents per day per mice.

· The Zebrafish repair and fully regrow their functional organs which includes heart, kidney, spinal cord and retina in comparison with other research models.

· The Zebrafish are known in reproducing at higher rate as it reproduces about 9,000 offspring (Aksoy et al, 2019). It is a relatively higher rate compared to that of mice which produces only 300 offspring in its life time.

· The zebrafish embryos are much transparent an aspect which allows the direct and non – invasive observation for development of organs. For the case of other research models such as rats and mice, their observations must be done under microscope observation.

b. Zebrafish as critical model for Blood Cancer Research Cells

It is be discovered that the spending of healthcare is out of control. With Zebrafish, there is likelihood of offering low – cost but higher volume approach of determining drugs of next level of development. The increase of funding for research of Zebrafish has a probability of accelerating the pace at which learning is done on the drug candidates. Besides, it will speed up the rate at which these drugs get into development pipeline and finally get the patients who are need of them at required time (Zhang et al, 2017). Through that quick response of Zebrafish, the cost of research is greatly reduced which makes the whole process of blood cancer treatment to be cost – effective. It is an aspect which has made the Zebrafish to be vital research model in treating blood cancer.

c. Impacts of Zebrafish model on Drug Discovery of Blood Cancer Research Cells

The Zebrafish are termed as the game- changer for the drug discovery and development since it leads to optimal treatment of disease. A perfect example is that when a human tumor specimen is being planted in Zebrafish, within five days the needed required results will be out (Zhang et al, 2017). The information relating to the drug metastasis and sensitivity will be known in that span. The next step will be selecting the type of therapy to be selected and the treatment will begin at the immediate effects. It is a scenario which will save on time and funds of doing the extensive research and hence Zebrafish model becomes cost – efficient.

D. Lessons learnt from Zebrafish Model on Blood Cancer Research Cells

Due to the high reproduction rate of the Zebrafish, a lot of discoveries are done with easy due to readily availability of specimens. It is a fact that researchers have learned a lot of amazing things with these specimens about organ development. For example, they have found new genes which causes human disease and the new therapies which can widely use to treat patients with disease. It has been easy to compare the human genomes with that of Zebrafish which has led to discoveries various previously unknown genes. These unknow genes have been difficult to discover since are the rare forms of the muscular dystrophy. Besides, they involved complicated genetic pathways of the human embryo development and heart physiology (Rauwerda et al, 2017). These tests have been severally done with the use of Zebrafish research models. These tests are currently tested to assess their viability when it comes to future treatments of blood cancer. It is an aspect which can be said to be cost – efficient as it saves the costs of producing human specimens for the test. Furthermore, it aids a lot in saving time needed for those complicated researches.

e. Cost- efficiency of Mouse model on Blood Cancer Research Cells

The mouse model is among the leading mammalian model for studying the human disease and the human health. One of the main aspects which is making it a favorite is because the economic choice. Besides, it breeds so well as the scientists have tremendous knowledge on mouse physiology, anatomy and its genes over more than 100 years (Perlman, 2016). Mostly important, it is easy to manipulate the genes of the mouse since mice are among the first mammalian species having their genes modified with the use of molecular tools.

The ability of manipulating the mouse genome is the rationale why this research model is relevant. Apart from that aspect of being easily manipulated, they are being termed as the cost – efficiency on study of human disease with many other reasons as listed below

· Biologically, mice are similar to the human beings and they get ill of many human diseases for the similar genetic reasons. Therefore, researching on mice is less expensive compared to researching on human beings or other big mammals hence cost – efficient.

· Mice are genetically manipulated when it comes to mimic virtual human disease or condition (Hugenholtz & de Vos, 2018). With the current sequencing together with genomic engineering technologies, the detailed and precise mutations which underlies human conditions can be easily introduced into mice. With the use mice model research, there is higher probability of yielding more precise results and extremely useful disease research information.

