THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

7. Biotechnology and Pharmacogenomics - Stephanie A. Flowers, PharmD, P. David Rogers, PharmD, PhD, FCCP

7-1. Introduction

Introduction

Since the discovery of the DNA (deoxyribonucleic acid) double helix half a century ago, significant use of biotechnology has been made for the improvement of human health (

Table 7-1). Accompanying these advances is a number of biological products with therapeutic applications. With the arrival of the postgenomic era, the field of pharmacogenomics has emerged and shows great promise to revolutionize the way in which pharmacy and medicine are practiced. This chapter highlights key concepts relevant to the practicing pharmacist in the areas of biotechnology and pharmacogenomics.

Biotechnology has revolutionized the pharmaceutical industry by imparting the ability to mass produce safe and pure versions of chemicals produced naturally in the body. A multitude of disease states have been affected by therapeutic agents derived through biotechnology, including AIDS (acquired immune deficiency syndrome), anemia, cancer, congestive heart failure, cystic fibrosis, diabetes, growth hormone deficiency, hemophilia, hepatitis B and C, and multiple sclerosis, to name a few.

Biotechnology is defined by the Merriam-Webster's Dictionary as "the manipulation (as through genetic engineering) of living organisms or their components to produce useful usually commercial products (as pest resistant crops, new bacterial strains, or novel pharmaceuticals)."

Key Terms

• Antibody (immunoglobulin): A protein produced by β-lymphocytes in response to antigen molecules determined to be nonself. Antibodies recognize and bind to antigens, resulting in their inactivation or opsonization for phagocytosis or complement-mediated destruction. A number of immunoglobulin (Ig) G products have been developed for therapeutic use in various immune disorders.

• Antigen: A molecule that elicits an antibody-mediated immune response.

• Bioinformatics: The application of computer sciences and information technology to the management and analysis of biological information.

• Biotherapy: Any treatment involving the administration of a microorganism or other biologic material.

• Clotting factor (blood factor): Chemical blood constituents that interact to cause blood coagulation.

• Combinatorial chemistry: A drug development strategy that uses nucleic acids and amino acids in various combinations to synthesize vast libraries of oligonucleotide or peptide compounds for high-throughput lead compound screening.

• Cytokine: An extracellular signaling protein that mediates communication between cells.

• DNA (deoxyribonucleic acid): A polynucleotide molecule consisting of covalently linked nucleic acids. DNA serves as the genetic material.

• Enzyme: A protein that catalyzes a chemical reaction.

• Gene: A region of DNA that encodes a specific RNA (ribonucleic acid) or protein responsible for a specific hereditary characteristic.

• Gene therapy: Therapeutic technologies that directly target human genes responsible for disease.

• Genome: The complete set of genetic information for a given organism.

[Table 7-1. Milestones in Biotechnology]

• Genomics: The scientific discipline of mapping, sequencing, and analyzing genomes. It encompasses structural genomics, functional genomics, and pharmacogenomics.

• Hormone: A chemical substance imparting specific cellular effects that is transmitted by the bloodstream to cells distant from its physiologic source.

• Hybridoma: A cell line generated by the fusion of antibody-producing β-lymphocytes with lymphocyte tumor cells for the production of monoclonal antibodies.

• Interferon: A member of a group of cytokines that prevents viral replication and slows the growth and replication of cancer cells.

• Interleukin: A member of a group of cytokines involved in orchestration and regulation of the immune response.

• Liposome: A microscopic, sphere-like lipid droplet that functions as a therapeutic carrier.

• Monoclonal antibody: An antibody derived from a hybridoma cell line.

• Pharmacogenomics: The scientific discipline of using genomewide approaches to understand the inherited basis of differences between individuals in the response to drugs. This field is an expansion of the field of pharmacogenetics, which traditionally considered such inherited differences on a gene-by-gene basis.

• Plasmid: A small, circular, extrachromosomal DNA molecule capable of replication independent of that of the genome.

• Polymerase chain reaction (PCR): A molecular biologic technique for amplification of specific DNA molecules.

• Protein: A functional product of a specific gene consisting of amino acids linked together through peptide bonds in a specific sequence.

• Proteomics: The scientific field of the study of sequencing and analyzing the expression, modification, and function of proteins on a genomewide or global scale.

• Recombinant DNA (rDNA) technology: The application of DNA molecules derived by joining two DNA molecules from different sources.

