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68 Cards in this Set
- Front
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5 general principles of Organ Transplantation |
1. Match compatible blood type & HLA 2. Multi-drug immunosuppressive tx for synergistic effect (allows lower dose/toxicity for each drug w/ higher efficacy) 3. Intensive induction tx, followed by lower-dose maintenance 4. Monitor for rejection, drug toxicity, & infection 5. Reduce/remove drugs that are causing more problems than benefits |
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Induction therapy typically involves a combination of .......... |
immunosuppressive + biologics (monoclonal or polyclonal antilymphocytic Abs) |
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Induction therapy w/ biologic agents is used to delay the use of nephrotoxic calcineurin inhibitors & to intesify immunosuppresson in high risk pts? What pts are at high risk of rejection? |
repeat transplant pts broadly presensitized pts African-American pts pediatric pts |
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Biologics may be either polyclonal or monoclonal. Which are safer? |
Monoclonal: anti-CD3 mAb (muromonab-CD3 or OKTC), anti-IL-2R mAbs (daclizumab, basiliximab) *monoclonals are made from a single source & have more specificity & less variability in efficacy/toxicity |
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How are Monoclonal Ab's made? |
Hybridoma technology: fuse tumor myeloma cell w/ splenic b cell--> grow in culture media where only fused cells can grow |
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_________ is used as induction therapy tx of acute organ transplant rejection MOA: binds E chain of CD3 on T cell receptor complex--> internalization of T cell receptor--> rapid depletion of T cells & prevents remaining T cells from recognizing Ag--> prevents T cell from producing IL-2--> reduced T cell function |
muromonab-CD3 *made using mice |
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Why are repeated txs w/ muromonab-CD3 (or other mouse monoclonal Abs) CONTRAINDICATED? |
repeat use--> immunization of pt against mouse determinants of Ab--> neutralizes immunosuppressive effects |
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Glucocorticoids are administered before injection of muromonab-CD3 to prevent the release of cytokines & reduce first dose rxns. *also require resuscitation facility What SEs does muromonab-CD3 toxicity cause? |
-"cytokine release syndrome" = fever, chills, N/V, malaise, diarrhea, myalgia--> ARDS, PE, CV collapse (rare, but fatal) (reduced w/ glucocorticoids & successive doses) -Anaphylaxis -"Rebound" organ rejection (when stopped) -Inc infection & cancer |
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What cytokines are responsible for "cytokine release syndrome" (30 mins after injection)? (cytokines are released by activated T cells or monocytes) |
TNF-alpha IL-2 & IL-6 IFN-gamma |
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Why are polyclonal Ab's not as safe? |
polyclonals: lymphocyte immune globulin (ATGAM) antithymocyte globulin/ ATG (THYMOGLOBULIN) are made from multiple sources & efficacy & toxicity varies btwn batches, HOWEVER they have a broader target & are more potent |
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How are polyclonal Ab's made? |
repeated injections of human thymocytes (ATG) or lymphocytes (antilymphocyte globulin, ALG) into animals--> then purifying the serum immunoglobulin fraction |
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_____________ can be used in combo w/ monoclonal Abs for induction therapy, initial rejection, & steroid resistant rejection MOA: act on small, long-lived lymphocytes--> deplete T cells ("thymus dependent" lymphocytes) |
ALG (Antilymphocyte Abs) *obtained from immunization of large animals (horses, etc) |
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What are the SEs of ALG toxicity? |
Pain & redness around the injection site Anaphylaxis & serum sickness (type 3 HSN) Histocytic lymphomas Inc risk of cancer *depletion of T cells can also impair DTH & cellular immunity |
