Exam 3 Flashcards

Question

Endemic vs. Epidemic vs. Pandemic

Answer 1

Endemic - disease is constantly present in a certain geographic area or amongst a certain group of people Epidemic - an unexpected increase in the number of disease cases in a specific geographical area Pandemic - when disease spreads over a wide geographical area, usually affecting a large number of people

Answer 2

Virus genomes can be either DNA or RNA, allowing viruses to make copies of themselves once they enter a susceptible cell

Answer 3

>400 different viruses known to infect humans >200 known to cause disease in humans

Answer 4

Smallpox vaccine by Edward Jenner in 1798

Answer 5

Vaccines available for some (but not all) disease-causing viruses

Answer 6

1. Virus targeted: these drugs directly target specific viral components or processes, such as viral enzymes, proteins, or genetic material 2. Broad-spectrum virus targeted: these drugs have activity against a wider range of viruses, often by interfering with essential viral functions like replication or assembly 3. Broad-spectrum host targeted: these drugs target cellular processes or pathways that are essential for viral replication but not for normal host cell function

Answer 7

- wild waterfowl are natural reservoir for virus - can infect humans, pigs, birds, horses, cats, dogs - multiple subtypes (e.g., H1N1, H5N1 - current "bird flu") - can cause pandemic (widespread, affecting large number of people) flu

Answer 8

- primarily a human disease - generally milder than A - no subtypes, but 2 lineages: B/Yamagata and B/Victoria - though tsequence of viral genoe changes more slowly than influenza A

Answer 9

- human major host - causes mild or even no symptoms in healthy adults - rather different from A and B

Answer 10

primarily infects cattle

Answer 11

RNA genome, but segmented!

Answer 12

1. Hemagglutinin 2. Neuraminidase

Answer 13

Process where two or more different influenza viruses co-infect a single host cell and exchange RNA segments. This leads to new virus strains with novel gene combinations, potentially resulting in significant changes in the virus's behavior and immune system recognition.

Answer 14

They were created from a quadruple reassortment, meaning 4 different influenza viruses co-infected a single host cell and exchanged RNA segments, yielding H1N1

Answer 15

Influenza reassortment has **never** been observed between influenza A and influenza B, but both viruses can reassort within their own types

Answer 16

Vaccine effectiveness can vary year to year, but when "well matched" it can reduce illness by about 40-60%

Answer 17

CDC recommends treatment begin **ASAP** (best efficacy) for hopsitalized people, people with severe, complicated, or progressive illness, and people at risk for complications from influenza. More or less used in those that or more susceptible. In certain circumstances, can even be used for chemoprophylaxis.

Answer 18

When taken as early as possible is best: 1. Can lessen symptoms 2. Can shorten illness duration 3. May reduce risk of complications 4. Some studies have found benefit in hospitalized patients

Answer 19

1. Entry into host cell and disassembly of the infectious virus particle (virion) 2. Replication of the viral genome/transcription of viral mRNA 3. Synthesis of the viral proteins by the host cell translation machinery 4. Reassembly of these components into progeny virus particles and exit from host cell

Answer 20

Hemagglutinin and neuraminidase are the two major virion surface proteins of influenza viruses A and B. Hemagglutinin promotes binding and entry of influenza at sialic acid receptors, which hold the virus particles to the host cell. Neuraminidase allows budding and release of influenza from the cell. It acts as a sialidase enzyme, breaking down sialic acid molecules that hold the virus particles to host cells.

Answer 21

Neuraminidase allows budding and spread of influenza progeny from the host cell, so neuraminidase inhibitors are antivirals that prevent this process and are active against influenza A and influenza B. 3 common neuraminidase inhibitors: 1. Oseltamivir (Tamiflu) 2. Zanamivir (Relenza) 3. Peramivir (Rapivab)

Answer 22

Oseltamivir (Tamiflu) is an antiviral neuraminidase inhibitor that is recommended by CDC for hospitalized patients, those with complicated/progressive illness, and pregnant women with influenza A or B. -Orally bioavailable -Usually taken for 5 days (can be more) -Side effects: nausea, vomiting Only 2 of 2800+ viral samples tested this year had reduced susceptibility to oseltamivir (but both were susceptible to zanamivir, an inhaled powder).

