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Hunter Syndrome Pathophysiology and Elaprase Production
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Hunter Syndrome Pathophysiology and Elaprase Production

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Questions and Answers

What is the main purpose of inserting the IDS gene into the albumin locus?

  • To decrease the amount of mRNA transcripts in the liver cells
  • To increase the expression of the I2S enzyme in the liver cells
  • To reduce the symptoms of Hunter syndrome in the liver cells (correct)
  • To construct AAVs with three different plasmids

    • What is the role of the I2S protein in the hepatocyte cells?

  • To increase the amount of GAGs in the lysosome
  • To construct AAVs with Zn finger nucleases
  • To facilitate the breakdown of GAGs in the lysosome (correct)
  • To reduce the expression of the IDS gene in the liver cells

    • What is the function of the AAVs in gene therapy?

  • To construct Zn finger nucleases
  • To increase the amount of mRNA transcripts in the liver cells
  • To deliver the IDS gene to the liver cells (correct)
  • To reduce the expression of the IDS gene in the liver cells

    • What is the purpose of using Zn finger nucleases in gene therapy?

    <p>To induce double-strand breaks in the genome</p> Signup and view all the answers

    What is the result of inserting the IDS gene into the albumin locus?

    <p>Increased expression of the I2S protein in the liver cells</p> Signup and view all the answers

    What is the role of the albumin gene in gene therapy?

    <p>To serve as a locus for the insertion of the IDS gene</p> Signup and view all the answers

    What is the goal of gene therapy for Hunter syndrome?

    <p>To facilitate the breakdown of GAGs in the lysosome</p> Signup and view all the answers

    What is the function of the IDS gene in gene therapy?

    <p>To facilitate the breakdown of GAGs in the lysosome</p> Signup and view all the answers

    What is a common feature of Systemic Lupus Erythematosus (SLE)?

    <p>Cyclic exacerbation of disease</p> Signup and view all the answers

    Which of the following is NOT a complication of Systemic Lupus Erythematosus (SLE)?

    <p>Hypertension</p> Signup and view all the answers

    What is the target of B cell-targeting therapies in autoimmune diseases?

    <p>B cell surface markers</p> Signup and view all the answers

    What is the mechanism of action of Rituximab (anti-CD20 mAb)?

    <p>Antibody-dependent cell-mediated cytotoxicity</p> Signup and view all the answers

    What is a hallmark feature of lupus nephritis?

    <p>Immune complex deposition</p> Signup and view all the answers

    What is a complication of long-term steroid use in Systemic Lupus Erythematosus (SLE)?

    <p>Damage from medications</p> Signup and view all the answers

    What is a characteristic clinical feature of Systemic Lupus Erythematosus (SLE)?

    <p>All of the above</p> Signup and view all the answers

    What is the mechanism of action of anti-CD19 mAb in autoimmune diseases?

    <p>B cell depletion</p> Signup and view all the answers

    What is the primary function of autoantibodies secreted by plasma cells in autoimmune diseases?

    <p>To promote autoimmune diseases</p> Signup and view all the answers

    What is the major challenge in targeting plasma cells for autoimmune disease treatment?

    <p>All of the above</p> Signup and view all the answers

    What is the limitation of Bortezomib treatment in autoimmune diseases?

    <p>Increased risk of infections</p> Signup and view all the answers

    What is the goal of personalized medicine in autoimmune diseases?

    <p>To consider each patient and disease individually</p> Signup and view all the answers

    What is the purpose of genome-wide screening in autoimmune diseases?

    <p>To detect genetic mutations</p> Signup and view all the answers

    What is the benefit of integrating multiple datasets in autoimmune disease research?

    <p>To identify correlations between genetic and environmental factors</p> Signup and view all the answers

    What is the primary goal of preventive medicine in autoimmune diseases?

    <p>To identify and manage risk factors</p> Signup and view all the answers

    What is the purpose of longitudinal monitoring of high-risk patients in autoimmune diseases?

    <p>To predict disease progression</p> Signup and view all the answers

    What is the primary mechanism by which HER2 is activated?

    <p>Heterodimerization with other HER family members</p> Signup and view all the answers

    Which of the following HER family members does not possess tyrosine kinase activity?

    <p>HER3</p> Signup and view all the answers

    What is a characteristic of HER2 in breast cancer?

    <p>Amplification of the HER2 gene</p> Signup and view all the answers

    What is the function of the extracellular domain of HER2?

    <p>To adopt a conformation resembling a ligand-activated state</p> Signup and view all the answers

    What are the consequences of HER2 activation on cell behavior?

    <p>Cell growth, survival, and cell cycle progression</p> Signup and view all the answers

    What is the primary reason for the chronic progressive nature of Hunter syndrome?

    <p>Accumulation of partially degraded GAGs</p> Signup and view all the answers

    What is the consequence of HER2 shedding its extracellular domain?

    <p>Constitutive activation of HER2</p> Signup and view all the answers

    What is the consequence of incorrect glycosylation of the I2S protein?

    <p>Impaired binding to the mannose-6-phosphate receptor</p> Signup and view all the answers

    What is the mechanism by which Elaprase replaces the deficient I2S protein in Hunter syndrome?

    <p>Lysosomal targeting through mannose-6-phosphate receptor</p> Signup and view all the answers

    What is the result of the accumulation of partially degraded GAGs in Hunter syndrome?

