Med Chem II Exam 2 Full Set

Réussis tes devoirs et examens dès maintenant avec Quizwiz!

(GLP-1 Analog) MOA - Augments glucose-dependent insulin secretion; slows gastric emptying Use - Type 2 diabetes SC, Pen injection *Dose: 30mg once weekly* *t1/2 = 5 days* ADR: *pancreatitis* C/I: *patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)* *REMS*

Albiglutide

(GLP-1 agonist) MOA - Augments glucose-dependent insulin secretion and slows gastric emptying Use - Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes SC, Pen Injection t1/2 = 5 days (Once weekly dosing) ADRs: Pancreatitis BBW - personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2) REMS

Albiglutide

MOA • Humanized PD-L1 monoclonal antibody • Blocks tumor PD-L1 binding to PD-1and B7.1 (aka. CD80) receptors on T-cell Indication • *Metastatic NSCLC* in patients who have undergone Pt-chemotherapy but with disease progression • *Urothelial carcinoma* in patients who have undergone Pt-chemotherapy but with disease progression.

Atezolizumab

• Humanized IgG1 monoclonal antibody. MOA • *Inhibits VEGF-A* (that stimulates new tumor blood vessel formation, *angiogenesis*) by binding. Bevacizumab binds directly to VEGF to form a protein complex which is incapable of further binding to VEGF receptor sites. Indications • *Metastatic colon cancer in combination with standard chemotherapy.* • *Ovarian cancer* • Originally approved for breast cancer, but the approval was revoked in 2011. • Lack of evidence that it extended life or improved quality of life, and it caused serious adverse effects. Black box warning: GI perforations (because its inhibiting blood vessel growth), surgery and wound healing complications, and hemorrhage

Bevacizumab

(Bone-forming Agents) Appropriate intake of calcium = increases peak BMD and may reduce the overall risk of developing osteoporosis Recommended amounts = Teens - 1300 mg/day Premenopausal women and men - 1000 mg/day Postmenopausal women - 1200 mg/day

Calcium Salts

• Cancer cells produce tumor antigens on their surfaces. • Antigen-presenting cells (APC) (dendritic cells) display these foreign antigens complexed with major histocompatibility complexes (MHCs) on their surfaces • Antigen-bound APCs activate B cells and T cells. • When activated by APC, B cells become plasma cells that make antibodies. These antibodies mark tumor cells for elimination. • T cells activated by APC multiply and seek out and destroy tumor cells bearing the specific tumor antigens. • Activated T cells kill target cancer cells • Dying cancer cells release additional cancer antigens, propagating the cancer immunity cycle • *APCs, B cells, T cells and NK cells interacting with the tumor antigens are the core components of the immune response that work to eliminate cancer cells.* • Cancer can result from compromised immune system. Cancer immunotherapy is aimed at boosting the immune system. Types of cancer immunotherapy • Immune checkpoint inhibitors • Cytokines • Cancer vaccines *Immune checkpoint inhibitors* • Immune checkpoints are *inhibitory pathways* built into the immune system for controlling the duration and amplitude of physiological immune responses in order to minimize collateral tissue damage . For example, PDL1 or PDL2 interaction with PD1 receptor and CD80 or CD86 interaction with CTLA4 receptor. -PDL = program cell death ligand • Tumors co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance particularly against T cells that are specific for tumor antigens. • Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be blocked by antibodies. • Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first checkpoint immunotherapeutics to achieve FDA approval. • Programmed cell death protein-1 (PD1) inhibitors are the second class of checkpoint immunotherapeutics to achieve FDA approval

Cancer immunotherapy

• Cetuximab is a chimeric monoclonal antibody. MOA • *It binds specifically to the extracellular domain of the human EGFR* (ErB-1;HER1) • Indication • Indicated for *K-ras mutation-negative, EGFR-expressing colorectal cancer and for head and neck cancer* in combination with other treatments • In July 2009, a genetic test for the KRAS mutation was approved by the FDA as an indication for Erbitux treatment of colon cancer. *This was the first genetic test to guide treatment of cancer.* In July 2012, the FDA approved a real time PCR companion diagnostic test for KRAS, the *therascreen*1 KRAS test [*KRAS is a proto oncogene of the ras family. KRAS mutation is predictive of a very poor response to cetuximab]*. Black box warning: Infusion reactions and cardiopulmonory arrest (closely monitor serum electrolytes)