• Restriction endonucleases: An enzyme capable of cleaving a DNA molecule in a site-specific manner.

• Ribozymes: RNA molecules with intrinsic enzymatic activity.

• RNA (ribonucleic acid): A polynucleotide molecule consisting of covalently linked ribonucleic acids. Messenger RNA (mRNA) serves as the template for protein synthesis. Transfer RNA (tRNA) serves as the adaptor molecules between amino acids and mRNA during protein synthesis. Ribosomal RNA serves as a component of the ribosome and participates in protein synthesis.

• Small molecule chemistry: The field of drug development focusing on small organic nucleotide-or peptide-based molecules derived through either combinatorial chemistry or rational drug design.

• Single nucleotide polymorphism: Common DNA sequence variations among individuals involving a single nucleotide substitution.

• Vaccine: A preparation of antigenic material administered to stimulate the development of antibodies conferring active immunity against a particular pathogen or disease.

Biological Products

Many FDA-approved biological products are currently on the market, including blood factors, cytokines, enzymes, growth factors, hormones, interferons, monoclonal antibodies, and vaccines. A list of such biological products is provided in

Table 7-2.

[Table 7-2. Approved Biological Products]

Gene Expression and Protein Synthesis

Proteins are the major macromolecular component of the cell and are responsible for conducting most of a cell's biological activity. Proteins consist of a linear polymer of amino acids linked together in a specific sequence. This specific sequence is responsible for a protein's structure and function. The initial code for the synthesis of a given protein is stored in a gene on a sequence of DNA that is part of a chromosome within the nucleus of a cell.

The central dogma of molecular biology is that DNA encodes RNA, which, in turn, encodes protein. A given amino acid within a protein is encoded by a triplet of nucleic acid base pairs within the gene encoding the protein. This triplet is called a codon. There are 64 codons encoding 20 different amino acids as dictated by the genetic code.

An overview of transcription, translation, and post-translational modification is shown in

Figure 7-1.

Recombinant DNA Technology

Recombinant DNA (rDNA) technology uses several molecular biological tools to insert a desired DNA fragment with a specific purpose in proximity to other DNA fragments within a DNA molecule. Most often, a gene encoding a desired protein is isolated through screening of the genomic library or by use of the viral enzyme reverse transcriptase to generate complementary DNA (cDNA) from the mRNA transcript of the gene. Enzymes called restriction endonucleases allow

[Figure 7-1. Gene Expression: The Synthesis of Proteins]

the cleavage of DNA in the plasmid at very specific locations. The gene is then ligated into a vector, such as a plasmid, for gene cloning or for control of the expression of the encoded protein.

An expression vector is a plasmid designed to allow inducible expression of the inserted gene within a host cell (such as the bacterium Escherichia coli or the yeast Saccharomyces cerevisiae). This mechanism permits production of large quantities of the desired protein. The protein must then be isolated and purified for further use. Such techniques, used on an industrial scale, mass produce therapeutically useful biological products such as cytokines, enzymes, hormones, blood factors, and vaccines (

Figure 7-2).

[Figure 7-2. Summary of Typical rDNA Production of a Protein from Either Genomic DNA or cDNA]

Cytokines (i.e., molecules secreted by cells) orchestrate the immune response and activate immune cells such as lymphocytes, monocytes, macrophages, and neutrophils. Therapeutically useful recombinant cytokines include interferons, interleukins, and colony-stimulating factors. Examples of these include interferon beta-1b (Betaseron), which is used to treat acute relapsing-remitting multiple sclerosis; aldesleukin (IL-2) (Proleukin), which aids in the management of metastatic renal cell carcinoma and melanoma; and oprelvekin (IL-11) (Neumega), which treats thrombocytopenia caused by chemotherapy.

An enzyme is a protein that catalyzes a specific chemical reaction. Numerous different enzymes with therapeutic use have been produced using rDNA technology. Alteplase (Activase), for example, treats acute myocardial infarction, pulmonary embolism, and stroke. Dornase alfa (Pulmozyme) treats respiratory complications that develop in cystic fibrosis. Eptifibatide (Integrelin) is used to treat acute coronary syndromes.

Hormones—chemical substances transmitted through the bloodstream—are designed to impart specific cellular effects to cells distant from their physiologic source. Since the introduction and success of recombinant human insulin in 1982, many other recombinant hormones have been developed, such as human growth hormone, which treats growth hormone deficiency in pediatric patients, and follitropin alfa and beta (Gonal-F and Follistim, respectively), which are used to remedy ovulatory failure.