    <p>Thickening of skin and organs</p> Signup and view all the answers

    What is the function of the IDS gene?

    <p>Production of the I2S protein</p> Signup and view all the answers

    What is the limitation of Elaprase in the treatment of Hunter syndrome?

    <p>Inability to cross the blood-brain barrier</p> Signup and view all the answers

    What is the effect of Bortezomib on plasma cells?

    <p>Induce plasma cell apoptosis</p> Signup and view all the answers

    What is the mechanism of action of Atacicept?

    <p>Bind to BAFF and APRIL</p> Signup and view all the answers

    What is the outcome of CD19-targeting CAR-T cell therapy in clinical trials for SLE?

    <p>High efficacy in 5 out of 5 patients</p> Signup and view all the answers

    What is the limitation of Bortezomib treatment in autoimmune diseases?

    <p>Adverse effects</p> Signup and view all the answers

    What is the effect of Rituximab on SLE?

    <p>Not very effective for SLE</p> Signup and view all the answers

    What is the current understanding of long-term remission in CD19-targeting CAR-T cell therapy for SLE?

    <p>Unknown</p> Signup and view all the answers

    What is the underlying pathology of lupus nephritis?

    <p>Immune complex deposition</p> Signup and view all the answers

    What is the goal of B cell-targeting therapies in autoimmune diseases?

    <p>Depletion of autoreactive B cells</p> Signup and view all the answers

    What is a characteristic feature of systemic lupus erythematosus (SLE)?

    <p>Cyclic exacerbation of disease</p> Signup and view all the answers

    What is a common complication of long-term steroid use in SLE?

    <p>Osteoporosis</p> Signup and view all the answers

    What is the mechanism of action of Rituximab (anti-CD20 mAb)?

    <p>Antibody-dependent cell-mediated cytotoxicity</p> Signup and view all the answers

    What is a characteristic clinical feature of SLE?

    <p>All of the above</p> Signup and view all the answers

    What is the direct consequence of decreased clearance of apoptotic cells in Systemic Lupus Erythematosus (SLE)?

    <p>Prolonged exposure of potential auto-antigens</p> Signup and view all the answers

    What is the target of B cell-targeting therapies in autoimmune diseases?

    <p>B cell surface markers (CD20, CD19)</p> Signup and view all the answers

    What is the role of IFNα in Systemic Lupus Erythematosus (SLE)?

    <p>Promoting tissue damage and inflammation</p> Signup and view all the answers

    What is a complication of SLE?

    <p>All of the above</p> Signup and view all the answers

    What is the characteristic feature of lupus nephritis?

    <p>Deposition of immune complexes in kidneys glomeruli</p> Signup and view all the answers

    What is the consequence of decreased anti-inflammatory heme oxygenase-1 (HO-1) in Systemic Lupus Erythematosus (SLE)?

    <p>Increased tissue damage and inflammation</p> Signup and view all the answers

    What is the role of infiltrating immune cells in Systemic Lupus Erythematosus (SLE)?

    <p>Promoting tissue damage and inflammation</p> Signup and view all the answers

    What is the consequence of reduced elimination of autoreactive B cells in Systemic Lupus Erythematosus (SLE)?

    <p>Increased activation of autoreactive B cells</p> Signup and view all the answers

    What is the characteristic feature of immune complexes in Systemic Lupus Erythematosus (SLE)?

    <p>Deposition in kidneys glomeruli</p> Signup and view all the answers

    What is the consequence of decreased ILC2 cells in Systemic Lupus Erythematosus (SLE)?

    <p>Increased tissue damage and inflammation</p> Signup and view all the answers

    What is a crucial step in the development of metastatic cancer?

    <p>Cell transformation</p> Signup and view all the answers

    How do growth factors and integrin signaling affect normal healthy cells?

    <p>They promote proliferation</p> Signup and view all the answers

    What is the role of E-cadherin in normal healthy cells?

    <p>It inhibits proliferation</p> Signup and view all the answers

    What is the consequence of acquiring successive hallmark capabilities and DNA mutations in normal cells?

    <p>They become cancerous</p> Signup and view all the answers

    What is the role of VEGF in cancer cells?

    <p>It promotes angiogenesis</p> Signup and view all the answers

    What is the function of telomerase in cancer cells?

    <p>It maintains telomere length</p> Signup and view all the answers

    What is the result of p53 loss in cancer cells?

    <p>It promotes genomic instability</p> Signup and view all the answers

    What is the role of MMPs in cancer cells?

    <p>They break down the extracellular matrix</p> Signup and view all the answers

    What is a characteristic of autoantibodies in SLE?

    <p>They are against molecules in nuclei</p> Signup and view all the answers

    What is the significance of the presence of immune deposits on the inside and outside surfaces of the glomerular capillaries in SLE?

    <p>It appears thickened</p> Signup and view all the answers

    What is the relationship between mortality in SLE and early organ damage?

    <p>Mortality in SLE is linked to early organ damage</p> Signup and view all the answers

    What is the role of TLR7 and TLR9 in SLE?

    <p>They are 'danger sensors' on antigen presenting cells and B cells</p> Signup and view all the answers

    What is the pattern of disease exacerbation in SLE?

