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| any substance other than one that is required for normal bodily function, that when introduced to the body alters bodily functions |
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| Natural preparations (galenicals) |
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| crude preparations of drugs obtained by plants and animals |
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| drugs that are purified from crude elements. Morphine was the first |
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| pure compounds that have been chemically modified such as adding acetyl groups to morphine to make heroin |
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| Purely synthetic compounds |
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| pretty much custom designed drugs |
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| name given by the manufacturer |
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| Nonproprietary (generic) name |
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| drug is applied in small volumes and low concentrations and only works on the site applied (is localized) |
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| a topical injection into the CSF that bypasses the blood-brain barrier |
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| drugs that are absorbed through the skin such as a nicotine patch |
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| Oral mucosa route (sublingual) |
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| this means under the tongue. This has rapid absorption because it doesn't have to go through the digestive system or through the liver (first pass effect) |
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| the situation where a drug's concentration is greatly reduced by the metabolism of the liver before it reaches the circulatory system |
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| Stomach and intestine route |
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| long surface area of GI tract allows for better absorption of drug. Absorption depends on pH, solubility of drugs, concentration, and gastric emptying rate |
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| Rectal mucosa (suppositories) route |
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| useful when patients are unconscious or nauseous. bypasses first pass effect |
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| Pulmonary epithelium route |
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| drug is inhaled and is very fast |
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| injection into the skin, has a slow and even drug absorption |
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| absorbs aqueous solutions really fast, oily drugs has a slow and even drug absorption |
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very fast: once injected, rapid removal of drug is impossible. you can immediately get the right blood concentration of the drug
slow: to get the right blood concentration of the drug, blood levels are titrated. Constant blood concentrations can be maintained |
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| used to target the drug into specific tissues or organs (such as a tumor) |
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| Injection into body cavities |
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| seldom used because of risk of infection or injury |
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| a drug has to be soluble in body fluids for it to be effective |
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| drugs that show greater affinity for the lipid (fatty) portions of cell membranes |
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the relative solubility of a drug in oil to water
P = C of oil/C of water
an estimate of Pm/b: C of membrane/C of buffer |
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| Low partition coefficient = |
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| High partition coefficient = |
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| oil soluble. drugs diffuse between lipids |
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| Passive diffusion of water soluble drugs |
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| drugs with a low PC that are small enough to travel through aquaporins |
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| Passive diffusion of lipid soluble drugs |
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| drugs with a high PC that travel through cell membranes. Must have some degree of water solubility to pass unstirred water layers |
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| Amine and organic acidic drugs come in these two forms |
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non-protonated and protonated
amines: is uncharged when you increase pH ie: in its unprotonated form
organic acids: is uncharged when you decrease pH ie: in its protonated form |
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| Uncharged molecules are better for absorption because |
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| it makes it easier to pass membranes |
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| the equilibrium constant for the dissociation that yields H+. This is low for basic drugs and high for acidic drugs |
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| pKa = what? This is also equal to what? |
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| -log(Ka). This is also equal to the pH where 50% of the drug is ionized |
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| The single most important variable affecting rate of g.i. absorption of drugs is |
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| the rate of stomach emptying |
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| permit the movement of molecules between cells of the SAME TYPE. Example of facilitated diffusion |
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| continuous tight junctions in epithelial membranes that block off intercellular spaces. Essentially can't get through them |
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| capillaries that have patches of maculae on them. drugs can travel in between the patches |
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| found in exretory and secretory organs. Basically little windows on the capillary that doesn't impede drug movement |
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| capillaries where their intercellular spaces are completely blocked off such as in the blood brain barrier |
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| What kind of compound can cross the blood brain barrier? |
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| compounds with a high partition coefficient |
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| Volume of distribution of a drug in water Vd = |
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| Mass of the drug/Concentration of drug in water....M/C |
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| a dissociation constant that describes the free drug concentration at which 50% of the binding sits on the protein have been occupied. Also equals K2/K1 |
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| Liver is structured into what? |
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detox
formation of bile
metabolism
most important organ for biotransformation! |
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remove waste
maintain water/electrolyte balance
endocrine functions |
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| Three processes that form urine: |
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| filtration, selective and passive reabsorption, excretion |
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| Occurs when the waste passes through the glomerular capillaries which removes proteins and cellular elements because it's impermeable to them |
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| Selective and Passive Reabsorption in the kidney |
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| occurs in the renal and proximal tubules, reabsorbs glucose, amino acids, bicarbonate and water from the glomerular filtrate |
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| part of the tubule which dips from the cortex of the kidney into the medulla. site where urine is concentrated |
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| impermeable to solute, permeable to water so water moves out |
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| Thin section of ascending loop of Henle |
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| impermeable to water, permeable to solute, so solute moves out |
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| Thick section of ascending loop of Henle |
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| impermeable to water. Ions are actively transported out |
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| Presence of ADH has what effect on urine? |
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| makes the collecting duct permeable to water and so water moves out leaving the urine concentrated |
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| Absence of ADH has what effect on urine? |
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| the tubule becomes only slightly permeable to water so the urine is dilute |
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| Binding to plasma proteins |
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| decreases the effect of the drug because it lowers the free drug concentration which is what you need to have successful binding at the sites of action. Also decreases elimination of the drug |
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| Uptake and distribution of drug's three phases: |
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| vessel rich group includes the brain, heart and liver |
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| vessel poor group, ligaments, bone and teeth |
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| the chemical transformation of a xenobiotic within a living organism |
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| Consequences of drug biotransformation |
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| Activation, maintenance of activity, inactivation |
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| Phase I reactions of biotransformation |
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| the oxidation, reduction and hydrolysis of a drug may activate it, produce no change, or inactivate it |
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| Phase II reactions of biotransformation |
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| happens when a substance combines with a functional group from Phase I to produce a polar drug conjugate. Most of the time this will decrease the activity of the drug |
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| Enterohepatic circulation |
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| circulation from the liver to gallbladder to the intestine and then back into the liver |
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| involved in oxidation reactions in biotransformation |
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| a phase II reaction where an oxygen atom is inserted across a carbon carbon double bond and then an epoxide hydrolase adds a hydroxyl group to it |
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| involves the conjugation of drugs with glucuronic acid that can allow the drug to enter the enterohepatic circulation system |
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| describes the rates of the various steps of drug absorption, drug distribution, and elimination by biotransformation and excretion. Investigate the time course of drug concentrations in blood plasma |
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| investigate the intensities and time courses of the responses to drugs |
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| Concentration at time t = |
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| C0e-^kt where k is the rate constant |
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| Half life of drug elimination t(1/2) = |
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the time period during which the concentration decrease to one half of its previous value.