Answer 23

Zanamivir (Relenza) is an antiviral neuraminidase inhibitor antiviral used to treat influenza, and it is taken as an inhaled powder (major limitation)

Answer 24

Baloxavir marboxil (Xofluza) is an antiviral that acts as an inhibitor of one of the subunits of the influenza RNA polymerase complex in influenza viruses A and B, blocking RNA synthesis. - taken by those 5+, within 48 hours of symptoms - Not studied in pregnant/nursing, hospitalized, those with complicated/progressing illness - Given as single oral dose (very long half life) - Side effects: diarrhea, bronchitis Effects on symptoms similar to oseltamivir (Tamiflu), but reduces viral load more quickly than oseltamivir. 1 of 2700+ viral samples tested had reduced susceptibility to baloxavir marboxil (Xofluza). Main issue: it chelates with polyvalent cations (like calcium), decreasing the amount of drug that gets absorbed; shouldn't be taken with products like milk

Answer 25

artificial DNA created by joining two or more pieces of DNA that are normally not found together in nature (e.g., typical plasmid used for research) Recombinant DNA technology allows new types of drugs to be manufactured (field of Biotechnology).

Answer 26

1. rDNA-based versions of human proteins like insulin or erthyropoietin (EPO) 2. Synthetic proteins that combine pieces of human proteins with other sequences (as in the anti-cancer drug Herceptin) 3. rDNA-based micro-organism proteins that act as vaccines (like Gardasil for HPV) 4. rDNA-based vectors for gene therapy

Answer 27

The human pancreas contains ~1 million islets of Langerhans (total mass ~1 gram) that produce insulin

Answer 28

Endocrine hormones make good drugs because they function normally if they are delivered into the bloodstream

Answer 29

Insulin is one part of the system that maintains glucose in a normal range: 1. After a meal, blood glucose increases 2. Insulin level increases in response to increased blood glucose 3. Insulin causes cells of the body to take-up glucose, reducing the blood glucose level 4. Blood glucose levels are maintained in a normal range in healthy individuals due to this process

Answer 30

1. Insulin binds to cell surface receptors on target cells when blood glucose is high (after meal) 2. Insulin increases expression of glucose transporters, especially GLUT4 on muscle and fat cells 3. Glucose uptake then increases, and glucose is used to build and store glycogen and fatty acids Without insulin, glucose builds up outside cells (in bloodstream) and can cause hyperglycemia

Answer 31

Failure to produce or respond to insulin leads to hyperglycemia, or high blood glucose Consequences of hyperglycemia: 1. Ketoacidosis (can be fatal) 2. Decreased consciousness or confusion 3. Dehyration due to glycosuria and osmotic diuresis 4. Acute hunger/thirst 5. Long term health problems such as heart disease, kidney disease, eye damage, nerve damage, etc.

Answer 32

Diabetes mellitus type 1 is an autoimmune disease that destroys islet beta cells (cells that produce insulin). This causes an inability of the body to produce insulin and causes chronic hyperglycemia. Sometimes called juvenile diabetes but can also arise later in life. Cause(s) are uncertain but are likely a combination of environmental exposures and genetic susceptibility.

Answer 33

Destruction of iselts of Langerhans (producers of insulin) in diabetes type 1 may take months to years. As insulin production drops, blood glucose will increase from normal value of 70-120 mg/dL, and the disease is largely asymptomatic until blood glucose surpasses ability of the kidneys to clear the ~200 mg/dL threshold (renal threshold). - Once blood glucose is above the renal threshold, symptoms can come on rapidly and severely, typically in younger children but can occur in adulthood

Answer 34

From 1920s-1980s all insulin was isolated from animal sources (cow, pig, horse, fish etc.), but there are concerns for animal-derived (or human-derived) drugs: 1. May contain pathogens 2. Treatment to kill pathogens often not possible because it would damage the drug 3. Difficult to control health status of donors and other aspects of supply chain 4. Finite supply of raw materials available

Answer 35

recombinant DNA (rDNA) technology

Answer 36

Uses naturally occurring proteins or synthetic designs, and manufacturing typically occurs in a factory setting where it is straightforward to achieve FDA-mandated Good nufacturing Practices. Contamination risks for rDNA drugs are very low compared to human or animal-derived products. Human proteins used as drugs often have very high specificity for their targets, so they can produce a very specific medical outcome with few side effects (as compared to small molecule drugs that often have many potential targets and side effects).