    <p>Cyclic</p> Signup and view all the answers

    What is the significance of the survival probability graph in SLE?

    <p>It shows the effect of early organ damage on mortality</p> Signup and view all the answers

    What is the target of autoantibodies in SLE?

    <p>Molecules in the nuclei</p> Signup and view all the answers

    What is the consequence of the presence of immune deposits on the glomerular capillaries in SLE?

    <p>It leads to an increase in disease severity</p> Signup and view all the answers

    What is the primary factor that determines the volume of distribution for a drug that is very lipophilic?

    <p>Total body water</p> Signup and view all the answers

    A drug has a volume of distribution of 0.2 L/kg body weight. What is the most likely compartment that the drug is restricted to?

    <p>Extracellular fluid</p> Signup and view all the answers

    What is the primary mechanism by which the kidney excretes unchanged active drugs?

    <p>Tubular secretion</p> Signup and view all the answers

    What is the relationship between the volume of distribution and the total amount of drug in the body?

    <p>Vd = total amount of drug in the body / [plasma]</p> Signup and view all the answers

    A drug has a high volume of distribution (>0.55 L/kg body weight). What is the most likely explanation for this?

    <p>The drug is highly lipophilic</p> Signup and view all the answers

    What is the primary factor that determines the renal clearance of a drug?

    <p>Glomerular filtration rate</p> Signup and view all the answers

    What is the primary determinant of the time required to reach a steady state concentration of a drug in the plasma?

    <p>Plasma half-life</p> Signup and view all the answers

    What is the rate of elimination for a drug that follows first-order elimination kinetics?

    <p>Driven by the plasma concentration</p> Signup and view all the answers

    What is the effect of a small increase in dose on the plasma concentration of a drug that follows zero-order elimination kinetics?

    <p>A disproportionate increase in plasma concentration</p> Signup and view all the answers

    What is the relationship between the dose rate and the clearance of a drug at steady state?

    <p>Dose rate is equal to clearance</p> Signup and view all the answers

    What is the formula for calculating the plasma half-life of a drug?

    <p>t½ = 0.693 x Vd / CL</p> Signup and view all the answers

    What is the effect of repeated dosing on the plasma concentration of a drug that follows first-order elimination kinetics?

    <p>The plasma concentration will reach a steady state</p> Signup and view all the answers

    What is the primary factor that determines the time to eliminate a drug from the plasma?

    <p>Plasma half-life</p> Signup and view all the answers

    What is the relationship between the dosage interval and the mean steady state plasma concentration of a drug?

    <p>The dosage interval does not affect the mean steady state plasma concentration</p> Signup and view all the answers

    What is the primary factor that determines the reabsorption of a drug in the kidneys?

    <p>Lipid solubility</p> Signup and view all the answers

    What is the effect of enzyme metabolism on lipid-soluble drugs?

    <p>Makes them more water-soluble</p> Signup and view all the answers

    What is the formula for calculating the total amount of a drug eliminated via the kidneys?

    <p>Amount filtered + amount secreted - amount reabsorbed</p> Signup and view all the answers

    What is the primary difference between Phase I and Phase II reactions in drug metabolism?

    <p>Phase I reactions involve functionalization, while Phase II reactions involve conjugation</p> Signup and view all the answers

    What is the expected difference in renal clearance between a very lipophilic drug and a highly ionized drug?

    <p>The lipophilic drug would have a lower renal clearance</p> Signup and view all the answers

    What is the primary role of drug metabolism in the body?

    <p>To make lipid-soluble drugs more water-soluble</p> Signup and view all the answers

    What is the purpose of using three different AAVs in gene therapy for Hunter syndrome?

    <p>To deliver the IDS gene, ZF1, and ZF2 plasmids</p> Signup and view all the answers

    What is the expected outcome of inserting the IDS gene into the albumin locus?

    <p>Enhanced breakdown of GAGs in hepatocytes</p> Signup and view all the answers

    What is the role of Zn finger nucleases in gene therapy for Hunter syndrome?

    <p>Editing the genome to repair the IDS gene mutation</p> Signup and view all the answers

    What is the consequence of inserting the IDS gene into the albumin locus in theory?

    <p>Lessened burden of Hunter syndrome on hepatocyte cells</p> Signup and view all the answers

    What is the purpose of using gene therapy to treat Hunter syndrome?

    <p>To deliver the IDS gene to liver cells to produce I2S protein</p> Signup and view all the answers

    What is the benefit of using AAVs in gene therapy for Hunter syndrome?

    <p>Targeted delivery of the IDS gene to liver cells</p> Signup and view all the answers

    What is the goal of gene therapy for Hunter syndrome?

    <p>To express the IDS gene in liver cells</p> Signup and view all the answers

    What is the expected outcome of gene therapy for Hunter syndrome?

    <p>Lessened burden of Hunter syndrome on hepatocyte cells</p> Signup and view all the answers

    What is a consequence of HER2 amplification in breast cancer?

    <p>More aggressive disease</p> Signup and view all the answers

    What is the mechanism of action of therapeutic antibodies in cancer treatment?

    <p>All of the above</p> Signup and view all the answers

    What is the name of the gene that encodes the HER2 receptor?

    <p>ERBB2</p> Signup and view all the answers

    What is the purpose of conjugating therapeutic antibodies with other molecules?

