Drug Abuse PPT by nirav


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Drug Abuse PPT by nirav

  1. 1. Drug abuse and addiction 14-times Olympic gold medal winner Michael Phelps caught with cannabis pipe
  2. 2. Confusion in definition !!! <ul><li>Various terms like </li></ul><ul><li>Drug addiction </li></ul><ul><li>Drug abuse </li></ul><ul><li>Drug dependence </li></ul><ul><li>Drug habituation </li></ul>
  3. 3. American Psychiatric Association 's Diagnostic and Statistical Manual of Mental Disorders (DSM) <ul><li>New term – substance dependence </li></ul><ul><li>a cluster of symptoms indicating that individual persists with use of the substance despite significant substance related problems </li></ul>
  4. 4. Substance Dependence <ul><ul><ul><ul><li>A. A maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period : </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Recurrent substance use in situations in which it is physically hazardous </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Recurrent substance-related legal problems </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>B. The symptoms have never met the criteria for Substance Dependence for this class of substance. </li></ul></ul></ul></ul></ul>
  5. 5. Pharmacology behind addiction - reinforcement <ul><li>The capacity of drugs to produce effects that make the user wish to take them again </li></ul><ul><li>all addictive drugs activate the mesolimbic dopamine system and increase dopamine level </li></ul><ul><li>Starting point is ventral tegmental area (VTA ) </li></ul><ul><li>This tiny structure projects into </li></ul><ul><li>nucleus accumbens </li></ul><ul><li>amygdala </li></ul><ul><li>prefrontal cortex </li></ul>
  7. 8. Animal models
  8. 9. Animal models <ul><li>Addiction is a disease that does not respect animal boundaries </li></ul><ul><li>Addicted rats with cocaine </li></ul><ul><li>Prolong self administration of cocaine </li></ul><ul><li>Behavior closely resemble human </li></ul><ul><li>addiction </li></ul><ul><li>Rats administered the drug despite </li></ul><ul><li>negative consequences </li></ul>
  9. 10. The Dopamine Hypothesis of Addiction <ul><li>Experiments in monkeys </li></ul><ul><li>dopamine neurons in the VTA are most efficiently activated by a reward </li></ul><ul><li>Few drops of fruit juice – not anticipated </li></ul><ul><li>1 st - only juice </li></ul><ul><li>2 nd - juice + sound </li></ul><ul><li>3 rd – only sound </li></ul><ul><li>Accuracy of this hypothesis?? </li></ul>
  10. 11. TOLERANCE <ul><li>Reduction in response to the drug after repeated administrations </li></ul><ul><li>Innate tolerance </li></ul><ul><li>genetically defined sensitivity to a drug that is observed the first time that the drug administered </li></ul><ul><li>Acquired tolerance </li></ul>
  11. 12. Acquired tolerance <ul><li>Pharmacokinetic tolerance </li></ul><ul><li>Changes in the distribution or metabolism of a drug after repeated administrations such that a given drug produces a lower blood concentration than the same dose did on initial exposure </li></ul><ul><li>Pharmacodynamic tolerance </li></ul><ul><li>Adaptive changes that have taken place within systems affected by the drug so that response to a given concentration of the drug is reduced </li></ul>