· Mice can be easily inbred to produce genetically identical or similar strains with no cots at all. The uniformity allows for more precise and repeatable demonstrations since the process of yielding genetically identical strains is costless. A perfect example which has adopted this strategy is the Jackson Laboratory which now maintains at least 9000 genetically defined mice strains.

· The mice have accelerated or faster lifespan as one mouse year is equaling approximately 30 years of human beings’ years (Hugenholtz & de Vos, 2018). Thus, the entire cycle of life can be easily studied with either two or three years which saves a lot of time and cash to be used in research.

· The concept of mice is well understood since they have been in use in biomedical research for almost a century. Therefore, it takes less time to capture the required results which is an aspect of cost – efficient.

· Due to their small size in nature and reproducing at higher rate, mice are termed to be cost effective and efficient tool for research. Besides, they are easy to handle which also makes them easy to transport in various places of research.

f. Overall Critical concepts of mouse model on Blood Cancer Research Cells

Through the mice research model; several diseases can be modelled by altering specific gene central structures to the normal biological process. It is a scenario that has made it possible for a thousand of diseases to be researched, and their colonies produced genetically (Hugenholtz & de Vos, 2018). It is also discovered that mice are small with a short generation time, making specimens readily available and reducing space management. It is also noted that the time factor is saved when using the mice’s sample compared to any other large mammal exhibiting the same characteristics with human beings. It can be therefore said that mice are the selection model not just because of exhibiting similar genomic levels with humans but also cost-effective. Being able to produce a considerable number of specimens for testing at a short period makes them be categorized as a cost-efficient research drug testing tool.

g. Comparison of Zebrafish model with Mouse model on Blood Cancer Research Cells

The maintenance cost of Zebrafish is far much less compared with that of mouse model. Actually, it is 1/1000th that of mice model. The small the size the small economical organism it is. For example, a standard tank usually contains 70 specimens while one cage can carry maximum of 5 mice. The economical aspect in terms of space makes it to be more suitable. Another concept of comparison is about reproduction rate. Zebrafish produces 9000 offspring in lifetime compared with mouse which produces maximum of 300 offspring (Aksoy et al, 2019). Therefore, using Zebrafish makes provides researchers with more specimen hence it is termed to be cost – efficient. Lastly Zebrafish embryos are transparent compared with that of mouse model. The Zebrafish embryos do not need inspection under microscope as that of mouse means that it is cost – efficient in relation to time.

6. Animal studies on FDA guidance

FDA has developed the guidance document to assist industries to do design evaluation strategies for and reporting the suitability of animal studies over various conditions. Animal studies involve different cardiovascular devices such as intracardiac devices results of animal studies assessed by these devices in a typical way provide evidence of the device safety and the potential performance when used applied in a living system. The guidance intends to come up with suitable practices for the approach, conducting and presenting the data of animals used (Kurki, 2019). Besides, it guides to show evidence that the device used is adequately safe for the early human experience. The guidance traces its references on various pre-existing monitoring requirements involving concepts of animal care. Also, the FDA keeps the Memorandum of understanding (MOU) with the department of National Institutes of Health. The main concern of MOU is to address the common areas of monitoring practice under which the processes of animal studies should be carried.

A. Recommendations of FDA guidance

On the matter of animal studies, there are several FDA recommendations that should follow general principles in establishing the strategies to be used. These recommendations include the following.

· There should following of Good Laboratory Practices (GLP) for all animal studies which involves cardiovascular devices submitted to Agency

· The animal model in selection for the study should be accepted generally for the study band device type. It is necessary to have a considerable amount of scientific evidence to show the animal model has utility for study of a product class.

· There should full demonstration of sufficient safety, which includes the performance together with handling to capture a higher level of efficacy of the device.

· There should be in vivo settings to provide FDA with initial valuations of how devices interact with the biological system (Golding, Khurana & Zaitseva, 2018). Besides, the settings should reveal how the biological system may affect the device, for example, the corrosion of device and structural deformities.

· There should high observations of excellent practices of the refinement, the reduction and the replacement using the most updated standards of humane veterinary care.

b. Biopharma requirements on animal testing.