Cetuximab

(GLP-1 Analog) *Fusion protein* that consists of 2 identical, disulfide-linked chains MOA - Augments glucose-dependent insulin secretion; slows gastric emptying Use - Type 2 diabetes SC, Pen injection *Dose: 1.5 mg weekly* ADR: *pancreatitis* C/I: *patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)* REMS

Dulaglutide

(GLP-1 agonist) MOA - Augments glucose-dependent insulin secretion and slows gastric emptying SC, Pen Injection t1/2 = 5 days (Once weekly dosing) ADRs: Pancreatitis BBW - personal or family history of medullary thyroid carcinoma and endocrine neoplasia REMS

Dulaglutide

(GLP-1 Analog) 39 AA peptide - *Resistant to the action of DPP-IV* Pharmacologic effects: *reduces HbA1c levels*; appetite reduction; modest weight loss Use - Type 2 diabetes *SC administration* *t1/2 = 3 hrs* ADRs: *acute pancreatitis* - *No risk of hypoglycemia when in combo w/ Metformin* - *Risk of hypoglycemia when in combo w/ Sulfonylurea* C/I: *pts with a history of medullary thyroid carcinoma* *REMS*

Exenatide

(GLP-1 agonist) Structure • Exenatide is a 39-amino acid peptide analog of GLP-1, isolated from the saliva of the Gila monster (Heloderma suspectum). • It has only 53% homology to human GLP-1, but acts as a full agonist at the GLP-1 receptor! • Resistant to the action of DPP-IV Half-life • It has as an in vivo half-life of approximately 3 hours. (vs 2 minutes of GLP1) Pharmacological effects: • Reduce HbA1c levels in type II diabetic patients on sulfonyl urea • Other pharmacological effects: - Causes appetite reduction - Associated with modest weight loss. Recently it has been shown to reduce liver fat in humans - fatty liver is one malignancy associated with type 2 DM favorable property Indication • Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Dosing • It is administered by sc injection as either a 5 or 10 µg dose using a pen-injector device. It is usually administered twice a day. • An extended release form (Bydureon®) suitable for once weekly sc administration received approval in 2012 Hypoglycemia • There is no risk of hypoglycemia when used in combination with metformin. There is a risk for hypoglycemia when used in combination with a sulfonylurea. AEs • Acute pancreatitis, including some fatal • Black box warning: Exenatide extended release (ER) causes an increased incidence in thyroid C-cell tumors at clinically relevant exposures in rats compared with controls. Human relevance is not established, but contraindicated in patients with a family history of medullary thyroid carcinoma. same for all drugs in the class • The drug has an FDA-approved Risk Evaluation and Mitigation Strategy (REMS) that the manufacturer is required to follow

Exenatide

• A humanized *antibody-drug conjugate (ADC)*. MoAb is conjugated with *calicheamicin*, a small molecule that breaks double stranded DNA. MOA • Gemtuzumab ozogamicin binds to the *CD33 antigen*. This antigen is expressed on the surface of leukemic blasts in more than 80% of patients with *acute myeloid leukemia (AML).* • The drug binds to CD33 to form a complex. The complex is internalized and calicheamicin is released. The released calicheamicin binds to DNA in the minor groove resulting in DNA double strand breaks and cell death. Indication • *Acute myeloid leukemia (AML).*

Gemtuzumab ozogamicin

Leuprolide (GnRH Agonists) MOA - stimulating the pituitary GnRH receptors, causing an increase in testosterone followed by *down regulation in the pituitary secretions of LH and FSH to the level of virtual castration in males* SC Injection or Implant Use - *advanced prostate cancer*

Leuprolide

Mix of Na salts of T4 & T3 - 4:1 ratio MOA - by *supplying the thyroid hormones in the ratio they are normally produced by the body* Use - replacement or supplemental therapy in patients with hypothyroidism

Liotrix

(GLP-1 Analog) Has the 7-37 AA residues of GLP-1 Use - Type 2 diabetes; *weigh control in pts with BMI>30* *t1/2 = 13 hrs (QD dosing)* *SC administration* ADR: *pancreatitis* C/I: *patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2)* *REMS*

Liraglutide

(GLP-1 agonist) Use - As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus; *For weight control in patients with BMI>30* *t1/2 = 13 hrs* *SC injections (Once daily)* ADR: *pancreatitis* BBW: personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2 (MEN2) REMS