    <p>To enhance therapeutic efficacy</p> Signup and view all the answers

    What is the percentage of breast cancer patients that exhibit HER2 amplification?

    <p>25%</p> Signup and view all the answers

    What is the primary function of therapeutic antibodies in cancer treatment?

    <p>To directly target cancer cells</p> Signup and view all the answers

    What is the result of HER2 amplification in breast cancer cells?

    <p>More aggressive disease</p> Signup and view all the answers

    What is the purpose of using therapeutic antibodies as single agents?

    <p>To directly target cancer cells</p> Signup and view all the answers

    What is the primary mechanism by which therapeutic monoclonal antibodies induce cell death?

    <p>Antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity</p> Signup and view all the answers

    What is the purpose of 'humanisation' of monoclonal antibodies?

    <p>To reduce the host immune response to the antibody</p> Signup and view all the answers

    Which of the following is a mechanism of action of therapeutic monoclonal antibodies that is dependent on the specific antigen recognised by the antibody?

    <p>Antigen-specific binding to cell surface receptors</p> Signup and view all the answers

    What is the role of FcγR in antibody-dependent cellular cytotoxicity?

    <p>Binding of the Fc portion of the antibody to activate NK cells</p> Signup and view all the answers

    What is the outcome of the activation of the complement cascade in antibody-dependent cytotoxicity?

    <p>Formation of the membrane attack complex</p> Signup and view all the answers

    What is the role of the Fc portion of the antibody in antibody-dependent cellular phagocytosis?

    <p>Binding to FcγR on phagocytic cells</p> Signup and view all the answers

    What is the outcome of antibody-dependent cellular phagocytosis?

    <p>Internalisation and degradation of the target tumour cell</p> Signup and view all the answers

    What is the difference between the mechanism of action of BRAF(V600E) and the resistance mutant in the context of MAPK signalling?

    <p>The resistance mutant has a different mechanism of action in MAPK signalling compared to BRAF(V600E)</p> Signup and view all the answers

    What is the primary function of telomerase in cancer cells?

    <p>To re-generate telomeres, rendering the cells resistant to replicative senescence</p> Signup and view all the answers

    Which of the following is a characteristic of the epithelial to mesenchyme transition (EMT)?

    <p>Downregulation of E-cadherin</p> Signup and view all the answers

    What is the consequence of telomere shortening to a critical length?

    <p>Cell undergoes replicative senescence</p> Signup and view all the answers

    Which hallmark of cancer is characterized by the avoidance of senescence?

    <p>Hallmark 5: Enabling replicative immortality</p> Signup and view all the answers

    What is the role of matrix metalloproteases (MMP) in cancer?

    <p>To promote cell invasion</p> Signup and view all the answers

    What is the outcome of the accumulation of genetic lesions in cancer cells?

    <p>The acquisition of 2-7 hallmark capabilities</p> Signup and view all the answers

    What is the role of oncogene expression in cancer cells?

    <p>To promote angiogenesis</p> Signup and view all the answers

    What is the characteristic of cancer cells that enables them to degrade and invade surrounding tissue?

    <p>The increased expression of MMP and Rac</p> Signup and view all the answers

    What is the consequence of HER2 overexpression in breast cancer?

    <p>Reduced survival rate</p> Signup and view all the answers

    What is the target of Trastuzumab (Herceptin)?

    <p>Extracellular domain of HER2</p> Signup and view all the answers

    What is the result of Trastuzumab/Herceptin treatment in metastatic breast cancer?

    <p>Increased clinical benefit</p> Signup and view all the answers

    What is the mechanism of action of Trastuzumab (Herceptin)?

    <p>All of the above</p> Signup and view all the answers

    What is the function of C-cbl ubiquitin ligase?

    <p>Promotes HER2 degradation</p> Signup and view all the answers

    What is the consequence of HER2 shedding its extracellular domain?

    <p>Increased HER2 activity</p> Signup and view all the answers

    What is the effect of Trastuzumab (Herceptin) on HER2-positive breast cancer cells?

    <p>G1 arrest</p> Signup and view all the answers

    What is the mechanism of action of Trastuzumab (Herceptin) on ADCC?

    <p>Activates antibody-dependent cellular cytotoxicity</p> Signup and view all the answers

    Which of the following factors affect reabsorption in the kidneys?

    <p>Lipid solubility and urine flow rate</p> Signup and view all the answers

    What is the purpose of drug metabolism?

    <p>To make lipid-soluble drugs more water-soluble</p> Signup and view all the answers

    What is the difference between Phase I and Phase II reactions in drug metabolism?

    <p>Phase I is functionalization, Phase II is conjugation</p> Signup and view all the answers

    What is the major determinant of the time required to reach steady state concentration of a drug?

    <p>Plasma half-life (t½)</p> Signup and view all the answers

    What is the formula for total amount eliminated via the kidneys?

    <p>Amount filtered + amount secreted - amount reabsorbed</p> Signup and view all the answers

    How does lipid solubility affect renal clearance?

    <p>Lipid-soluble drugs have lower renal clearance</p> Signup and view all the answers

    For a drug with zero-order kinetics, what is the relationship between plasma concentration and half-life?

    <p>Half-life varies with plasma concentration</p> Signup and view all the answers

    What is the formula to calculate the plasma half-life of a drug?