Answer 37

**endonuclease:** enzyme that cleaves NA in the middle of the polymer **exonuclease:** enzyme that cleaves nucleotides from the end of the polymer **terminal transferase:** enzyme that adds nucleotides randomly to the end of the polymer (no template needed) **DNA polymerase:** enzyme that synthesizes complementary sequence DNA using a template strand **DNA ligase:** enzyme that covalently joins two pieces of DNA

Answer 38

Paul Berg's laboratory made the first rDNA in the early 1970s. SV40 genome was manipulated to carry foreign DNA segments (initially from a bacterial virus, later from mammalian genes). - Refinements of this approach allowed expression of proteins from the hybrid genome

Answer 39

Plasmids are small circular pieces of extra-chromosomal DNA that replicate in bacteria. They are easy to manipulate in vitro, and are easy to re-introduce into bacteria like E. coli. The use of plasmids was a refinement that made rDNA technology easier.

Answer 40

Company founded in 1976 by Robert Swanson (money) and Dr. Herbert Boyer (science) that aimed to use rDNA to make drugs. The first Genentech product to market was rDNA-based insulin, using artificial genes for human insulin A and B peptide chains. Widely recognized as the first biotechnology company.

Answer 41

Once rDNA constructs are made, drug production is an industrial process: - Bacteria harboring the rDNA plasmids are grown in large quantities using a bioreactor or similar large-scale growth process - Proteins of interest are purified and chemically modified as required for specific drugs - In the case of rDNA-based insulin, bacterial protein sequences are cleaved away and the A and B peptide chains are chemically linked by disulfide bonds

Answer 42

rDNA based insulin (marketed as Humulin) was the first FDA approved rDNA-based drug (1982). Genentech partnered with Eli Lilly and Company for the clinical trials needed to prove rDNA-based insulin could be used in place of natural insulin.

Answer 43

rDNA allows insulin drugs with modified peptide sequences and altered pharmacokinetics, such as fast acting, intermediate acting, and long acting insulin

Answer 44

1. Insulin lispro 2. Insulin aspart 3. Insulin glulisine

Answer 45

regular insulin (unmodified sequence)

Answer 46

1. Insulin detemir 2. Insulin glargine

Answer 47

Epoetin (Procrit, Epogen, EPO) is an rDNA-derived version of the human hormone erythropoietin, a hormone that stimulates the formation of red blood cells, which are specialized for oxygen transport. It is used to treat certain types of anemia.

Answer 48

- Function: transport oxygen - RBCs have lost most specialized organelles, including the nucleus - Contain a special oxygen binding protein called hemoglobin, which makes up 97% of the dry weight of an RBC (35% of net weight) - Lifespan: ~120 days

Answer 49

Anemia is a diseased state caused by reduced blood hemoglobin concentraton. Symptoms: 1. Fatigue 2. Breathlessness 3. Paleness (skin, mucosal linings, nail beds) 4. Increaed cardiac output (sweatiness, palpitations) 5. Others, specific to type of anemia

Answer 50

1. Genetic disorders, like sickle cell anemia 2. Autoimmunity 3. Premature birth (associated with low erythropoietin) 4. Iron deficiency 5. Vitamin B12 deficiency 6. Chemotherapy 7. Renal disease

Answer 51

All cell types in the blood come from a common stem cell present in the bone marrow. The RBC (erythrocyte) lineage is one offshoot from this common stem cell.

Answer 52

Signaling by the erythropoietin receptor (EpoR) stimulates cell proliferation and differentiation in the erythroblast lineage. In other words, EpoR activity stimulates development along the lineage of the common stem cell that makes all cell types in the blood, including RBCs.