Animal testing forms an integral part of pharmaceutical research. Presently, before the new compound or a drug enters the clinical trial on humans, it must be tested on non – human trials. The pharmaceutical firms must get that proof of drug being “safe” before human trials are being implemented (Macdonald, 2019). The animals are much necessary and used in biopharma testing for various reasons. One of the reasons is to determine whether the drug is toxic. The test is carried by investigating how the compound is broken and its effects on the subject system.

During this testing, there are some requirements which need to be considered. It is essential to discover that what happens in the subject or animal model may not happen the same to human beings. Animal testing has some room of limitations about their results. However, currently, only those animals who exhibit almost similar characteristics with human beings can give nearly accurate information. It is an aspect which raises a scenario of how many animals the scientists must kill in the name of research.

It is required that the drug’s metabolic profile be tested using chemosynthetic livers. Through this testing, a fraction of the time is taken to test an animal model and yield a more detailed result. However, the Food and Drug Administration must give regulatory approval (Pridgeon, 2018). Besides, the necessary technology is vital to investigate how various drugs taken at equal times might interact and their results. It is a scenario that helps assess the time response time factor, which in turn suggests the recovery period.

Since the drug makers are required to prove the tolerability and safety of drugs before the trials, there is a need to replace animal testing with other testing methods. Some of the developed alternatives include 3D human cells and tissue models, which are designed to mimic the functioning of the human organ (Pridgeon, 2018). These alternatives are termed to be more effective since they do not hinder drug development and are beneficial to animals. However, there are some disorders that cannot be addressed using alternatives, and animal testing is needed. Researchers, together with pharma industries, have made some progress to reduce animal testing, although it cannot be eliminated. However, there is a requirement or projection that as the research is being done, it will reach a situation whereby animals will be irrelevant for pharma research and development.

Experiments that Biopharma need to know while Validating Anticancer Drugs Testing

Introduction

Biopharma is one of the subsets in the pharmaceutical industry. In pharmaceutical companies, production of medicines takes place for managing or curing diseases in human beings as well as protecting them from infections. The main products in the industry involve drugs that are used for human illnesses. However, other products such as livestock feed supplements, vitamins and health products for animals are for the pharmaceutical industry (Dora et al., 2017). In the subset of biopharma medicines and drug products, they are manufactured in biological methods such as yeast, bacteria and mammalian cells. The drugs are different from the synthesized pharmaceuticals such as blood, vaccine, blood components, tissues, somatic cells, gene therapies, living medicine and also therapy proteins for therapeutic or Vivo diagnostic purposes. The essay evaluates the experiments that biopharma requires to know while validating anticancer drug testing.

In the process of testing the drugs animals are sometimes used. They examine the produced biologics vaccines, medicines, and other produced medical devices to determine the safety of the product before using in human bodies (Jain et al., 2018). In biologics and drugs, the primary focus on the animals is the drug nature, the chemistry and the effects as well as the possibility and extends of body damage. The significant animals’ measures done in animal testing involves, the quantity of a drug or biologic that the animal absorbs in the blood, the breaking down of the medical product in the animal’s body, the level of toxicity of the product its components when broken down and finally the period of excreting the product and its components from the body (Lawrence et al., 2016).

In the aspects of the medical devices, animal testing focusing on evaluating its ability to function while in the body with the loving tissues without causing damage to them. Most of the tools are biocompatible with human tissues such as ceramic, and therefore they do not require animal testing. However, new materials intended to be introduced for human use are exposed to biocompatible testing in animals. All the test done in an animal causes effects in blood cells.

Non-animal testing is not a scientific recommended or alternative testing from animal testing, making animal testing highly used. FDA is now supporting measures to reduce the level of animal testing (Jones et al., 2016). It is, therefore, researching and carrying development plans of alternative animal testing to reduce the exposure of blood cells to cancer. The use of animal testing in medical products that are regulated by FDA, the manufactured are required to consider FDA’s regulations through Good Laboratory Practices for Nonclinical Laboratory studies (Mukherji et al., 2017). Furthermore, the FDA encourages independent animal care, and use committees use in matters of laboratory tests on animals.