Clotting or blood factors are chemical blood constituents that interact to cause blood coagulation. Patients suffering from hemophilia A (caused by factor VIII deficiency) and hemophilia B (caused by factor IX deficiency) have benefited greatly from rDNA technology. Factors VII, VIII, and IX are available in recombinant forms for clinical use.

Vaccines—preparations of antigenic material administered to stimulate the development of antibodies—confer active immunity against a particular pathogen or disease. Vaccine development has also benefited from advances in rDNA technology. Traditional vaccine production used killed or non-virulent organisms, microbial toxins, or actual microbial components to elicit long-term immune protection. Safer and more specific vaccine antigens have been devised as recombinant proteins. This technology has led to the very successful recombinant hepatitis B vaccine.

Monoclonal Antibodies

Antibodies, proteins produced by the immune system's β-lymphocytes, use specific methods to recognize foreign molecules within the body. Subsets of β-lymphocyte clones produce identical antibodies that recognize the same antigen. These identical antibodies are monoclonal. Fusing β-lymphocytes with lymphocyte tumor cells produces a hybridoma. This fused cell type is immortal and can be cultured in large quantities for the mass production of a given monoclonal antibody.

Monoclonal antibodies that bind to and inactivate their targets can be developed and have great therapeutic utility (

Figure 7-3). Nomenclature of monoclonal antibodies is highly structured. The first component of the name is product specific. The second component indicates its therapeutic use: ci for cardiovascular use, li for use in inflammation, and tu for use in cancer. The third component indicates the type of monoclonal antibody: mo for murine, xi for chimeric, and zu for humanized. The fourth component, mab, represents monoclonal antibody. An example of a monoclonal antibody used clinically is abciximab (ReoPro), which prevents blood clots following percutaneous transluminal coronary angioplasty (PTCA) and prevents unstable angina prior to PTCA. Another example, infliximab (Remicade), is used to treat Crohn's disease and rheumatoid arthritis.

Gene Therapy

Gene therapy is an excellent example of the therapeutic application of biotechnology. This technology holds promise for the treatment of inherited disorders, as well as acquired illnesses such as infectious diseases and cancer.

The molecular goal of gene therapy is to repair or correct a dysfunctional gene by selectively introducing recombinant DNA into cells or tissues, thereby allowing the expression of a functional gene product.

Novel drug delivery strategies must be used to introduce exogenous DNA into the cell to treat retroviruses, lentiviruses, and adeno-associated viruses. These novel drug delivery strategies also have applications for nonviral delivery systems (e.g., liposomes or uncomplexed plasmid DNA).

Alternative approaches using ribozymes (e.g., RNA repair) may prove effective. The enzymatic activity of these RNA molecules can be used to repair defective mRNAs.

[Figure 7-3. Production of Monoclonal Antibodies]

Chimeric RNA and DNA oligonucleotides make use of the cell's DNA mismatch repair apparatus to correct mutations at the genomic level. Antisense oligonucleotides for gene inactivation have proved clinically useful. Fomivirsen (Vitravene), one such agent, targets the mRNA of human cytomegalovirus (CMV). This agent is indicated for the treatment of CMV retinitis in patients with AIDS.

Drug Delivery

Biotechnology has facilitated the development of novel drug delivery strategies. The use of liposomes has had a positive effect on drug delivery. Drugs can be formulated into liposomes (i.e., microscopic, spherical lipid droplets). The outer membrane of the liposome fuses with the membrane of the target cell, thereby facilitating highly targeted drug delivery. Such technology has greatly improved the therapeutic index of the antifungal drug amphotericin B. Lipid-based formulations now allow greater quantities of the drug to be delivered with substantially less toxicity to the patient.

Another promising approach is the use of immunotoxins. These delivery agents combine a monoclonal antibody with a toxin such as an anticancer or antimicrobial agent, thereby allowing targeted drug delivery with minimal toxicity.

Another novel strategy is the use of PEGylation—that is, the addition of polyethylene glycol (PEG) to therapeutic proteins to minimize the deleterious immune response to an individual protein.

Pharmacogenomics

Pharmacogenomics is the scientific discipline of using genomewide approaches to understand the inherited basis of differences between individuals in the response to drugs. This field is an expansion of the field of pharmacogenetics, which traditionally considered such inherited differences on a gene-by-gene basis.