0.693/k |
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| Slope of log concentration over time graph (one compartment model) = |
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% of drug molecules that enter body systems through circulation
AUC (oral)/AUC (i.v.) |
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the volume of body fluid from qhich a drug is removed per unit time. = V/t
It also equals kV
C = kV
Cl = kV |
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| area under curve that reflects the extent of absorption |
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At a steady state, Q =
L = |
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| when the rate of approach to the steady state depends on the elimination rate constant. The time to hit this plateau is roughly 5 half lives |
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the time to reach a fraction of Css
f = 1-e^[-.693t/t(1/2)] |
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The first dose administered that gets you in between Ctox and Cther
L = V*Ctox |
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keeps the blood concentration between Cther and Ctox
Dm = (Ctox - Cther)*V |
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| the fraction of drug removed by the liver |
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| Glomerular filtration rate (GFR) |
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| the rate at which plasma water is filtered... it's about 120 mL/min |
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called log doe response curves, they describe the dose response relationship over a wide range of doses
are typically sigmoidal shaped |
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| a measure of a drug exerting an effect. represented by alpha |
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alpha (intrinsic activity)*[DR] (the concentration of drug-receptor complexes
or alpha*[D][R]/K+[D] |
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the dissociation constant of the receptor. also is a meausure of affinity. the higher the kd, the lower the affinity. the lower the kd, the higher the affinity
kd = k-1/k+1 |
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| the effective dose to which 50% of patients will respond |
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| the lethal dose to which 50% of patients will die |
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| TI = TD50/ED50. this should be as high as possible for a good drug |
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| Certain safety factor (CSF) = |
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| any site that a drug binds to without leading to an effect |
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| binding that leads to an effect |
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| It's uncommon for a drug to bind covalently to a receptor. Why? |
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| most drugs bind reversibly |
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| How do you do a binding assay? |
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| mix samples of tissue with radioactive drug. let the mixture settle, filter out the drug-receptor complexes, wash away unbound drug and determine how much radioactivity you have. This will give you total binding which includes both specific and nonspecific |
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| How do you determine binding of drug that is specific to its receptor? |
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| perform a binding assay but this time add in a lot of unlabled "cold" drug. this cold drug will win the competition with specific binding sites. to determine the specific binding of the radioactive drug, you would then subtract non-specific binding from total binding |
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| is something that has an affinity for a receptor, but exerts no effect once it binds to it. can block the effect of agonists |
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| has an affinity for a receptor and exerts an effect on it once it binds |
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| don't affect the maximal possible response of agonists of the receptor. shifts the concentration response curve to the right. this happens because there is competition between the agonist and antagonist and there will be times when the agonist wins |
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| bind to receptor sites so tightly that agonists will not get a chance to bind there afterwards. obviously will decrease maximal response with the EC50 will still be the same. this is because if the agonist happens to get to the receptor first it can still have some type of effect |
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| Non-competitive modulators |
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| binds to a different site on the receptor which will either decrease the maximal response (while keeping EC50 the same), decrease the EC50 without affecting maximal response, or increase the EC50 without affecting maximal response. |
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| has partial efficacy even at 100% receptor occupation |
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| drug acts only as long as it occupies the receptor |
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| drug action is proportional to the rate of combination between the drug and the receptor |
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| Response vs drug concentration curves |
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| can tell you which drugs exert more effect (by looking to see how high the response is) and how potent a drug is compared to another by looking to see which one requires less concentration to reach its respective EC50. Note: just because a drug has a higher response doesn't mean it's more potent |
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| del Castillo-Katz mechanism |
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D + R <--> DR <--> DR*
(binding)(gating)
DR is when the drug is bound to the receptor but it's inactive. DR* is when the complex is active |
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| is expressed as kd = k-1/k+1 |
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beta/alpha. measured in the gating state of the del Castillo-Katz mechanism
DR<-->DR* |
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| The equation p = E/(1+E) represents what |
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| The maximum fraction of receptors found in the active state in the presence of a ligand |
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| How are EC50, KD and efficacy related? |
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| EC50 tells you nothing about binding affinity, only potency? |
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| more dopamine receptors than normal are found as a result of dopamine-releasing neurons being destroyed |
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| a startle disease due to a decreased potency of glycine at the glycine receptor |
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| Insulin-resistant diabetes |
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| there are fewer drug receptors with which insulin can interact with |
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| a receptor disease where antibodies decrease the number of receptors at the neuromuscular junction |
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