Answer 53

EpoR activates the JAK/STAT signal transduction pathway: 1. JAK kinases activate, forming an EpoR dimer 2. EpoR dimer activates STAT, forming a STAT dimer 2. STAT dimers activate transcription of key genes in the erythroblast lineage

Answer 54

Erythropoietin (EPO) is produced by special O2-sensing cells in the kidney. Specifically, it is increased within hours of low blood O2 levels. - Trigger can be low atmospheric O2 levels (e.g., move from sea level to high altitude) - Trigger can be blood loss that reduces blood O2 density EPO circulates as an endocrine hormone, and reduced EPO production by diseased kidneys is one cause of anemia. Therefore, exogenous EPO can treat certain types of anemia.

Answer 55

1. Chemotherapy-induced anemia, which is caused by poisoning of blood cell lineages 2. Renal disease-induced anemia, which results in decrease in endogenous EPO production

Answer 56

EPO is a glycoprotein (protein + carbohydrate modifications), and bacteria do not add the required carbohydrate modifications, as they do with insulin. - Manufacture must instead use mammalian cell culture for production, where carbohydrate modifications are added as EPO moves through the ER and Golgi apparatus

Answer 57

A faster path to approval is possible for follow-on biologic drugs that are similar to approved biologic drugs. Can also be made by same drug company that makes a variant (e.g., for altered pharmacokinetics) or a generic form of an off-patent biologic.

Answer 58

Erythropoietic-stimulating rDNA drug used for the treatment of anemia that is a sequence modified, highly glycosylated erythropoietin (EPO) with increased half-life

Answer 59

Erythropoietic-stimulating rDNA drug used for the treatment of anemia that is a chemically modified peptide that mimic erythropoietin (EPO)

Answer 60

Blood doping seeks to improve VO2max by increasing the oxygen carrying capacity of the blood

Answer 61

Beginning with the availability of recombinant EPO, drug-based doping became a major problem in endurance sports, for these drugs improve VO2max by increasing the oxygen carrying capacity of the blood

Answer 62

Recombinant EPO increased VO2max by ~12% Time to exhaustion at 80% VO2max increased ~50%

Answer 63

Blood viscosity increases with hematocrit in a non-linear fashion, and this increased blood viscosity greatly increases the risk of clotting, heart attack, stroke, and pulmonary embolism. Many untimely deaths of endurance athletes are suspected to be the result of blood doping with EPO.

Answer 64

1. Recombinant EPO (epoetin alpha) is present in the blood and urine of users: - Recombinant EPO is manufactured in Hamster cells that give it a slightly different glycosylation pattern than human EPO, and there are tests that can identify recombinant EPO (as opposed to endogenous EPO) based on this difference in carbohydrate modifications. 2. Using blood doping to alter the hematocrit also affects normal developmental processes for the blood, and parameters like the ratio of reticulyte hematocrit to total hematocrit can be used to identify users.

Answer 65

A group of small cholesterol-based drugs related related to endogenous androgenic endocrine hormones including the male sex steroid testosterone

Answer 66

Androgenic: promote male characteristics Anabolic: promote protein synthesis/build lean muscle mass

Answer 67

Endogenous steroid hormones are small lipophilic hormones based on choesterol. They activate intracellular receptors that act as hormone-regulated transcription factors. **Glucocorticoids:** regulate inflammation and metabolism **Mineralocorticoids:** regulate fluid and salt balance **Sex steroids:** regulate reproductive physiology, bone density, muscle mass, etc.; includes testosterone, etc.

Answer 68

Testosterone is the major male sex hormone produced by the testis (levels 10-20x the circulating levels in females). Roles: 1. Triggers male development 2. Stimulates spermatogenesis in adult males 3. Triggers secondary male sex characteristics in many tissues (muscle, hair, bone, brain, vocal cords, etc.)

Answer 69

Leydig cells in the testis

Answer 70

The functions of the testis are controlled by endocrine signals from the hypothalamus/anterior pituitary

Answer 71

An intracellular receptor that, when bound by androgens, enters the nucleus and acts as a transcription factor. Present in many cell types in both males and females.

Answer 72

1. Treatment of prostate cancer 2. Treatment of benign prostatic hyperplasia (BPH) 3. Treatment of male pattern baldness 4. Certain conditions in women that cause excess androgen production (anabolic steroids are always contraindicated in women)

Answer 73

GnRH agonists suppress the hypothalamic-pituitary-gonadal axis, reducing luteinizing hormone (LH) and, consequently, testosterone. These drugs cause continuous administration of gonadotropins, as opposed to the natural pulses of the pituitary, which desensitizes the gland and causes it to stop producing sex hormones GnRH agonists are used to treat prostate cancer and some breast cancers. Drug class includes lueprorelin (Lupron).