In the early stages of the drug, research FDA plays little role. In the act, the FDA does not issue authority to companies to develop new medicines or responsibility. The significant part of the FDA comes after the manufacture of the drug. It decides if the drug is safe for use in human bodies by reviewing tests submitted by scientists of the drug developer (Mukherji et al., 2017). FDA considers the human testing results, and then gives a verdict of the drug whether can be introduced in the market, the label and the wording about precautions, side effects or directions of use.

Type of animal experiments to meet FDA standards

Animal Rule

FDA passed the regulation in 2002, approving some drugs based on human safety testing same as animal effectiveness testing (Lawrence et al., 2016). The rule enables the FDA to be able to approve products for critical or life-threatening conditions mostly caused by exposure of lethal or permanent impacting deadly biological, radiological, nuclear substances and chemicals. The rule is applicable in cases such as a biological threat to human existence but not permitting clinical testing, and the other argument is if the biological risk is hazardous to extend that exposing clinical trial to the patient will be termed unethical. For instance blood cancer that affects blood cells, bone marrow. (Mukherji et al., 2017).

The animal rule by FDA is with two fundamental goals, first is the demand for evidence, and the second is the need for patient’s wellbeing (Akseli et al., 2016). The product being investigated is tested in healthy adult patients for assurance of drug safety to regulators. In contrast, for its effectiveness, the product is proved by the use of live animals which are infected with the agent. Ensures that blood cells are not affected to reduce cases of blood cells ability to work typically.

Animal Rule History

FDA has approved a few products by application of the rule. The first product to be supported using the government was Levaquin in 2012 April (Mukherji et al., 2017). In the same year, December FDA made the first approval foe biologic product using the animal rule. The product was inhalation anthrax. Also, in 2013, botulism antitoxin has approved a product manufactured by Cangene. The newest approval was in 2005 for treating patients with plaque a bacterial infection recognized for killing a third of the human population in the 1300s (Jain et al., 2018). Commonly referred to as Black Death. It aims at protecting blood cell alterations.

Bioavailability Experiment

Bioavailability involves the percentage of the administered drug that can be found in the systematic circulation (Dora et al., 2017). Medication that is administered intravenously has a bioavailability of 100% however of it administered via routes the bioavailability of always lower than for administering intravenously as a result of first metabolism and internal endothelium absorption. The main aim of bioavailability is to ensure that patients with poor absorption are dosed as required (Lawrence et al., 2016). Experimenting bioavailability ensures the forecasted efficacy is met by the drug user none unless the drug has a narrow therapeutic window. Oral administration of anti-cancer drugs is affected inadequate bioavailability of the drugs due to wide variability, which has adverse effects on blood cancer treatment. The bioavailability of the blood cancer can be improved. However, biopharma companies need to invest much on drug solubility experiments.

Efficacy Experiment

Efficacy refers to the maximum responses that can be achieved from a pharmaceutical drug which is undergoing research or the capacity to cause therapeutic effects it could be a small quantity of the drug (Jain et al., 2018). The goal of efficacy is to demonstrate whether the drug possesses health benefits over control or other interventions when applied in an ideal situation. The maximum response of the drug is reduced when the efficacy is low. The experiments on animals help to access the effectiveness before approving the drug. Biopharma companies developing blood cancer drugs need to carry operations aiming at improving the efficacy of the drugs to have positive impacts in blood cells and curb blood cancer in the patients.

Toxicity Experiment

Toxicity of drug in experiment refers to a type experiment that measures extend to which the drug could be harmful to the patients. Toxicity is due to the accumulation of the drug in the bloodstream, which causes adverse effects to the body. It may be contributed by issuing high doses to a patient making it plenty in the blood, or it could be the failure of the liver or the kidney (Dora et al., 2017). The organs are responsible for removing the blood from the body. Thus, their failure allows the blood to accumulate. The experiments on anticancer drugs need to study the impact of the drug on the blood cells when taken in overdose or not excreted. The biopharma companies should ensure the effect of high anticancer drug level in the blood has fewer impacts on blood cells. Moreover, more experiment on the effectiveness of drug elimination from the body is vital.