  12. 13. Acquired tolerance <ul><li>Learned tolerance </li></ul><ul><li>Reduction in the effects of a drug owing to compensatory mechanisms that are acquired by past experiences </li></ul><ul><li>Behavioral tolerance </li></ul><ul><li>Skills that can be developed through repeated experiences with attempting to function despite mild to moderate intoxication </li></ul><ul><li>Conditioned tolerance </li></ul><ul><li>- This develops when environmental cues such as sight or smell consistently paired with the administration of drug </li></ul>
  13. 14. Acquired tolerance <ul><li>Acute tolerance </li></ul><ul><li>Rapid tolerance developing with repeated use on a single occasion such as in a “binge” </li></ul><ul><li>Reverse tolerance= Sensitization </li></ul><ul><li>- Increase in response with repetition of the same dose of the drug </li></ul>
  14. 15. Acquired tolerance <ul><li>Cross tolerance </li></ul><ul><li>When repeated use of a drug in a given category confers tolerance not only to that drug but also to other drugs in the same structural and mechanistic category </li></ul><ul><ul><ul><ul><li>Barbiturates  BDZs </li></ul></ul></ul></ul><ul><li> Amphetamine  Cocaine. </li></ul>
  15. 16. Physical dependence <ul><li>A state that develops as a result of the adaptation produced by a resetting of homeostatic mechanisms in response to repeated use of drug </li></ul><ul><li>Indicates new balance in presence of drug </li></ul><ul><li>Need of continuous presence of drug </li></ul><ul><li>Withdrawal syndrome is the actual evidence of physical dependence </li></ul>
  16. 17. Withdrawal Syndrome <ul><li>Abrupt termination of drug in a physically dependent person </li></ul><ul><li>Appearance of various signs and symptoms – characteristic of the category of the drug </li></ul><ul><li>Two origins </li></ul><ul><li>Removal of the drug of dependence </li></ul><ul><li>CNS hyperarousal owing to readaptation to the absence of the drug of dependence </li></ul>
  17. 18. Psychological dependence <ul><ul><ul><li>Motivational component : great subjective need, compulsion, drive to get the drug </li></ul></ul></ul><ul><ul><ul><li>Will take drug periodically </li></ul></ul></ul><ul><ul><ul><li>Although physical dependence for a drug may not occur, “ drug-seeking behavior” is present </li></ul></ul></ul>
  18. 19. Classification of drugs of abuse <ul><li>Drugs that activate GPCR </li></ul><ul><li>Drugs that bind to ionotrophic receptor and ion channels </li></ul><ul><li>Drugs that bind to transporter of biogenic amines </li></ul>
  19. 20. Drugs that activate GPCR Partial agonist 5-HT 2A R LSD, mescaline disinhibition Weak agonist GABA b R Gamma- hydroxybutyric acid(GHB) disinhibition agonist CB1R Cannabinoids disinhibition agonist μ - OR Opiods Effect on DA neurons Action Molecular target drugs
  20. 21. Drugs that bind to ionotrophic receptor and ion channels Effect on DA neurons Action Molecular target drugs - antagonists NMDA Phencyclidine, ketamine disinhibition Positive modulator GABA A Benzodiazepines Excitement, disinhibition? GABA A ,5-HT3, nACh, NMDA Alcohol Excitement, disinhibition? Agonist nAChR Nicotine
  21. 22. Drugs that bind to transporter of biogenic amines Effect on DA neurons Action Molecular target drugs Blocks DA uptake Reverses transport SERT>DAT, NET Ecstasy Blocks DA uptake Reverses transport DAT,SERT, NET,VMAT Amphetamine Blocks DA uptake Inhibitor DAT,SERT, NET Cocaine
  22. 23. <ul><li>Drugs that Activate G io -Coupled Receptors </li></ul><ul><li>Opioids </li></ul><ul><li>Cannabis </li></ul><ul><li>LSD </li></ul>