    <p>t½ = 0.693 x Vd/CL</p> Signup and view all the answers

    What is the primary location of enzymes involved in drug metabolism?

    <p>Intra-cellularly</p> Signup and view all the answers

    What is the rate of elimination for a drug that follows first-order kinetics?

    <p>Directly proportional to plasma concentration</p> Signup and view all the answers

    What is the dosage interval that does not affect the mean steady state concentration achieved?

    <p>Dosage interval equal to the half-life</p> Signup and view all the answers

    What is the formula to calculate the maintenance dose rate of a drug?

    <p>DR = CL x target Cp</p> Signup and view all the answers

    What is the relationship between clearance and rate of elimination at steady state?

    <p>Rate of elimination is equal to clearance</p> Signup and view all the answers

    What is the characteristic of a drug that follows zero-order kinetics?

    <p>Rate of elimination is independent of plasma concentration</p> Signup and view all the answers

    What is the unit of measurement for Volume of Distribution (Vd)?

    <p>Volume (L or mL)</p> Signup and view all the answers

    What is the primary mechanism of renal clearance?

    <p>Glomerular filtration and tubular secretion</p> Signup and view all the answers

    What is the relationship between Volume of Distribution (Vd) and drug distribution?

    <p>Vd is directly proportional to the extent of drug distribution</p> Signup and view all the answers

    What is the impact of high molecular weight and extensive protein binding on Volume of Distribution (Vd)?

    <p>Vd decreases significantly</p> Signup and view all the answers

    What is the consequence of a drug being very lipophilic?

    <p>Vd is high due to extensive distribution</p> Signup and view all the answers

    What is the relationship between the total amount of drug in the body and the plasma concentration?

    <p>Vd = total amount of drug in the body / [plasma]</p> Signup and view all the answers

    What is the primary determinant of the time required to reach a steady state concentration with repeat dosing?

    <p>Plasma half-life (t½)</p> Signup and view all the answers

    What is the relationship between the plasma half-life (t½) and the volume of distribution (Vd) and clearance (CL) for most drugs?

    <p>t½ = 0.693 x Vd / CL</p> Signup and view all the answers

    A very lipophilic molecule has a volume of distribution close to which of the following values?

    <p>~0.55 L/kg body weight</p> Signup and view all the answers

    What is the effect of a relatively small change in dose on the plasma concentration of a drug that exhibits zero-order kinetics?

    <p>A disproportionate increase in plasma concentration</p> Signup and view all the answers

    What is the equation that describes the rate of elimination at steady state?

    <p>Rate of elimination = CL x Cp</p> Signup and view all the answers

    What is the primary mechanism by which renal clearance of a drug occurs?

    <p>Tubular secretion and glomerular filtration</p> Signup and view all the answers

    What is the primary factor that determines the time required for the plasma concentration to fall by half?

    <p>Plasma half-life (t½)</p> Signup and view all the answers

    A drug has a high volume of distribution due to which of the following properties?

    <p>High lipophilicity</p> Signup and view all the answers

    What is the relationship between the plasma half-life (t½) and the time required to eliminate the drug?

    <p>The time required to eliminate the drug is equal to 4-5 times the plasma half-life</p> Signup and view all the answers

    What is the primary factor that determines the renal clearance of a drug?

    <p>All of the above</p> Signup and view all the answers

    A drug is metabolized to an inactive form through which of the following pathways?

    <p>Metabolic degradation</p> Signup and view all the answers

    What is the effect of the dosage interval on the mean steady state plasma concentration?

    <p>The dosage interval has no effect on the mean steady state plasma concentration</p> Signup and view all the answers

    What is the equation that describes the maintenance dose rate?

    <p>Maintenance dose rate = CL x target Cp</p> Signup and view all the answers

    What is the unit of volume of distribution?

    <p>L/kg body weight</p> Signup and view all the answers

    A drug has a high volume of distribution due to which of the following mechanisms?

    <p>Distribution throughout total body water</p> Signup and view all the answers

    What is the relationship between the volume of distribution and the total amount of drug in the body?

    <p>Vd = total amount of drug in the body / [plasma]</p> Signup and view all the answers

    What is the main purpose of Phase II drug metabolism?

    <p>To make the metabolite more water-soluble</p> Signup and view all the answers

    What is the common feature of Phase II drug metabolism reactions?

    <p>They are potentially saturable</p> Signup and view all the answers

    What is the typical fate of the metabolite in Phase II drug metabolism?

    <p>It is excreted in the urine or bile</p> Signup and view all the answers

    What is the main site of Phase I drug metabolism?

    <p>Liver and other tissues</p> Signup and view all the answers

    What is the consequence of Phase I drug metabolism?

    <p>The metabolite may be active or toxic</p> Signup and view all the answers

    What is the main difference between Phase I and Phase II drug metabolism?

    <p>Phase I involves oxidation, while Phase II involves conjugation</p> Signup and view all the answers

    What is the effect of Phase II drug metabolism on the drug's half-life?

    <p>It decreases the half-life</p> Signup and view all the answers

    What is the relationship between Phase II drug metabolism and clearance?

    <p>Phase II metabolism increases clearance</p> Signup and view all the answers

    What is the primary reason for the variability in warfarin dosing despite adjusting for CYP2C9 status?