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________ is used for induction therapy in acute renal transplant rejection (w/ immunosuppressives) & acute rejection of other organs, & to reduce severity of GVHD after BMT MOA: deplete circulating lymphocytes by direct cytotoxicity (BOTH complement & cell-mediated) AND block lymphocyte fxn by binding cell surface molecules |
ATG (antithymocyte Abs) *purified gamma globulin obtained from immunization of rabbits |
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ATG contains various cytotoxic Abs that bind to what targets? |
CD2 CD3, CD4, CD8 (T cells) CD8, CD 11a, CD18 CD 25, CD44, CD45 HLA class I & class II on T cells |
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What are the SEs of ATG toxicity? |
fever, chills, & hypotension Serum sickness (type 3 HSN) & glomerulonephritis Anaphylaxis (rare) Leukopenia, thrombocytopenia Inc risk of infection & cancer |
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What are the 2 types of biologics used for induction therapy? |
1. depeleting agents- destroy host immune cells (lymphocyte immune globulin, antithymocyte globulin, & muromonab-CD3 mAb) 2. immune modulators- prevent action of immune cells (muromonab-CD3mAb, anti-IL-2R mAb (bind to alpha chain of IL-2R & block IL-2 from activating T cells) |
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T/F muromonab-CD3 mAb is BOTH a depleting agent & an immune modulator |
TRUE |
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What is the difference btwn chimeric & humanized monoclonal Abs? |
chimeric = entire variable domains are from mouse, rest of Ab is human humanized = CDR (complementary determining region) of the variable domains is human, rest of variable domain is mouse (may be a mix^) *CDR determines Ag binding specificity for Fab (Fab is formed by the variable domains of the light & heavy chains, coming together at the N-terminal ends)(constant region of heavy chain = Fc portion, determines isotype & fxn (type of Ig)) |
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What is the downfall of chimeric monoclonal Abs? (humanized have longer half-life & are better) |
recipients eventually develop Ab's to the mouse variable domains & neutralize them--> inhibits therapeutic effects (eventually become resistant to meds*) |
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_______ & ________ are IgG1 monoclonal Abs that bind IL-2 receptor alpha chains on activated lymphocytes---> block IL-2 from binding *immune modulators (less SE's than depleters*) used in Induction phase (prophylaxis) Which is humanized & preffered? |
Daclizumab (zenapax) & Basiliximab (simulect) *Daclizumab is humanized & preferred over chimeric basiliximab |
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What drugs are used in combo for Maintenance therapy? (Induction phase is predominantly biologics = Abs) |
Calcineurin inhibitor + Glucocorticoid + Mycophenolate mofetil (purine metabolism inhibitor) (usually cut out glucocorticoids in diabetic pts receiving pancreatic transplants) |
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_____________, is used in maintenance therapy* MOA: targets downstream pathway of T-cell receptor signalling--> binds cyclophillin--> inhibiting calcineurin--> inhibits NFAT production of IL-2, IL-3, IFN-gamma--> no T cell proliferation/activation (w/o IL-2) no B cell or granulocyte activity* |
Calcineuron inhibitor: Cyclosporine (normally, Ag binds to T cell receptor--> IP3 pathway activation--> intracellular influx of Ca2+--> activates calcineurin (phosphatase)--> dephosphorylates NFAT--> NFAT enters nucleus & binds DNA--> IL-2, IL-3, etc production--> T cell proliferation (IL-2) |
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__________ can be used for BOTH solid & BMT transplants *BUT does NOT work on primed T cells (that have already seen Ag), only on naive cells *causes severe nephrotoxicity!! |
Cyclosporine |
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__________, is also a calcineuron inhibitor that is used in maintenance therapy*, of SOLID organ transplant * Targets downstream pathway of T-cell receptor signalling by binding to BOTH cyclophilin & FKBP--> more POTENT effects, but also more toxic* What SE's does it cause? |
Calcineurin inhibitor: Tacrolimus SE's: (2N, 3H) Nephrotoxicity* Neurotoxicity Hyperglycemia Hypertension Hyperkalemia |