Answer 74

GnRH antagonists suppress the hypothalamic-pituitary-gonadal axis, reducing luteinizing hormone (LH), and consequently, testosterone. GnRH antagonists are used to treat prostate cancer. Drug class includes degarelix (Firmagon).

Answer 75

They reduce prostate size by ~25%, and for many men they are an attractive alternative to transurethral resection of the prostate (TURP).

Answer 76

Androgen receptor antagonists completely inhibit the binding of endogenous androgens to the androgen receptor. They are approved for the treatment of metastatic prostate cancer. 3 examples: 1. Flutamide 2. Enzalutamide 3. Bicalutamide

Answer 77

Abiraterone (Zytiga) is an FDA approved drug for the treatment of castration-resistant prostate cancer that acts as an inhibitor of the CYP17 enzyme. CYP17 is needed for the synthesis of androgens, including testosterone.

Answer 78

1. Hormone supplementation in cases of deficiency 2. Treat muscle loss associated with trauma or disease (e.g., HIV, renal dialysis, some anemias) 3. Female-to-male gender reassignment 4. Anti-aging therapy (controversial) 5. Male contraception (experimental)

Answer 79

Oral administration is not used because oral testosterone is subject to high first-pass metabolism by the liver. Instead, injectable testosterone enanthate and testosterone cypionate are used: - Can be administered intramuscularly - Injected every 2-4 weeks - Increases plasma testosterone to physiologic concentrations in hypogonadal men Other routes of administration that avoid first-pass metabolism include: - Transdermal testosterone patches - Topical gel formulation - Sub-lingual tablet

Answer 80

<3.0 ng/mL

Answer 81

Androgen drugs are not FDA approved for use in aging men that do not meet the definition of hypogonadism

Answer 82

1. Estrogen-progestin combinations 2. Progestin-only contraception

Answer 83

Combination estrogen-progestin contraceptives suppress GnRH, LH, and FSH secretion and follicular development. Primary birth control mechanism: inhibit ovulation Secondary mechanisms: 1. Alterations in tubal peristalsis needed for transport of both egg/sperm 2. Alterations in endometrial receptivity 3. Alterations in cervical mucus secretions

Answer 84

Continuous low-dose oral progestins can be used in situations where estrogen treatment is not desirable. It prevents ovulation 70%-80% of the time by: 1. Alters the frequency of GnRH pulsing 2. Decreases anterior pituitary gland responsiveness to GnRH This form of contraceptive is 96%-98% effective, suggesting secondary mechanisms also important.

Answer 85

Male contraception is experimental and aims to produce azoospermia (absence of sperm in the ejaculate). - This is difficult because even 99% reduction would still leave possibility of fertility, and want to avoid suppression of libido or ED In clinical trials androgen + progestin was superior to androgen alone (e.g., testosterone + norgestrel), and on average, 60% of men become azoospermic but there are significant adverse effects.

Answer 86

Anabolic steroids are schedule III controlled substances and illegal to use or distribute without a prescription

Answer 87

1. Anabolic steoids shut down normal synthesis of testosterone by feedback inhibition on the hypothalamus, causing abnormal ratios of testosterone to its precursors and metabolites. - A test:epitest ratio >4:1 is considered evidence of doping 2. Synthetic steroids are typically manufactured from plant sterols, giving them a unique carbon isotope that can be detected by mass spectrometry

Answer 88

Dementia is the progressive deterioration of memory and cognitive function; it is **NOT** a single disease. 2 types: 1. Reversible dementia: theoretically can treat underlying cause and reverse dementia 2. Irreversible dementia: caused by an incurable condition

Answer 89

Approximately 5-10% of all AD, defined as AD diagnosed before age 65 (can be much earlier). Approximately half of cases are familial, from inheritance of a mutant gene: APP, PSEN1, PSEN2, but other cases have no obvious cause.