Lenalidomide drug

It was introduced in 2004 and a product of Celgene. The drug was initially made for the treatment of multiple myeloma with thalidomide accepted as the therapeutic modality (Storti et al., 2017). FDA approved the medication in 2005 December; however, it has evidenced haematological disorders of myelodysplastic syndromes (Mateos et al., 2018). It’s also called Revlimid and is an immunomodulatory drug.

The drug is said to be rapidly absorbed by oral administration to the patient. Lenalidomide has three hours as the half-life with its excretion facilitated by urine. The initial dosage is recommended to be adjusted to patients with either moderate or severe renal impairment. Comparing patients with severe renal impairment and average impairment, the one with an acute renal impairment will have a decrease in drug clearance of 66% – 75% which is a significant figure (Storti et al., 2017). Moreover, the patient’s o hemodialysis from experience shows 80% decrease in clearance of the drug from the blood compared to persons with typical renal impairment. Lenalidomide has not altered the absorption rate by food that the patient’s feeds. The drug is partially removed by hemodialysis despite having a component of 30% as protein (Mateos et al., 2019). Therefore, the drug has high bioavailability, has less toxicity and efficacy. Thalidomide was created to improve the efficiency of lenalidomide. Accumulations of the drug do not occur following multiple doses. These make the drug possess fewer effects on cells in the blood.

Lenalidomide is not broken down much in the body, thus having limited metabolism. The elimination is purely renal. For instance, upon admission of a single dose containing 25mg to healthy humans for the experiment, 90% of the drug will be excreted through urine while 4% of the donation will get out the body in the faeces (Mateos et al., 2018). In the standard of healthy humans, it will take three hours while in MDS patients, it takes three to five hours. Relating to toxicity, the most adverse situations relate to blood and lymphatic system disorders, administrative site conditions, general disorders, gastrointestinal disorders and skin combined with subcutaneous tissue disorders. However, by caring more experiment of the drug, adverse effects in blood cells can be reduced and help immune in blood.

Melphalan

Melphalan is alkylating nitrogen mustard used as an antineoplastic in the form of Levo isomer-melphalan and another kind of isomers (Mateos et al., 2019). The drug is toxic to the bone marrow but has less vesicant achievement. It is also a potential carcinogen drug. The drug is primarily made for relaxing treatment of multiple myeloma even for palliation of non-resectable epithelial carcinoma of the ovaries. The drug has frequently been used in chemotherapy, especially during surgery for rectifying breasts cancer. The associated conditions also include amyloidosis, and related therapy is cell transplant therapies for allogeneic stem cell (Mukherji et al., 2017).

The absorption of melphalan is limited, and it’s variable for a range between 25% and 89% when using oral dose which is associated with its protein binding of 60-90% which has irreversible bound (Dora et al., 2017). It has adverse effects on blood cells and makes the treatment ineffective. Melphalan is inactively metabolized, its components split to mono and dihydroxy within the body. The elimination of the drug is poor through urine or faeces. For a 24 hours experiment on the urine as the means of excreting melphalan, it was found only 10% of the drug was eliminated from the body via renal clearance (Hansen et al., 2019). Inadequate recreation means makes the drug to accumulate in the blood and change the normal functioning of the blood cells. Melanin has a half-life of one hour and thirty minutes in the human blood system.

About toxicity melphalan, it causes vomiting, diarrhoea, bleeding of the intestinal tract, ulceration of mouth while the supreme toxicity is the suppression of bone marrow as demonstrated in rats. However, studies have shown that melphalan has significant effects on blood cells and components. For patient prescribed to use melphalan as an anticancer drug, may experience low blood counts, could have a temporary decrease of platelets, white blood cells and red blood cells. (Hansen et al., 2019).