Liraglutide

(Amylin Agonist) MOA - delays gastric emptying, suppresses glucagon release, and has a central nervous system anorectic effect via unknown mechanisms IM Use - Type 1 and Type 2 diabetics *Used together with insulin for those who are unable to achieve their target postprandial blood sugar levels on insulin alone*

Pramlintide

(Bone-forming Agents) *Nonhormonal bone-forming agent* MOA - *promotes the proliferation and activity of osteoblasts* Essential: this therapy be coupled with oral calcium supplementation

Sodium fluoride

(Bone-forming Agents) *1st approved bone forming agent* Recombinant human parathyroid hormone 1-34 MOA - *increase the number of osteoblasts* *SC Injection* Use - *postmenopausal osteoporosis; glucocorticoid-induced osteoporosis*; increase bone mass in *men with primary or hypogonadal osteoporosis* who have a high risk of fracture

Teriparatide

From thyroid glands of hogs T4/T3 ratio - 2.5: 1 Disadvantages: - *Protein antigenicity* - Product stability - *Variable hormone concentrations* - Laboratory monitoring of patient

Thyroidglobin

6-Mercaptopurine MOA - Inhibits the de novo biosynthesis of purine nucleotides (AMP and GMP) by *inhibiting glutamine amidophosphoribosyl transferase, the rate-limiting enzyme in the synthesis of these purine nucleotides.* - Incorporates into the DNA and the RNA. • Since the major mechanism of action of mercaptopurine is inhibition of de novo purine nucleotide biosynthesis rather than incorporation of false nucleotides into DNA, there is a lower risk for mutagenesis and secondary malignancy compared to thioguanine. What are the mechanisms of resistance? - *attenuated active uptake via nucleoside transporters and - Deficiency in the activating of HGPRT enzyme* Has multiple active metabolites -5-thioinosine monophosphate -6-thiomethylinosine monophosphate (inhibits AMP and GMP synthesis by inhibiting amidophosphoribosyl transferase) -6-thiomethyinosine triphosphate gets incorporated into RNA and deoxy form into DNA Indication • Used in the treatment of acute lymphatic and myelogenous leukemia. Dosing • It is available in an *oral dosage* form, but absorption can be erratic and is reduced by the presence of food. Side effects • Bone marrow suppression is the major use-limiting toxicity, although the drug can be hepatotoxic in high doses. • *Major metabolizing enzyme is thiopurine S-methyltransferase (TPMT).* *Patients with inherited little or no TPMT activity are at increased risk for severe PURINETHOL toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction.* General: Thiopurine Antimetabolites • The two currently marketed purine anticancer agents are *6-Mercaptopurine* (6-MP, Purinethiol®) and *6-Thioguanine* (6-TG, Tabloid®). They are *prodrugs* and *must* be converted *to ribonucleotides by hypoxanthine guanine phosphoribosyl transferase* (HGPRT) before they can exert their cytotoxic actions. • *Subsequently converted to ribosylated triphosphate derivatives, which can inhibit the de novo synthesis of purines, inhibit DNA replication, as well as get incorporated into DNA and RNA.* • All 3 species are active • Triphosphates gets into DNA

.

MOA • *Binds to CD52*, an antigen present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes undergo cellular lysis. Indications • As a second-line therapy for *chronic lymphocytic leukemia (CLL).* For CLL patients who have been treated with alkylating agents and who have failed fludarabine therapy. • For *T-cell-prolymphocytic leukemia (T-PLL), an aggressive tumor for which no standard treatment exists.* • Approved for MS also. Off Label uses (Picture) Black box warning: Bone marrow suppression, Infusions reactions, cytopenia, malignancies on FDA REMS program *General: Monoclonal antibodies* • Tumor-specific monoclonal antibodies (MoAbs) *target tumor cell antigens or cell surface receptors.* • MoAbs-antigen complex recruits endogenous immunomodulator and cell-destroying cytokines (e.g., natural killer cells, macrophages) to stop the advancement of the cancer. • The engineering of *humanized or chimeric MoAbs* has significantly attenuated the risk of immunologic responses to the murine-derived proteins found in the early agents. *Humanized antibodies* are antibodies from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans. • However, black box warnings for most MoAb anticancer agents caution against such potentially fatal events as *infusion/ hypersensitivity reactions, cytopenias, hemorrhage, hepatotoxicity, infection, tumor lysis syndrome, cardiomyopathy, and cardiopulmonary arrest.*