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________, is also a calcineurin inhibitor, used in maintenance therapy*, of solid or BMT transplant but it DOES NOT cause nephrotoxicity (less potent) What SE does it cause? What is the MOA? |
Calcineurin inhibitor: Sirolimus (Rapamycin) SE: myelosuppression (thrombocytopenia) MOA: Targets downstream pathway of IL-2 receptor signalling--> binds mTOR on FKBP--> inhibits mTOR (kinase)--> prevents T cell proliferation |
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T/F Although Sirolimus (Rapamycin) is considered a calcineuron inhibitor, it DOES NOT inhibit calcineurin OR inhibit production of IL-2 |
TRUE |
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__________, used in maintenance therapy* MOA: bound to CBG in circulation--> dissociate & enter cell--> bind to INTRACELLULAR receptor (GR)--> induces conformational change--> causes GB to dissociate from HSP90 & IP--> enters nucleus w/ GR (as complex)--> complex binds GRE (on DNA)--> gene transcription--> suppress cytokine (IL-1 & IL-6) production |
Glucocorticoids (corticosteroids) *decr cytokine production via neg feedback (low cytokines--> decr endogenous cortisol production) |
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How do corticosteroids downregulate inflammatory responses (anti-inflammatory effects)? (*inhibit cellular immunity) |
1. inhibition of inflammatory mediators- downregulation of IL-1 & IL-6, T cells inhibited from making IL-2 & proliferating 2. inhibition of inflammatory cell migration- interfere w/ neutrophil & monocyte activity 3. promotion of lymphocyte apoptosis- via increased IkB--> decr NFKB & activation of endonucleases |
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Glucocorticoid (corticosteroid) uses? SE: growth retardation in children, hyperglycemia, cataracts, osteopenia, avascular necrosis of bone, inc risk of infection |
Uses: -maintenance therapy for BOTH solid organ transplants & BMT -autoimmune dz (flares) -asthma (inhalant w/ beta agonist, avoids systemic SEs) (try to avoid in diabetics if possible*) |
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____________is an antimetabolite used for maintenance therapy* post-solid organ transplant & post-BMT, lupus, & RA MOA: Inhibits monophosphate dehydrogenase--> inhibits purine synthesis--> Inhibits T & B cell production What is the active metabolite that this drug is hydrolyzed to? |
Mycophenolate mofetil hydrolyzed to mycophenolic acid |
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_________ is a cytotoxic antimetabolite used for kidney transplants* (renally excreted!) MOA: converted to 6-mercaptopurine--> the to 6-thioinosinic acid--> inhibits inosinic acid--> Inhibits purine synthesis--> inhibits DNA replication & lymphocyte proliferation |
Azathioprine *used in anything involving immunosuppression of kidney* |
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Azathioprine degradation (via xanthine oxidase & renal excretion is inhibited by _____________ *requires dose lowering of azathioprine |
Allopurinol |
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_________ is an alkylating agent--> destroys proliferating lymphoid cells *used in SLE, MS, Wegener's granulomatosis *may cause hemorrhagic cystitis! |
Cyclophosphamide |
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_______ is the DOC* for RA & GVHD (post-BMT) MOA: inhibits DNA synthesis--> prevents lymphocyte proliferation |
Methotrexate |
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What drugs are used to tx transplant rejection? |
high dose PULSATILE glucocorticoids polyclonal antilymphocyte Abs (ALG) muromonab-CD3 mAbs (biologics (polyclonal & monoclonal) are the MOST potent agents!!) |
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If rejection is d/t high levels of anti-HLA Abs (anti-alloantigen Abs), what can you do to decrease these? |
plasmapheresis (remove the Abs) IVIG (competitive inhibition, IVIG binds Ags) *can be used in any disorder where pt is creating Abs to something in body (alloantigens or autoantigens (attacked by autoimmune abs) |
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_________ is the DOC for ITP, Autoimmune hemolytic anemia, & Acute Glomerulonephritis (AGN) |
prednisone (glucocorticoid) |