Answer 90

Increased risk for early onset AD in Down syndrome

Answer 91

Most common type of AD, defined as AD diagnosed after age 65. May be influenced by genetic factors (e.g., APOE4), and may also be influenced by environmental factors, lifestyle, other health factors, and even trauma.

Answer 92

Neuropathological component of Alzheimer's disease, aggregated (fibrillary) forms of beta-amyloid **extracellularly**

Answer 93

Neuropathological component of Alzheimer's disease, contain primarily abnormal tau proteins **in** neurons

Answer 94

AD is proposed to be a continuum of severity, with lesser forms as MCI and higher forms consisting of increasingly severe AD

Answer 95

1. Acetylcholinesterase inhibitors (3 drugs) 2. Glutamate receptor partial antagonist (1 drug) 3. Abeta targeting antibodies (immunotherapy) (2 drugs, recently approved, some controversy and limitations, 1 going to be discontinued

Answer 96

Hypothesis: AD is due to a decrease in acetylcholine (ACh) levels and dysfunction of cholinergic neurons in the brain. This is believed because neuronal death is prevalent in AD, a result of decreased ACh.

Answer 97

Acetylcholinesterase inhibitor FDA approved to treat Alzheimer's disease. Prevents the breakdown of ACh. Only modest impacts on cognition, function, and behavior in Alzheimer's disease patients, **DO NOT** impact disease course. Not all patients will see benefit. Can cause side effects some of which due to effects in periphery.

Answer 98

There is elevated glutamate activity in AD; this is why memantine (Namenda), a glutamate receptor partial antagonist, is used to treat AD

Answer 99

Glutamate NMDA-type receptor non-competitive partial antagonist that is FDA approved to treat Alzheimer's disease. It may have actions at other receptors as well. Usually given in combination with AChE inhibitor, called Namzaric (combination of memantine and donepezil). Has modest effects, **DOES NOT** alter disease course. Side effects (less than 7% of patients): headache, confusion , constipation

Answer 100

Goal: clear (or prevent worsening of) Abeta forms that are proposed to cause the disease Antibody: a protein complex made and used by the immune system to neutralize foreign invaders. Each antibody recognizes a specific protein sequence (antigen or epitope). Can be engineered in a lab. Lecanemab-irmb (Leqembi): antibody that binds with high affinity to Abeta oligomers/protofibrils. It was FDA approved in early 2023 in AD, and treatment is initiated in MCI with confirmed amyloid presence.

Answer 101

Antibody treatment for Alzheimer's disease that binds with high affinity to Abeta oligomers/protofibrils. FDA approved in 2023, and treatment is initiated in MCI or early dementia *only* with confirmed amyloid presence. Mechanism: 1. Antibody binds with high affinity to Abeta oligomers/protofibrils 2. Antibody recruits macrophages and encourages the "eating" of Abeta In 2023 clinical trial, lecanemab-irmb (Leqembi) significantly reduced amyloid plaque burden relative to those who received the placebo. In this same trial, the drug also had modest improvements with regard to cognitive decline (slowed decline). Side effects: - Risk for amyloid related imaging abnormalities (ARIA) (edema, microhemorrhage) in about 20% of patients - Rare fatal brain hemorrhage in some patients - Infusion reactions

Answer 102

1. Not enough racial and ethnic diversity in trials 2. Difference in cognitive decline was only 2.7% (0.45 on 18 point scale) 3. ARIA and hemorrhage risk 4. Does modest efficacy justify cost and patient burden?

Answer 103

Infectious disease - a condition caused by the invasion and multiplication of pathogenic microorganisms, such as bacteria, viruses, fungi, parasites, and prions, within the body Pathogen - the specific microorganism that causes the disease

Answer 104

Sir Alexander Fleming went on vacation in 1928 and deduced something in mold (Penicillium rubens) was preventing Staph bacteria growth. He tried to purify penicillin, but was unstable; however, crude extract did prevent the growth of other types of bacteria

Answer 105

1939-1941 scientists in England purified enough penicillin for animal studies and to treat one human, but summer 1941 they went to the US...Dept. of Agriculture Labs in Peoria, IL made some improvements and searched for strains of Penicillium rubens that produced more penicillin. Scientists at UW were involved in mutagenizing cantaloupe strain and screening for better producers, and they developed a strain that produced about 9x more penicillin than original cantaloupe strain. - Decided not to patent, and before end of WWII, industry was making enough penicillin for civilian use

Answer 106

A naturally derived, synthetic, or semi-synthetic substance antagonistic to the growth of other microorganisms Antibiotic can be used to refer to drugs that target bacteria or drugs that target other microorganisms

Answer 107

1. Innate resistance (insensitivity) 2. Acquired resistance

Answer 108

Evolution! In the hundreds of millions of years that antibiotics have been produced by some microbes to act on their neighbors, evolutionary pressure has been at work for the bacteria under attack to devise resistance mechanisms to survive.