    <p>Polymorphisms in the warfarin target, vitamin K reductase complex (VKORC1)</p> Signup and view all the answers

    What is the primary goal of pharmacogenomics in drug therapy?

    <p>To predict the response of individuals to drugs based on their genetic makeup</p> Signup and view all the answers

    What is the definition of clearance in pharmacokinetics?

    <p>The volume of plasma cleared of drug per unit time</p> Signup and view all the answers

    What is the relationship between the dose rate and clearance in steady-state pharmacokinetics?

    <p>The dose rate is inversely proportional to clearance</p> Signup and view all the answers

    What is the impact of CYP2C9 polymorphisms on warfarin metabolism?

    <p>Reduced enzymatic activity leading to slower metabolism</p> Signup and view all the answers

    What is the primary factor that determines the half-life of a drug?

    <p>The clearance of the drug</p> Signup and view all the answers

    What is the minimum effective concentration of a drug?

    <p>The lowest concentration of the drug in the plasma that produces a therapeutic effect</p> Signup and view all the answers

    What is the primary factor that determines the reabsorption of drugs in the plasma?

    <p>Urine flow rate</p> Signup and view all the answers

    What is the primary goal of achieving a steady-state concentration of a drug?

    <p>To ensure the drug is present at the target site for a sufficient amount of time</p> Signup and view all the answers

    Which of the following is a characteristic of Phase I reactions in drug metabolism?

    <p>Functionalisation</p> Signup and view all the answers

    What is the primary purpose of drug metabolism?

    <p>To make drugs more water soluble</p> Signup and view all the answers

    What is the formula for calculating the total amount of a drug eliminated via the kidneys?

    <p>Amount filtered + amount secreted - amount reabsorbed</p> Signup and view all the answers

    Which of the following drugs would have a higher renal clearance?

    <p>A highly ionised drug</p> Signup and view all the answers

    What is the primary location of the enzymes involved in drug metabolism?

    <p>Intra-cellularly</p> Signup and view all the answers

    What is the primary purpose of enzymatic metabolism in Phase I reactions?

    <p>To increase the polarity of the drug</p> Signup and view all the answers

    What is the primary difference between Phase I and Phase II reactions in drug metabolism?

    <p>Phase I reactions involve functionalisation, while Phase II reactions involve conjugation</p> Signup and view all the answers

    Study Notes

    Hunter Syndrome Pathophysiology

    • Caused by the accumulation of partially degraded GAGs, leading to thickening of tissue and compromising of cell and organ function over time.
    • Results in thickening of skin and organs.
    • Incorrect glycosylation of the I2S protein may interfere with lysosomal targeting through impaired binding to the mannose-6-phosphate receptor.

    Elaprase (Idursulfase) Production for Enzyme Replacement Therapy (ERT)

    • Produced through gene therapy, where the functional IDS gene is inserted into the albumin gene in liver cells.
    • Constructed AAVs are used to deliver the IDS gene to the liver, where hepatocytes express the I2S protein.

    Mechanism of Action of Elaprase in Hunter Syndrome

    • The I2S protein produced in the liver breaks down GAGs in the lysosome, reducing the burden of Hunter syndrome on hepatocyte cells.
    • In theory, this should facilitate the breakdown of GAGs, lessening the symptoms of Hunter syndrome.

    Clinical Success and Limitations of Elaprase

    • Has shown reduction of Hunter syndrome symptoms in the liver and potentially other organs.
    • Limitations include the need for frequent injections and potential immune responses to the enzyme.

    Systemic Lupus Erythematosus (SLE)

    • Characterized by cyclic exacerbation of disease, leading to irreversible tissue damage.
    • Clinical disease onset includes symptoms such as rash, nephritis, arthritis, leukopenia, CNS inflammation, and carditis.
    • Complications include renal failure, atherosclerosis, pulmonary fibrosis, and stroke.

    Current Treatment for Autoimmune Diseases

    • B cell-targeting therapies, such as anti-CD20 mAb and anti-CD19 mAb, aim to deplete B cells and reduce autoimmune responses.
    • Examples of B cell-mediated pathogeneses in autoimmune diseases include lupus and rheumatoid arthritis.

    Potential Target for Autoimmune Diseases

    • Autoantibody-secreting plasma cells, which are derived from autoreactive B cells, are key effector molecules in autoimmune diseases.
    • Depleting plasma cells while redirecting the immune response towards non-autoreactive cells may be a potential strategy.

    Future Perspectives for Treating Autoimmune Diseases

    • New diagnostics, including genome-wide screening and detailed disease stratifying, may improve diagnosis and treatment.
    • Personalized medicine, harnessing high-level data machinery, may allow for individualized treatment approaches.
    • Preventive medicine, identifying risk factors and groups, may help prevent autoimmune disease onset.

    Systemic Lupus Erythematosus (SLE)

    • Activation of the innate immune system is part of the inflammatory response in SLE.
    • Decreased clearance of apoptotic cells leads to prolonged exposure of potential autoantigens.
    • Decreased anti-inflammatory heme oxygenase-1 (HO-1) production contributes to pro-inflammatory responses.
    • Infiltrating lesions and decreased ILC2 leading to increased pro-inflammatory cytokines.
    • Decreased elimination of autoreactive B cells contributes to the development of SLE.