Alemtuzumab

Yescarta • CAR-T cell immunotherapy - *a CD19-directed genetically modified autologous T cell immunotherapy* - Patients' T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. • Indication - *Large B-cell lymphoma, relapsed or refractory after 2 or more lines of systemic therapy* • PK - Anti-CD19 CAR T cells displayed an initial rapid expansion followed by a decline to near baseline levels by 3 months post axicabtagene ciloleucel infusion - Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 14 days after infusion • Boxed Warning - *Life threatening cytokine release syndrome* - Neurological toxicities • Cost Consideration - One time cost of $373,000 • Approved in 2017

Axicabtagene Ciloleucel

MOA • A new class of MoAb known as *bi-specific T-cell engager (BiTE)* that works by linking the CD19 antigen on malignant (and normal) B cells with the CD3 antigen on T cells resulting in T cell-induced cytotoxic action on B cells. Indication • *Acute lymphoblastic leukemia; treatment of Philadelphia chromosome negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia* AEs • Myelosuppression, serious and often fatal infections, hepatotoxicity.

Blinatumomab

Chimeric Antigen Receptor expressing T-cell (CAR-T) therapy - A personalized cancer immunotherapy • T cells are collected from a patient blood via apheresis • T cells are *reengineered in a laboratory to produce CAR T cells.* The T cells are genetically engineered, by introducing DNA into them via a chiral vector, to produce chimeric antigen receptors (CARs) on the surface of the cells. CARs allow the T cells to recognize targeted tumor cells' antigen. • The reengineered CAR T cells are "expanded" (multiplied) • At the treatment center CAR T cells are infused into the patient. Many patients are given a brief course of one or more chemotherapy agents, called "lymphodepletion," before they receive the infusion of CAR T cells. CAR T cells that have been returned to the patient's bloodstream multiply in number. CART-T cells recognize and attach themselves to tumor cells that have the targeted antigen on their surface. • The CAR T cells may *help guard against recurrence.* CAR T cells may eradicate all of the cancer cells and may remain in the body months after the infusion has been completed. The therapy has resulted in long-term remissions for some types of blood cancer. • Called a *"living medicine."*

Chimeric Antigen Receptor expressing T-cell (CAR-T) therapy

• *A murine antibody-drug conjugate (radioimmunotherapy).* MoAb ibritumomab complexed with the chelator tiuxetan, to which a radioactive isotope (either yttrium-90 or indium-111) is added. MOA • *Ibritumomab tiuxetan binds specifically to the CD20 antigen* found on normal and malignant B cells. The CD20 antigen is expressed on B lymphocytes and on > 90% of B-cell non-Hodgkin's lymphomas (NHL). • The antibody binding to the CD20 allows *radiation from the attached isotope (mostly beta emission) to kill the cell and some nearby cells.* • In addition, *the antibody itself may trigger cell death via antibody-dependent cell-mediated cytotoxicity (ADCC),* complement-dependent cytotoxicity (CDC), and apoptosis. Together, these actions eliminate B cells from the body, allowing a new population of healthy B cells to develop from lymphoid stem cells. Indication • *For the treatment of relapsed or refractory B cell non-Hodgkin's lymphoma*

Ibritumomab tiuxetan

MOA • Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a key *inhibitory* cell surface protein on T-cells. • CTLA-4 blocking leads to activation T cells which leads to antitumor activity. • Iipilimumab is a human monoclonal antibody that binds to *CTLA-4 thereby blocking CD80 or CD86 binding to CTLA-4.* Indication • Approved in 2011 for *treatment of unresectable metastatic melanoma.* • Black box warning: Severe immune reactions

Ipilimumab

• L-Asparaginase is an enzyme isolated from Escherichia coli. • The mechanism of action of Elspar (L-asparaginase) is thought to be based on *selective killing of leukemic cells* due to depletion of plasma asparagine. • Indication: Indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with *acute lymphoblastic leukemia (ALL)*. • Side effects: Anaphylaxis and serious allergic reactions, thrombosis, and fulminant glucose intolerance.