  23. 24. Opioids – God's own medicine <ul><li>Among the remedies which it </li></ul><ul><li>has </li></ul><ul><li>pleased Almighty God to give to man to relieve his </li></ul><ul><li>sufferings, none is so universal and so efficacious </li></ul><ul><li>as </li></ul><ul><li>opium .“ </li></ul><ul><li>Thomas Sydenham </li></ul>
  24. 25. Heroin- most commonly abused opiate <ul><li>Widely available in black market </li></ul><ul><li>Iv use , highly lipid soluble, quick action </li></ul><ul><li>Effects starts within a minute </li></ul><ul><li>“ high” , “kick” </li></ul><ul><li>euphoria </li></ul><ul><li>Intense pleasure = sexual orgasm </li></ul><ul><li>warmth - all these remain for several minutes </li></ul><ul><li>period of sedation and tranquility upto 1 hr </li></ul><ul><li>Total duration 3-5 hrs </li></ul>
  25. 26. <ul><li>Features of opioid action </li></ul><ul><li>- Analgesia </li></ul><ul><li>Altered mood </li></ul><ul><li>Euphoria </li></ul><ul><li>Dysphoria </li></ul><ul><li>Miosis </li></ul><ul><li>Sedation </li></ul><ul><li>Nausea , vomiting </li></ul><ul><li>Respiratory depression </li></ul><ul><li>Constipation </li></ul>
  26. 27. Tolerance – opioids <ul><li>High degree of tolerance </li></ul><ul><li>Euphoria </li></ul><ul><li>Sedation </li></ul><ul><li>Nausea , vomiting </li></ul><ul><li>Mental clouding </li></ul><ul><li>Minimal tolerance – miosis, constipation </li></ul><ul><li>Cross tolerance between opiods – not complete </li></ul>
  27. 28. Physical dependence and withdrawal syndrome - opioids Yawning ,fever Dysphoric mood, craving for drug Tachycardia Anxiety Gooseflesh Insomnia Sweating Irritability Mydriasis Restlessness signs symptoms
  28. 29. Rx of withdrawal syndrome <ul><li>Methadone therapy – 20-30mg </li></ul><ul><li>Clonidine , Lofexidine </li></ul><ul><li>Activation of endogenous opioid system </li></ul><ul><li>acupuncture </li></ul>
  29. 30. Rx of opioid addiction <ul><li>Methadone substitution therapy </li></ul><ul><li>Inpatient treatment </li></ul><ul><li>Partial agonist maintenance </li></ul><ul><li>Buprenorphine </li></ul><ul><li>Buprenorphine + naloxone </li></ul><ul><li>Antagonist treatment - naltrexone </li></ul>
  30. 31. <ul><li>CANNABINOIDS </li></ul><ul><li>ganja- marijuana-hashish- charas </li></ul>
  31. 32. CANNABINOIDS <ul><li>The most famous users of cannabis were the ancient Hindus of India and Nepal </li></ul><ul><li>The herb was called </li></ul><ul><li>ganjika in Sanskrit </li></ul>
  32. 33. CANNABINOIDS – ganja- marijuana-hashish- charas <ul><li>Delta 9-tetrahydrocannabinol (THC) </li></ul><ul><li>CB1 receptor action </li></ul><ul><li>presynaptic inhibition of GABA neurons in the VTA </li></ul><ul><li>Disinhibition of DA neurons </li></ul>
  33. 34. Common Routes- CANNABINOIDS <ul><li>Smoking </li></ul><ul><li>Oral ingestion </li></ul><ul><li>Cannabis tea </li></ul><ul><li>Cannabis+alcohol = green dragon </li></ul>
  34. 35. actions - cannabis <ul><li>Euphoria </li></ul><ul><li>Feeling of well-being </li></ul><ul><li>Relaxation </li></ul><ul><li>Grandiosity </li></ul><ul><li>Long term effects </li></ul><ul><li>Panic, Anxiety </li></ul><ul><li>Frank psychosis </li></ul><ul><li>Depression </li></ul><ul><li>Amotivational syndrome </li></ul>