    Cyclic Exacerbation of Disease

    • Lupus nephritis results from the deposition of immune complexes in kidneys, leading to thickened glomerular capillaries.
    • Mortality in SLE is linked to early organ damage, with a lower survival probability in patients with early damage.

    Autoantibodies in SLE

    • Autoantibodies in SLE are against molecules in nuclei, including dsDNA, ribonucleoproteins, and other nuclear proteins complexed with nucleic acids.
    • These autoantigens are ligands for 'danger sensors' such as TLR7 and TLR9 on antigen-presenting cells and B cells.

    Clinical Disease Onset and Damage

    • Clinical disease onset includes rash, nephritis, arthritis, leukopenia, CNS inflammation, and carditis.
    • Irreversible tissue damage includes renal failure, atherosclerosis, pulmonary fibrosis, and stroke.

    Current Treatment for Autoimmune Diseases

    • B cell-targeting therapies, such as anti-CD20 mAb and anti-CD19 mAb, can be used to deplete B cells.
    • Rituximab, an anti-CD20 mAb, has been tested in clinical trials for SLE, but has limited efficacy.

    Potential Treatment for SLE

    • Bortezomib, which induces plasma cell apoptosis, has been tested in clinical trials for SLE, but has adverse effects.
    • Atacicept, which binds both BAFF and APRIL, has been tested in clinical trials for SLE, but has safety issues.
    • CD19-targeting CAR-T cells have been tested in clinical trials for refractory SLE and have shown high efficacy.

    Plasma Half-Life (t½)

    • Plasma half-life (t½) is the time taken for the amount of drug in the plasma to fall by half.
    • It is a major determinant of:
      • Dosing frequency
      • Time to eliminate the drug (4-5 t½s)
      • Time required to reach steady state with repeat dosing (4-5 t½s)

    First Order Elimination Kinetics

    • Rate of elimination is driven by Cp (concentration of drug in plasma)
    • Constant/repeated dosing will achieve a steady state Cp
    • Time to reach steady state is determined by t½
    • Time for "removal" is determined by t½

    Zero Order Kinetics

    • Rate of elimination is independent of Cp
    • For some drugs (e.g. alcohol, aspirin), t½ will vary with plasma [ ]
    • Relatively small changes in dose can lead to disproportionate increase in plasma concentration

    Volume of Distribution (Vd)

    • A theoretical concept: volume into which a drug appears to be distributed with a concentration equal to that of plasma
    • Relates the plasma concentration to the total amount of drug in the body
    • Vd = total amount of drug in the body / [plasma] or Vd = dose / [plasma]
    • Units: volume (or volume/kg body weight)

    Volume of Distribution Examples

    • Vd ~0.05 L/kg body wt: drug retained in vascular 'compartment' (e.g. high mw; extensive protein binding)
    • Vd ~0.2 L/kg body wgt: drug restricted to extracellular fluid (e.g. low MW but hydrophillic)
    • Vd ~0.55 L/kg body wgt: drug distributed throughout total body water (e.g. very lipophilic, digoxin)

    Renal Clearance

    • Glomerular filtration (urine) depends on [free drug] in plasma and GFR
    • Tubular secretion (urine) depends on specific transporters (e.g. OAT, OCT)
    • Reabsorption (plasma) depends on lipid solubility and urine flow rate
    • Total amount eliminated via kidneys = amount filtered + amount secreted – amount reabsorbed

    Drug Metabolism

    • Makes lipid soluble drugs more water soluble so that they can be excreted via the kidneys
    • Depends on many different types of enzymes, mostly located intracellularly
    • Enzymatic metabolism of drugs:
      • Phase I reactions: CATABOLIC, "Functionalisation" (e.g. oxidation, reduction, hydrolysis) → ∴ polarity
      • Phase II reactions: ANABOLIC, "Conjugation" (e.g. combined with endogenous molecule)

    Gene Therapy for Hunter Syndrome

    • Used to treat Hunter syndrome by delivering the IDS gene to the liver cells
    • The IDS gene is added to the albumin gene in liver cells using an AAV vector
    • This results in the production of the I2S enzyme, which breaks down GAGs in the lysosome

    AAV Vector Construction

    • Three plasmids are needed: one for the IDS gene, one for ZF1, and one for ZF2
    • The plasmids are constructed in vitro
    • The AAV vector is used to deliver the IDS gene to the liver cells

    Comparison of Genome Editing Platforms

    • Zn finger nucleases, TALENs, and CRISPR/Cas9 are compared as genome editing platforms
    • Each platform has its own advantages and disadvantages

    Cancer Hallmarks

    • Hallmark 5: Enabling replicative immortality
      • Cancer cells overexpress telomerase, which re-generates telomeres, allowing cells to divide indefinitely
    • Hallmark 6: Activation of invasion and metastasis
      • Cancer cells degrade and invade surrounding tissue, promoting tumor spread
      • Involves downregulation of E-cadherin and increased expression of proteins that promote cell invasion

    Monoclonal Antibody Therapy

    • The first monoclonal antibodies were generated in mice, but had limited therapeutic benefit
    • Humanization of monoclonal antibodies improved their therapeutic potential
    • Mechanisms of action of therapeutic monoclonal antibodies include:
      • Indirect mechanisms: ADCC, CDC, and ADCP
      • Direct mechanisms: antigen-specific binding, blocking of ligand binding site, inhibition of receptor signaling, and apoptosis of target cells