L-Asparaginase and Peg-Asparaginase

MOA • Nivolumab is a monoclonal antibody that *blocks the binding of PDL1 or PDL2 with PD1 receptor,* causing anti-tumor response. Indication • *Unresectable or metastatic melanoma* with disease progression following ipilimumab and a BRAF inhibitor . • *Non-small cell lung cancer,* metastatic • So far approved for about 10 cancer types • Currently undergoing clinical trials for a variety of cancers including NSCLC, where it has shown positive results

Nivolumab

• Human monoclonal antibody. MOA • Binds to the extracellular domain of the *EGFR*, preventing its activation. Indication • For the treatment of *EGFR-expressing metastatic colorectal cancer with disease progression despite prior treatment.* • In July 2009, the FDA updated the labels to include information about KRAS mutations (KRAS mutation is predictive of a very poor response to the drug; see Cetuximab) • Black box warning: Dermatologic toxicities, infusion reactions.

Panitumumab

Pembrolizumab MOA • Binding of PDL1 or PDL2 with PD1 receptor leads to inhibition of T cell. Pembrolizumab is a monoclonal antibody that *blocks the binding of PDL1 or PDL2 to the PD1 receptor*, causing anti-tumor response. Indication • *Unresectable or metastatic melanoma* with disease progression following ipilimumab and a BRAF inhibitor • *Non-small cell lung cancer, metastatic* • So far approved for 12 types of cancer • Currently undergoing clinical trials for a variety of cancers including NSCLC, where it has shown positive results. • First approval in 2014.

Pembrolizumab

• A *fully human MoAb* MOA • Binds to the vascular endothelial growth factor receptor 2 (*VEGFR2*) thereby blocking the binding of VEGFR2 to VEGF which is needed for downstream effects of VEGF *angiogenesis.* Indications • Colorectal cancer, metastatic ... • *Gastric cancer*, advanced or metastatic. Single-agent or in combination with paclitaxel. • *Non-small cell lung cancer* in combination with docetaxel. Black box warning. • Risk of hemorrhage, including severe and sometimes fatal hemorrhagic events.

Ramucirumab

• Rituximab is a chimeric MoAb. MOA • Rituximab binds specifically to the antigen *CD20 located on B lymphocytes.* *Rituximab destroys B cells, and is therefore used to treat diseases which are characterized by B cell proliferation, or dysfunctional B cells. This includes many lymphomas, leukemias, transplant rejection, and some autoimmune disorders* Indications • *CLL, non-hodkins lymphoma and rheumatoid arthritis* (because there's a lot of B cells in it) • Black box warning: Fatal infusion reactions, tumor lysis syndrome resulting in acute renal failure, mucocutaneous reactions, and leukoencephalopathy.

Rituximab

Kymriah • CAR-T cell immunotherapy • *a CD19-directed genetically modified autologous T cell immunotherapy* - Patients' T cells are reprogrammed with a transgene encoding a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing malignant and normal cells. • Indication - *Acute lymphoblastic leukemia* (relapsed or refractory) in patients up to 25 years of age • PK - High distribution into bone marrow - Tisagenlecleucel is present in blood and bone marrow and is measurable beyond 2 years • Boxed Warning - *Life threatening cytokine release syndrome* - Neurological toxicities • Cost Consideration - One time cost of $475,000 • Approved in 2017

Tisagenlecleucel

• Tositumomab is a murine IgG2a *ADC*. MOA • Tositumomab covalently binds to radionuclide *iodine-131* and causes cell death. 131I emits both beta and gamma radiation, and it decays with a t1/2 of 8 days. Indication • Relapsed or refractory *CD20-positive, non-Hodgkin's lymphoma* Black box warning • Serious allergic reactions (including anaphylaxis), prolonged and severe cytopenias, and radiation exposure.

Tositumomab

• Trastuzumab is a humanized MoAb. MOA • *Binds specifically to EGFR2* • The HER2 gene is amplified in 20-30% of early-stage breast cancers and has been associated with poor prognosis. Trastuzumab has been shown, in both in vitro assays and in animals, to *inhibit the proliferation of human tumor cells that overexpress HER2.* Indications: • *In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer.* • As a single agent for treatment of *HER2-overexpressing breast cancer* in patients who have received one or more chemotherapy regimens. • HER2 overexpressing metastatic *gastric cancer.* Black box warning: Cardiomyopathy, infusion reactions, pulmonary toxicity.

Trastuzumab


Ensembles d'études connexes

This is Sum Physics stuff you should use to get GigaBrain In physics

View Set

I271 Networking Essentials Cards

View Set

Renaissance Art 100 Module 11 Chapter 16

View Set

Leadership Final: Quiz Questions

View Set

finc 381 final (chapter 5 pt 2, 9-13, 16-18)

View Set

Brunner Ch 53 Assessment and Management of Patients with Male Reproductive Disorders

View Set