Answer 109

The clinical use of antibiotics produces an intrinsic selection for heritable resistance to said antibiotics in bacteria. I.e., some bacteria in a population are already resistant. When drugs start being used more and more, the bacteria naturally select for the traits that these resistant bacteria have.

Answer 110

1. Unnecessary/inappropriate use (over-prescribing) - **massive** problem, 709 prescriptions per 1000 people in US 2. Not taking complete dose 3. Using broad spectrum antibiotics when narrow spectrum ones would have killed target organism 4. Antibiotic use in livestock

Answer 111

1. Most bacteria have a cell wall while mammalian cells do not 2. Cell wall assembly is a complex process, and there are many enzymes that can be targeted as a result 3. Antibiotics work on the cell wall when cells are actively growing

Answer 112

Beta-lactams are antibiotics that halt production of the cell wall by binding to the transpeptidase at the Penicillin Binding Protein (PBP) site, resulting in the inhibition of transpeptidation, thus halting peptidoglycan synthesis. - Peptidoglycans compose the bacterial cell wall. Issues with beta-lactams: 1. Allergies 2. Not effective against all types of bacteria (no antibiotics are, however) 3. Some side effects, but rare 4. Bacterial resistance (e.g., beta-lactamases) Spectrum varies across beta-lactam families: - Penicillins vary drug-to-drug - Cephalosporins have broader spectrum of action than penicillins (overall more resistant to beta-lactamases)

Answer 113

A series of enzymes in bacteria that cleave the beta-lactam ring, allowing bacteria to be resistant to beta-lactam antibiotics like penicillin. Some newer semi-synthetic drugs in these antibiotic families are less susceptible to beta-lactamase activity, and beta-lactamase inhibitors like amoxicillin + clavulanate potassium (Augmentin) can be used with beta-lactam drugs to help circumvent this resistance mechanism. There is also concern for extended spectrum beta lactamase (ESBL) expressing bacteria, which are resistant to a wide spectrum of antibiotics.

Answer 114

Beta-lactamase inhibitor that is often used with beta-lactam antibiotics to circumvent the beta-lactamase resistance mechanism

Answer 115

1. Cell wall 2. Bacterial translation

Answer 116

Azithromycin (Zithromax, "Z Pak") is a semi-synthetic macrolide antibiotic that is slowly released by tissues to target bacterial translation. - Broad spectrum - Tissue concentration higher than serum concentrations - Once daily dosing and shortened duration of treatment 2 problems: 1. Can cause GI side effects 2. Can prolong QT interval

Answer 117

The healthy intestine contains large quantities of commensal "good" bacteria that interfere with the ability of pathogenic bacteria to colonize the gut. Broad-spectrum antibiotics kill this commensal bacteria, creating an ecological niche for other "bad" bacteria, which can lead to antibiotic-associated diarrhea (including that caused by C. difficile).

Answer 118

Rifampin (Rifadin), an antibiotic, decreases the efficacy of birth control pills due to induction of enzymes in the liver that metabolize the hormones in these pills (or basically any birth control method that uses hormones). Good news is that rifampin's main use is in TB. As for other antibiotics, no large studies have prove any effect on birth control efficacy, but some could be impacted.