    HER2 Amplification in Breast Cancer

    • HER2 amplification is associated with more aggressive disease and reduced survival
    • Trastuzumab (Herceptin) is a targeted therapy that binds to the extracellular domain of HER2, blocking HER2 heterodimerization and tyrosine kinase activity
    • Results of Phase III trials show that trastuzumab increases the clinical benefit of first-line chemotherapy in metastatic breast cancer that overexpresses HER2

    Plasma Half-Life (t½)

    • Plasma half-life (t½) is the time taken for the amount of drug in the plasma to fall by half.
    • It is a major determinant of dosing frequency, time to eliminate the drug, and time required to reach steady state with repeat dosing.
    • For most drugs, t½ is constant and can be calculated using the formula t½ = 0.693 x Vd / CL.

    Steady State and Dosing

    • The dosage interval does not affect the mean steady state concentration achieved or the rate at which it is achieved.
    • First-order elimination kinetics: rate of elimination is driven by Cp, and constant/repeated dosing will achieve a steady state Cp.
    • Time to reach steady state is determined by t½, and time for "removal" is also determined by t½.

    Zero-Order Kinetics

    • For some drugs (e.g., alcohol, aspirin), the rate of elimination is independent of Cp.
    • Plasma half-life (t½) will vary with plasma concentration for drugs with zero-order kinetics.
    • Relatively small changes in dose can lead to a disproportionate increase in plasma concentration.

    Clearance and Elimination

    • Rate of elimination = CL x Cp.
    • At steady state, dose in = dose out (rate of elimination).
    • Maintenance dose = dose rate equivalent to rate of elimination (RE).

    Renal Clearance

    • Total amount eliminated via kidneys = amount filtered + amount secreted - amount reabsorbed.
    • Reabsorption depends on lipid solubility and urine flow rate.
    • Predict the difference in renal clearance between a very lipophilic drug, a highly ionised drug, and a biological (large molecule).

    Drug Metabolism

    • Drug metabolism makes lipid-soluble drugs more water-soluble so they can be excreted via the kidneys.
    • It depends on many different types of enzymes, mostly located intracellularly.
    • Enzymatic metabolism of drugs involves Phase I reactions (catabolic) and Phase II reactions (anabolic).

    Volume of Distribution (Vd)

    • Volume of distribution is a theoretical concept that estimates the volume into which a drug appears to be distributed.
    • Vd relates the plasma concentration to the total amount of drug in the body.
    • Vd = total amount of drug in the body / [plasma] = dose / [plasma].
    • Units of Vd are volume (or volume/kg body weight).

    Types of Volume of Distribution

    • Vd ~0.05 L/kg body wt: drug retained in vascular 'compartment' (e.g., high mw, extensive protein binding).
    • Vd ~0.2 L/kg body wgt: drug restricted to extracellular fluid (e.g., low MW but hydrophilic).
    • Vd ~0.55 L/kg body wgt: drug distributed throughout total body water (e.g., very lipophilic, digoxin).

    Plasma Half-Life (t½)

    • t½ is the time taken for the amount of drug in the plasma to fall by half
    • It is a major determinant of dosing frequency, time to eliminate the drug, and time required to reach steady state with repeat dosing
    • For most drugs, t½ is constant and can be calculated using the formula: t½ = 0.693 x Vd / CL

    Steady State

    • The dosage interval does not affect the mean steady state concentration achieved or the rate at which it is achieved
    • The rate of elimination is driven by the plasma concentration (Cp) and constant/repeated dosing will achieve a steady state Cp

    Elimination Kinetics

    • First-order elimination kinetics: the rate of elimination is proportional to Cp
    • Zero-order elimination kinetics: the rate of elimination is independent of Cp
    • For drugs with zero-order kinetics, a relatively small change in dose can lead to a disproportionate increase in plasma concentration

    Volume of Distribution (Vd)

    • Vd is the theoretical volume into which a drug appears to be distributed with a concentration equal to that of plasma
    • It relates the plasma concentration to the total amount of drug in the body and is calculated using the formula: Vd = total amount of drug in the body / [plasma]

    Clearance (CL)

    • CL is the volume of plasma cleared of drug per unit time
    • Total CL is the sum of renal CL, hepatic CL, and other CL
    • CL depends on [free drug] in urine, urine flow rate, and GFR

    Renal Excretion

    • Renal CL includes glomerular filtration, tubular secretion, and reabsorption
    • The total amount eliminated via kidneys is the sum of the amount filtered, amount secreted, and amount reabsorbed

    Drug Metabolism

    • Metabolism makes lipid-soluble drugs more water-soluble so that they can be excreted via the kidneys
    • Phase I reactions (oxidation, reduction, hydrolysis) introduce a functional group to the drug molecule
    • Phase II reactions (conjugation with glucuronyl, glycyl, glutathione, acetyl, sulphate, methyl group) make the metabolite more water-soluble

    Pharmacogenomics

    • The use of genetic information to guide drug therapy
    • Genetic differences in the response of individuals to drugs can be predicted from knowledge of their genetic makeup

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    Understanding Hunter Syndrome's effects on tissue and organs, and the production of Elaprase for Enzyme Replacement Therapy through gene therapy.

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