  35. 36. Tolerance ,depenadence, withdrawal <ul><li>Tolerance develops rapidly </li></ul><ul><li>Withdrawal syndrome – mild </li></ul><ul><li>Restlessness </li></ul><ul><li>Irritability </li></ul><ul><li>Agitation </li></ul><ul><li>Insomnia </li></ul>
  36. 37. Rx of cannabis addiction <ul><li>No specific treatment </li></ul><ul><li>CB-1 receptor blocker - Rimonabant </li></ul>
  37. 38. GAMMA-HYDROXYBUTYRIC ACID (GHB) <ul><li>1 st introduced as a general anesthetic </li></ul><ul><li>Endogenous - during GABA metabolism </li></ul><ul><li>Pharmacology – complex </li></ul><ul><li>Binding site – GABA B receptor </li></ul><ul><li>Available in salt form </li></ul>
  38. 39. GHB – liquid ecstasy - club drug <ul><li>Euphoria </li></ul><ul><li>Feeling of wellbeing </li></ul><ul><li>a feeling of social closeness </li></ul><ul><li>Amnesia - date rape drug </li></ul>
  39. 40. LSD, MESCALINE & PSILOCYBIN <ul><li>Molecular target- 5-HT 2A R – Gq receptor </li></ul><ul><li>Hallucinogens </li></ul><ul><li>Altered sensory perception </li></ul><ul><li>Shape and color distortion </li></ul><ul><li>Distorted time perceptions </li></ul><ul><li>somatic symptoms- nausea, blurred vision, dizziness </li></ul>
  40. 41. LSD, MESCALINE & PSILOCYBIN <ul><li>No dependence </li></ul><ul><li>No addiction </li></ul><ul><li>Tachyphylaxis </li></ul><ul><li>Animal studies - no rewarding properties </li></ul><ul><li>- no DA increase </li></ul><ul><li>Ritanserin - 5-HT 2 R antagonist – in animal studies </li></ul>
  41. 42. <ul><li>Drugs that Mediate Their Effects Via Ionotropic Receptors </li></ul><ul><li>- nicotine </li></ul><ul><li>- alcohol </li></ul><ul><li>- benzodiazepines </li></ul><ul><li>- PCP,ketamine </li></ul>
  42. 43. <ul><li>NICOTINE </li></ul><ul><li>Most dangerous </li></ul><ul><li>dependence producing </li></ul><ul><li>drug </li></ul><ul><li>- 2 nd after alcohol </li></ul>
  43. 44. nicotine <ul><li>Nicotiana tabacum </li></ul><ul><li>nAchR – selective agonist </li></ul><ul><li>nAchR – expressed in VTA </li></ul><ul><li>Nicotine causes release of DA in NA and PFC </li></ul><ul><li>ά 4 β 2- containing channels important for reward </li></ul>
  44. 45. nicotine <ul><li>Most common route – smoking </li></ul><ul><li>Oral ingestion </li></ul><ul><li>action </li></ul><ul><li>some degree of euphoria and arousal </li></ul><ul><li>improves attention, learning, problem solving, and reaction time </li></ul><ul><li>Toxic dose - respiratory paralysis and severe </li></ul><ul><li>hypotension </li></ul>
  45. 46. Tolerance ,dependence, withdrawal -nicotine <ul><li>Some evidence for tolerance </li></ul><ul><li>Best feeling after a day of abstinence </li></ul><ul><li>Strong dependence </li></ul><ul><li>Mild withdrawal symptoms </li></ul><ul><li>Irritability </li></ul><ul><li>Anxiety </li></ul><ul><li>Restlessness </li></ul><ul><li>Impatience </li></ul>
  46. 47. Rx of nicotine addiction <ul><li>Nicotine substitution </li></ul><ul><li>Gum </li></ul><ul><li>Transdermal patch </li></ul><ul><li>Nasal spray </li></ul><ul><li>All these do not achieve peak nicotine level – but suppress the withdrawal </li></ul>
  47. 48. Rx of nicotine addiction <ul><li>SR preparation of bupropion </li></ul><ul><li>Rimonabant </li></ul><ul><li>Varenicline – partial agonist of ά 4 β 2 nAchR </li></ul>
  48. 49. <ul><li>Alcohol – ethanol </li></ul><ul><li>Most commonly abused drug </li></ul><ul><li>90% US adults have </li></ul><ul><li>experienced alcohol </li></ul>