Genetic differences in drug metabolism, drug disposition, and drug targets have a large effect on efficacy and toxicity. Comprehension of the relationships between specific genetic factors and drug response can be used to predict drug response and optimize drug therapy in any given individual.

Of particular significance are single nucleotide polymorphisms (SNPs). SNPs are differences in a single nucleotide base that occur at a significant frequency (usually > 5%) within the population. An SNP may or may not promote change in the encoded amino acid of a codon, or it may change the encoded amino acid but yield no change in the function of the encoded protein. When a SNP causes amino acid substitution, a phenotypic difference that carries clinical relevance may result. Even when the SNP results in no change in the encoded amino acid, it may be associated with a phenotypic change, thereby serving as a predictive marker of that change.

Examples of significant genetic polymorphisms that can influence drug response are shown in

Tables 7-3 and

7-4.

Examples of significant genetic polymorphisms in drug-metabolizing enzymes are shown in

Tables 7-5 and

7-6.

7-2. Key Points

• Biotechnology, as defined by Merriam-Webster's Dictionary, is "the manipulation (as through genetic engineering) of living organisms or their components to produce useful usually commercial products (as pest resistant crops, new bacterial strains, or novel pharmaceuticals)."

• The central dogma of molecular biology is that DNA encodes RNA, which, in turn, encodes protein.

• Recombinant DNA technology makes use of several molecular biological tools that allow for the placement of a desired DNA fragment in proximity to other DNA fragments within a DNA molecule for a specific purpose.

• Cytokines are molecules secreted by cells that orchestrate the immune response. They activate immune cells such as lymphocytes, macrophages, monocytes, and neutrophils.

• An enzyme is a protein that catalyzes a specific chemical reaction.

• Hormones are chemical substances transmitted by the bloodstream to cells distant from their physiologic source that impart specific cellular effects.

• Clotting or blood factors are chemical blood constituents that interact to cause blood coagulation.

• Vaccines are preparations of antigenic material administered to stimulate the development of antibodies for the purpose of conferring active immunity against a particular pathogen or disease.

• Subsets of β-lymphocyte clones produce identical antibodies that recognize the same antigen. These identical antibodies are said to be monoclonal. Fusing β-lymphocytes with lymphocyte tumor cells produces a hybridoma that can be cultured in large quantities for the mass production of a given monoclonal antibody.

[Table 7-3. Genetic Polymorphisms in Drug Target Genes That Can Influence Drug Responsea]

[Table 7-4. Genetic Polymorphisms in Disease-Modifying or Treatment-Modifying Genes That Can Influence Drug Responsea]

[Table 7-5. Pharmacogenomics of Phase I Drug Metabolisma]

• Gene therapy, an application of biotechnology, has great potential therapeutic benefit.

• Biotechnology has facilitated the development of novel drug delivery strategies, including liposomal technology, immunotoxins, and PEGylation.

• Pharmacogenomics is the scientific discipline of using genomewide approaches to understand the inherited basis of differences between individual responses to drugs.

• Single nucleotide polymorphisms are differences in a single nucleotide base occurring at a significant frequency (usually > 5%) within the population. They may result in no change in the encoded amino acid of a codon or a change in the encoded amino acid with no change in the function of the encoded protein. However, when the amino acid substitution attributable to a SNP results in a phenotypic difference, it may carry clinical relevance.

[Table 7-6. Pharmacogenomics of Phase II Drug Metabolisma]

7-3. Questions

1.

The process whereby the ribosome in the cytoplasm reads mRNA codons and matches them with the appropriate tRNAs (which, in turn, carry amino acids responsible for protein synthesis) is referred to as

A. transcription.

B. translation.

C. transformation.

D. transfection.

E. transduction.

 

2.

How many nucleotide triplets (or codons) exist for the encoding of the 20 possible amino acids specified by the genetic code?

A. 4

B. 12

C. 20

D. 61

E. 64

 

3.

Which of the following refers to a plasmid designed to allow for the expression of an inserted gene within a host cell for the production of the specified protein?

A. Cloning vector

B. Expression vector

C. Transcription factor

D. Translation initiation factor

E. Transposable genetic element

 

4.

Which of the following is an example of a recombinant DNA-generated cytokine used for the management of acute relapsing-remitting multiple sclerosis?