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Autoreactive tissue disorders (SLE, RA, MS, IBD) are initially tx w/ DMARDs (prednisone, cyclophosphamide, methotrexate, etc), if these fail, what drugs are used? |
biologics: Anti-TNF Abs (infliximab, etanercept, adalimumab) Abatacept (recombinant fusion protein) |
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Methotrexate is the DOC for RA, if sxs remain, what is the next step? |
add Anti-TNF Abs: Infliximab, etanercept, adalimumab |
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_________, a chimeric IgG1 monoclonal Ab--> Anti-TNF-alpha -used for RA & Crohn's disease* SE: develop ANA (already present in RA) & normal monoclonal Ab SE's *CI in CHF pts |
*Infliximiab (remicade) |
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______, dimeric fusion protein w/ human IgG1--> Anti- TNF-alpha & TNF-beta -used for RA, polyarticular juvenile RA*, & psoriatic arthritis* SE: develop anti-dsDNA Abs (seen in SLE), ANA |
Etanercept (enebrel) |
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_____, human IgG1 monoclonal Ab--> Anti-TNF-alpha -used in RA (only) |
Adalimumab (humira) |
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________ may also be used in pts w/ RA refractive to methotrexate (DMARDs) & is cheaper than Anti TNF-Abs w/ less global SEs *CI w/ Anti TNF-Abs & w/ Anakinra (IL-IR antagonist, also used for (adult) RA not responding to DMARDs) |
Abatacept |
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Abatacept is a recombinant fusion protein composed of chimeric CTLA-4 + human IgG Fc MOA? |
CTLA-4 on T cells binds to CD80/CD86/B7 on APCs (Abs)--> prevents costimulatory CD28 on T cells from binding to B7 (TCR recognizes autoimmune Ag presented by MHC on APC, but also requires costimulatory binding to be activated)--> prevents T cell activation--> T cell anergy--> decreases the amount of autoreactive T cells & CTLA-4 binding to B7 sends inhibitory signals to active T cells--> down-regulating activity |
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________ is a humanized IgG1 monoclonal Ab that binds to IgE fc region--> IgE antagonist *used to tx asthma |
Omalizumab (per Krishna) |
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Multiple Sclerosis (MS) is an inflammatory disease of CNS white matter. Auto-Abs to _____ & _____ cause (triad): mononuclear cell infiltration demyelination scarring (gliosis) *predominantly in females (20-35) *Type 4 HSN** |
Auto-Abs (activated T cells) to myelin basic protein (MBP) & myelin oligodendrocyte glycoprotein (MOG) *causes demyelination, sx depend on area affected |
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How is relapsing-remitting MS (85% of cases) tx? (reduces relapses by 33%) what is the MOA? |
IFN-Beta (1a or Ib) (or w/ Natalizumab, per Krishna) MOA: interferes w/ costimulatory molecules (B7/CD28 & CD40/CD40L)--> reduces T cell activation deviates response toward TH2--> dampens TH1 response interferes w/ T cell adhesion to endothelium--> prevents migration across BB |
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When relapsing-remitting pts who have been taking IFN-beta begin to show neurological deterioration, it becomes secondary progressive MS. How is this tx? (reduces relapses by 67% (better than IFN-Beta) MOA? |
Mitoxantrone MOA: intercalates DNA--> inhibits DNA synthesis |
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Immunostimulatory drugs are used to tx? (immunizations, cytokines, levamisole, thalidomide, BCG) |
infection Immunodeficiency cancer |
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_____________ is used post-surgery for Dukes class C colorectal cancer & to tx Hodgkin's disease *stimulates immune response by activating macrophages what SE's does it cause? |
Levamisole (ergamisol) (originally anti-parasitic) SE: agranulocytosis |
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__________ is used in Multiple Myeloma, Erythema nodosum leprosum (leprosy), & skin manifestations of SLE *Has mixed effects--> inhibits TNF-alpha & neutrophils & inc IL-10 (immunosuppressive), but also Enhances Cell Mediated Immunity what SE's does it cause? |
Thalidomide (thalomid) (originally sleep aid) SE: teratogenesis, thrombosis (in multiple myeloma pts) |