Bortezomib

Bortezomib is an anti-cancer proteasome inhibitor used in treating multiple myeloma together with cell lymphoma (Mateos et al., 2018). Numerous actions are involved in therapy which includes bortezomib. FDA approved the drug in 2003 as the first anti-cancer proteasome inhibitor. Despite approval by FDA, the drug is under investigations. Trials are still underway to investigate bortezomib’s efficacy in therapeutic situations such as solid tumours, leukaemia, and rheumatoid arthritis and myasthenia gravis.

Experiments have shown than bortezomib is cytotoxic substance to many types of cancer cells in vitro. The anti-cancer proteasome inhibitor leads to a delay in tumour growth in vivo, which are in the form of nonclinical models with multiple myeloma included (Mateos et al., 2018). The inhibitor is reversible. The absorption of bortezomib is high in all types of administrations. It spreads across the body after admission to all parts at an average rate. The inhibitor in the body aims to remove the boronic acid from its parent compound as the major metabolic pathway.

The main route of eliminating bortezomib is through renal (urine and faeces) and hepatic means. However, the half-life for the elimination from the body is between 40 and 193 hours for 1mg multiple dosing. For 1.3g various dosage, the half-life is 76-108 hours (Storti et al., 2017). In aspects of toxicity, the experiment in mouse was conducted using intraperitoneal administration for a continuous dose. The dose to be administered to a particular patient is individualized to avoid patients’ overdose. Upon overdose, the symptoms present include thrombocytopenia and severe hypotension. The overdose does not have antidote care is essential not to overdose patients. However, bortezomib has side effects on blood cells, and it reduces the number of red blood cells in the blood, causing anaemia and cause low cell count. Studies show that the efficacy of bortezomib makes it a useful agent in the body to minimize instances of therapy and toxicity.

Docetaxel

Docetaxel medication id, also known as Taxotere. It is a type of chemotherapy medication for treating a variety of cancer types. Docetaxel can be independently for treatments or alongside other treatments for chemotherapy (Jones et al., 2016). Some of the types of cancer it treats could be, breast cancer, stomach cancer, prostate cancer and head and neck cancer. The means of administering to the body is by injection into a vein but slow. Taxotere was approved in 1995, although it was patented in 1986 (Hansen et al., 2019). Docetaxel is recommended by WHO as one of the safest and most effective drugs in the health system and is available in generic medications.

The medication is, however, associated with common side effects. Examples of the side effects are low blood cell count, vomiting, muscle pains, numbness, and shortness of breath and hair loss. The severe consequences due to the medication are future cancers and allergic reactions. Persons with liver problems have a higher probability of developing side effects compared to a patient without a liver problem. The major-specific effects of docetaxel to blood cells include reduction of the number of platelets, low white blood cell count and reduces red blood cells in the plasma. The working procedure of docetaxel is by disrupting the normal functioning of microtubules and forbid cell multiplying.

Docetaxel is metabolized in the liver by oxidative. The clearance of the drug is related to body service and hepatic enzymes for the substance elimination from the body. Research has shown that patients with hepatic dysfunction have a reduction of docetaxel by 30% and have a higher risk of toxicity poisoning from taking the medication (Hansen et al., 2019). Renal recreation of docetaxel is only 5%, and therefore its impairments would have little effect on docetaxel elimination. The oral bioavailability of the drug is 8% when used alone for treatment; however, when combined with other medication is 90 %( Dora et al., 2017).

Conclusion

To sum up, Biopharma companies should focus on studying the toxicity, means of the excretion of the drugs, potential side effects on the patients and the effectiveness of their products. Testing is vital for the medications before introducing to the market since they may cause more negative impacts that the benefits intended. It has been evidenced from the available anticancer drugs such as docetaxel, melphalan, bortezomib and lenalidomide harm blood cells. Thus anticancer drug developers should carry testing and experiments on the possible impact of the drug to blood cells. Drug testing in animals helps the drug developers to recommend the appropriate doses, measure its effectiveness and improve the quality of the drugs. Examination of the medicines in animals such as mice and dogs should be emphasized by the biopharma companies when producing drugs to measure impacts on blood cells.

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