A. Interferon beta-1b (Betaseron)

B. Aldesleukin (IL-2) (Proleukin)

C. Eptifibatide (Integrelin)

D. Bivalirudin (Angiomax)

E. Abciximab (ReoPro)

 

5.

Alteplase (Activase) is a recombinant DNA protein of which of the following types?

A. Hormone

B. Enzyme

C. Clotting factor

D. Chemokine

E. Cytokine

 

6.

Which of the following biological agents is indicated for treatment of ovulatory failure?

A. Ganirelix (Antagon)

B. Glucagon (GlucaGen)

C. Follitropin alfa (Gonal-F)

D. Eptifibatide (Integrelin)

E. Thyrotropin (Thyrogen)

 

7.

Which of the following recombinant blood factors is available in recombinant form for clinical therapeutic use?

A. Factor III

B. Factor V

C. Factor VI

D. Factor VII

E. Factor X

 

8.

Recombinant DNA technology has led to the development of vaccines for which of the following diseases?

A. Hepatitis B

B. Hepatitis A

C. Haemophilus influenzae type B infection

D. Malaria

E. AIDS

 

9.

As dictated by the nomenclature for monoclonal antibodies, which of the following is a chimeric monoclonal antibody therapeutically used for inflammatory disease?

A. Abciximab

B. Infliximab

C. Palivizumab

D. Rituximab

E. Trastuzumab

 

10.

Which of the following is best described as the repair or correction of a dysfunctional gene by selectively introducing recombinant DNA into cells or tissues (ultimately leading to the expression of a functional gene product)?

A. Monoclonal antibody therapy

B. Gene therapy

C. Antiviral therapy

D. Cell therapy

E. Recombinant DNA therapy

 

11.

Fomivirsen (Vitravene) is an example of which of the following biological products?

A. A liposomal formulation

B. An antisense oligonucleotide

C. An siRNA molecule

D. A recombinant DNA-produced protein

E. A monoclonal antibody

 

12.

The use of liposomal technology has favorably affected the therapeutic index of which of the following drugs?

A. Cyclosporine

B. Itraconazole

C. Amphotericin B

D. Cisplatin

E. Propofol

 

13.

Which of the following is best described as the scientific discipline of using genomewide approaches to understand the inherited basis of differences between individuals in their response to drugs?

A. Pharmacogenomics

B. Functional genomics

C. Comparative genomics

D. Pharmacodynamics

E. Molecular genetics

 

14.

A single nucleotide polymorphism (SNP) always results in a change in which of the following?

A. The nucleotide sequence in the genome

B. The nucleotide sequence of a codon

C. The encoded amino acid of the codon

D. The encoded amino acid of the codon, with no change in function of the encoded protein

E. The encoded amino acid of the codon, with a clinically relevant change in the function of the encoded protein

 

15.

Which of the following is best described as "the manipulation (as through genetic engineering) of living organisms or their components to produce useful usually commercial products (as pest resistant crops, new bacterial strains, or novel pharmaceuticals)"?

A. Biology

B. Biotechnology

C. Biotherapy

D. Bioinformatics

E. Nanotechnology

 

16.

Which of the following is a drug discovery strategy that uses nucleic acids and amino acids in various combinations to synthesize vast libraries of oligonucleotide or peptide compounds for high-throughput lead compound screening?

A. Whole cell screening

B. Natural product screening

C. Gene therapy

D. Combinatorial chemistry

E. rDNA technology

 

17.

Which of the following is best defined as the application of computer sciences and information technology to the management and analysis of biological information?

A. Biometrics

B. Biotherapy

C. Bioinformatics

D. Biostatistics

E. Biotechnology

 

18.

Which of the following best outlines the central dogma of molecular biology?

A. RNA→DNA→Protein

B. DNA→RNA→Protein

C. Protein→RNA→DNA

D. DNA→Protein→RNA

E. Protein→DNA→RNA

 

19.

Which of the following biotechnology agents is indicated for treating anemia caused by chronic renal disease?

A. Epoetin alfa

B. Becaplermin

C. Filgrastim

D. Alemtuzumab

E. Sargramostim

 

20.

Which of the following products is indicated for prevention of blood clots post-PTCA?

A. Abciximab

B. Basiliximab

C. Infliximab

D. Trastuzumab

E. Becaplermin

 

7-4. Answers

1.