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Multiple myeloma pts taking thalidomide can be given _________ if they develop thrombosis |
Warfarin (Gemcitabine is also an alt. tx for multiple myeloma & lymphoma per Krishna) |
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__________ is used as an adjuvant in bladder cancer *activates macrophages--> enhances cell-mediated immunity |
BCG (Bacille Calmette-Guerin) *viable strain of bovine Tb (mycobacterium bovis) |
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Without _____________ there is no immune system. What limits their use? |
cytokines (IFN, CSF, IL) SEVERE systemic SEs--> fever, flu-like sx, anorexia, fatigue, malaise (may be enough to kill pt) |
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(G-/GM-)CSF & IL-3 push hematopoetic cells towards ________ lineage What is G-/ GM-CSF used for? |
myeloid lineage GM-CSF used in pre-term neonates, neutropenic pt, & cancer pts receiving chemo |
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_______ pushes hematopoetic cells towards lymphoid lineage |
IL-7 |
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_______ is used to tx hairy cell leukemia, malignant melanoma, kaposi's sarcoma, & Hep B & C |
IFN-alpha (IFN-beta used in MS*) |
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_____ is used to tx chronic granulomatous disease |
IFN-gamma |
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_____ is used to tx METASTATIC renal cell carcinoma *non-metastatic tx w/ surgery* |
IL-2 |
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___________ immunization involves administration of pre-formed abs from vaccinated individual (artificial) or from mother to fetus (natural) & conveys immediate, short lived (humoral immunity) protection against Ag, BUT, does NOT lead to development of cell mediated immunity |
Passive Immunization (IVIG & Hyperimmune globulins) (**Active immunizations (vaccinations) DO induce host immune response & lead to formation of cell-mediated immunity against future infection) |
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When are IVIGs indicated? (passive immunity, made from pooled plasma, largely IgG, non-specific) |
XLA, HyperIgM immunodeficiency risk of exposure to Rabies or Hep B (not-confirmed) Tetanus infection (or botulism, diptheria) |
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When are Hyperimmune globulins indicated? (passive immunity, made from high titers of Ag specific Ig's) |
Hep B infection Rabies (1 shot + 5 doses of vaccine) Tetanus infection Hemolytic Disease of Newborn VZV, CMV, RSV |
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when is Rho (D) immune globulin indicated? (hyperimmune globulin) |
to prevent hemolytic disease of the newborn give mother @ 28 wks & immediately after delivery (prevent development of anti-Rh IgG) If Rh (-) mother has hx of pregnancy w/ Rh (+) fetus (Rh + dad)--> Will develop Anti-Rh IgG--> Anti-Rh IgG crosses placenta & attacks second Rh (+) child---> hemolytic disease of newborn |
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________ is indicated in metastatic breast cancer *binds to tumor expressing human epidermal growth factor receptor (HER-2/neu)--> blocks ligand binding & down-regulates receptor |
*Trastuzumab (herceptin) |
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_______ is indicated in refractory cases of non-Hodgkin's lymphoma *murine-human monoclonal IgG1 (human Fc) Ab--> binds to CD20 on B cells--> Ab-dependent cellular cytotoxicity--> apoptosis of malignant lymphoma cells (doesn't interfere w/ healthy B cell signalling, bc only CD19 & CD21 are involved) |
*Rituximab (rituxan) (can also be used in RA to wipe out B cells, per Krishna) |
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________ is indicated for prophylactic tx of RSV in exposed neonates *monoclonal Ab--> binds fusion (f) protein of RSV--> neutralizes infectivity |
*Palivizumab (synagis) |
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________ is indicated post cardiac intervention (angioplasty, stent, etc) to prevent complications d/t clot formation *Fab monoclonal Ab--> binds to GPIIb/IIIa receptors on activated platelets (glycoprotein 2b/3a antagonist)--> prevents binding of adhesion molecules to receptor--> inhibits platelet aggregation |
*Abciximab (reopro) |