Answer 119

Treating TB: - minimum 6 months of therapy - antibiotic combinations Pathogen of TB is Mycobacterium tuberculosis: 1. Mycobacteria have a "waxy" cell wall that is different than other bacteria 2. Slow growing or even dormant 3. Intracellular pathogen 4. Quickly develops resistance to drugs, so drugs must be used in combination

Answer 120

Bedaquiline (Sirturo) is an FDA approved drug as part of combination therapy for active pulmonary multi-drug resistant TB that works by targeting the ATP synthase. - 5+ and only use when another effective treatment regimen cannot otherwise be provided - One trial indicated increase in all cause mortality - Prolongs QT interval and may have liver toxicities - CYP3A4 substrate

Answer 121

Tumor - abnormal mass of cells resulting from defects in normal control of cell survival, proliferation, and differentiation Benign tumor - does not invade the surrounding tissues or spread to other parts of the body Malignant tumor (= cancer) - can invade surrounding tissue and spread to other parts of the body (metastasize), will get worse Tumors are often named after where they arise

Answer 122

Regimen - treatment plan (drugs, dosages, durations) Adjuvant therapy - additional therapy given after primary treatment to decrease risk of cancer return Neoadjuvant therapy - treatment given to shrink tumor before main therapy (i.e., surgery)

Answer 123

Refers to therapy in which cytotoxic (cell killing) agents are deployed, targeting rapidly dividing cells (usually small molecules)

Answer 124

Important part of the cytoskeleton of the cell that acts as "tracks" for transport of material within the cell. - Part of the miotic spindle - Made of polymerized tubulin subunits - Dynamic structures They are often the target of chemotherapy drugs in cancer patients.

Answer 125

Placitaxel (Taxol) is a chemotherapy drug that was orginally discovered as natural product isolated from bark of yew tree that acts by binding to and stabilizing microtubules, which are essential components of the cell's cytoskeleton. This stabilization prevents the normal breakdown and reassembly of microtubules during cell division, leading to cell death in a variety of solid tumors. - Originally though to induce a "mitotic arrest" by poisoning the mitotic spindle, but now thought to cause abnormal chromosome segregation Side effects: typical chemo, such as nausea, vomiting, etc. Delayed toxicities: neuropathy, myelosuppresion - Nanoparticle formulation of this drug, such as nab-paclitaxel (Abraxane) may reduce some toxicities Resistances can arise from: 1. Increased expression of proteins that pump drug out of cell 2. Expression (increased or mutant) of proteins that promote mitosis or block cell death 3. Changes in tubulin

Answer 126

Goal of targeted cancer therapies is to attack tumor cells while sparing normal cells by targeting molecular pathways involved in cancer cell survival/progression

Answer 127

Some kinases have abnormal activity in cancer (over-expression, mutation, etc.), so they are often targets in targeted cancer therapies by kinase inhibitors. Chronic myeloid leukemia (CML) frequently harbors a specific chromosomal abnormality called a translocation (in CML cells called Philadelphia chromosome). The result of the Philadelphia chromosome is a fusion "oncoprotein" called BCR-ABL that harbors active ABL kinase activity. Imatinib (Gleevec) targets ABL kinases, selectively killing CML cells.

Answer 128

Imatinib (Gleevec) is a targeted cancer drug for Chronic Myeloid Leukemia (CML) and other forms of cancer that works by inhibiting the ABL kinase and other kinases important in other tumors. Estimated CML 5 year survival rate is now 95% due to this drug. Side effects: fluid retention, muscle cramps, others Resistance: common cause is due to point mutations in BCR-ABL, the "oncoprotein" formed by the Philadelphia chromosome in CML. - Drugs have been developed to inhibit imatinib-resistant BCR-ABL.

Answer 129

Nivolumab (OPDIVO) is a targeted cancer drug that can be used for variety of tumors that works by as an anti-PD1 antibody, allowing cytotoxic T cells to actively remove tumor cells by blocking PD-L1 from inactivating them by binding with PD-1 on T cells. AKA "checkpoint" inhibitor. Side effects: rash, fatigue, can more rarely see severe immune-related adverse events (irAEs) - thought to be caused by general immunologic enhancement caused by this drug Sometimes used in combination with an inhibitor of another "checkpoint," a kinase inhibitor, or traditional chemotherapy. Not all patients respond; one hypothesis as to why is that higher mutational load = better response to drug. - For some tumor types, FDA requires screening tumor for PD-L1 expression (biomarker for response to drug).

Answer 130

In the US, male, female, and overall cancer death rates are steadily declining

Exam 3 Flashcards

(155 cards)