B. Transcription is the process by which RNA polymerase copies a strand of DNA into complementary RNA. Transformation refers to the alteration of the heritable properties of a eukaryotic cell. Transfection is the introduction of foreign DNA into a eukaryotic cell. Transduction can refer to the transfer of DNA from one bacterium to another through a bacteriophage.

 

2.

D. There is degeneracy in the genetic code. Some amino acids may be encoded by as many as six codons, whereas others may be encoded by only one. Of the 64 possible codons, three are stop codons (UAA, UGA, and UAG).

 

3.

B. A cloning vector is used to carry a fragment of DNA into a cell for cloning. A transcription factor is a protein that regulates transcription in eukaryotic cells. A translation initiation factor, as its name implies, is involved in the initiation of translation. A transposable genetic element, or transposon, is a portion of DNA that can move from one part of the genome to another.

 

4.

A. Aldesleukin (IL-2) (Proleukin) is a recombinant cytokine indicated for the treatment of metastatic renal cell carcinoma and melanoma. Eptifibatide (Integrelin) is a recombinant enzyme indicated for treatment of acute coronary syndromes. Bivalirudin (Angiomax) is an enzyme indicated for use in coronary angioplasty and unstable angina. Abciximab (ReoPro) is a monoclonal antibody indicated for prevention of blood clots post-PTCA and unstable angina prior to PTCA.

 

5.

B. Alteplase (Activase) is a recombinant DNA protein of the enzyme type.

 

6.

C. Ganirelix (Antagon) is a recombinant hormone indicated for the treatment of luteinizing hormone surge during fertility therapy. Glucagon (GlucaGen) is a recombinant hormone indicated for treatment of hypoglycemia. Eptifibatide (Integrelin) is a recombinant enzyme indicated for the treatment of acute coronary syndromes. Thyrotropin (Thyrogen) is a recombinant hormone indicated for the treatment of thyroid cancer.

 

7.

D. The other factors listed are not clinically available in recombinant form.

 

8.

A. Although promising, this technology has not yet yielded vaccines for hepatitis A, malaria, AIDS, or infections caused by Haemophilus influenzae type B.

 

9.

B. Nomenclature of monoclonal antibodies is highly structured. The first component of the name is product specific; the second component indicates its therapeutic use (ci for cardiovascular use, li for use in inflammation, tu for use in cancer); the third component indicates the type of monoclonal antibody (mo for murine, xi for chimeric, zu for humanized); and the fourth component (mab) represents monoclonal antibody.

 

10.

B. The repair or correction of a dysfunctional gene by selectively introducing recombinant DNA into cells or tissues, ultimately leading to the expression of a functional gene product, is called gene therapy.

 

11.

B. Fomivirsen (Vitravene) is the first product based on this technology to come to market.

 

12.

C. Formulation of this antifungal agent as a liposomal preparation (Ambisome) has significantly reduced the nephrotoxicity and other adverse effects associated with this drug.

 

13.

A. The scientific discipline of using genomewide approaches to understand the inherited basis of differences between individuals in their response to drugs best describes pharmacogenomics.

 

14.

A. An SNP may occur outside of an open reading frame (coding region), it may induce a mutation where no change in encoded amino acid occurs, and it may or may not cause a functional change in an encoded protein.

 

15.

B. This definition by the Merriam-Webster's Dictionary best describes biotechnology.

 

16.

D. A drug discovery strategy that uses nucleic acids and amino acids in various combinations to synthesize vast libraries of oligonucleotide or peptide compounds for high-throughput lead compound screening is called combinatorial chemistry.

 

17.

C. The application of computer sciences and information technology to the management and analysis of biological information best defines bioinformatics.

 

18.

B. DNA is transcribed into mRNA, which is translated ultimately to protein.

 

19.

A. Becaplermin is indicated for the management of diabetic foot ulcers. Filgrastim is indicated for treatment of neutropenia. Alemtuzumab is indicated for treatment of chronic lymphocytic leukemia. Sargramostim is indicated for myeloid reconstitution after bone marrow transplant; after bone marrow transplant failure, as an adjunct to chemotherapy in acute myelogenous leukemia; and in peripheral blood progenitor cell transplant.

 

20.

A. Basiliximab is indicated for management of acute organ transplant rejection. Infliximab is indicated for the treatment of Crohn's disease and rheumatoid arthritis. Trastuzumab is indicated for the management of metastatic breast cancer. Becaplermin is indicated for the treatment of diabetic foot ulcers.

 

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