  49. 50. ethanol <ul><li>Complex pharmacology </li></ul><ul><li>Action on many receptors </li></ul><ul><li>GABA A ,5-HT 3 , nACh, NMDA </li></ul><ul><li>Inhibition of ENT1 </li></ul><ul><li>Available in various concentration </li></ul><ul><li>Mainly act as CNS depressant </li></ul>
  50. 51. William Shakespeare and action of ethanol in MACBETH <ul><li>Porter said that- </li></ul><ul><li>Drink provoke </li></ul><ul><li>- noise painting </li></ul><ul><li>- sleep </li></ul><ul><li>- urine </li></ul><ul><li>- Desire but takes away performance </li></ul>
  51. 52. Chronic alcohol abuse = alcoholism <ul><li>LIVER </li></ul><ul><li>Alcoholic fatty liver </li></ul><ul><li>A lcoholic hepatitis </li></ul><ul><li>C irrhosis </li></ul><ul><li>L iver failure </li></ul><ul><li>Neurotoxicity </li></ul><ul><li>- depression </li></ul><ul><li>Peripheral neuropathy </li></ul><ul><li>Gait disturbance </li></ul><ul><li>Wernicke-Korsakoff syndrome </li></ul>
  52. 53. alcoholism <ul><li>CVS </li></ul><ul><li>Cardiomyopathy and Heart Failure </li></ul><ul><li>Arrhythmias </li></ul><ul><li>Hypertension </li></ul><ul><li>Coronary Heart Disease </li></ul><ul><li>FETAL ALCOHOL SYNDROME </li></ul>
  53. 54. Tolerance , dependence, withdrawal - alcohol abuse <ul><li>Acute tolerance soon after administration of alcohol </li></ul><ul><li>Chronic tolerance due to altered metabolism </li></ul><ul><li>Cross tolerance with BZDs </li></ul><ul><li>Withdrawal syndrome is common and sometimes severe </li></ul>
  54. 55. Alcohol withdrawal syndrome <ul><li>Craving </li></ul><ul><li>Tremor </li></ul><ul><li>Sweating </li></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Tachycardia </li></ul><ul><li>Hypertension </li></ul><ul><li>Seizures </li></ul><ul><li>Visual hallucination </li></ul><ul><li>Delirium tremens </li></ul>
  55. 56. Rx of withdrawal syndrome - alcoholism <ul><li>Objective is to prevent </li></ul><ul><li>seizure,delirium,arrhythmia </li></ul><ul><li>Thiamine therapy </li></ul><ul><li>Electrolyte balance </li></ul><ul><li>BZDs – commonly used drugs – detoxification </li></ul><ul><li>Long acting BZDs </li></ul>
  56. 57. Rx of alcoholism <ul><li>Behavioral & psychosocial therapy </li></ul><ul><li>Naltrexone – 50 mg OD Nalmefene </li></ul><ul><li>Acamprosate – 333mg tid </li></ul><ul><li>Disulfiram -125-500mg/day </li></ul><ul><li>Topiramite </li></ul><ul><li>Ondensatrone </li></ul>
  57. 58. BENZODIAZEPINES (BZDs) <ul><li>Action on GABA A receptors </li></ul><ul><li>Increas e frequency of single channel opening </li></ul><ul><li>Disinhibition DA neurons –reward </li></ul><ul><li>Short acting BZDs – more commonly abused </li></ul>
  58. 59. BZDs <ul><li>Mild euphoric effect </li></ul><ul><li>Street lore – diazepam + methadone </li></ul><ul><li>With cocaine </li></ul><ul><li>Tolerance develops after months of use </li></ul><ul><li>- sedative effect </li></ul>
  59. 60. Benzodiazepine withdrawal <ul><li>Anxiety agitation </li></ul><ul><li>Insomnia </li></ul><ul><li>Dizziness </li></ul><ul><li>Paresthesia </li></ul><ul><li>Muscle cramps </li></ul><ul><li>Seizure </li></ul>
  60. 61. Rx of BZDs addiction <ul><li>Gradual reduction of dose </li></ul><ul><li>Long acting BZD can be used for substitution </li></ul><ul><li>Carbamazepine phenobarbitone </li></ul><ul><li>Withdrawal symptoms Rx by phenobarbitone </li></ul><ul><li>Specific antagonist – flumazenil </li></ul>
  61. 62. KETAMINE & PHENCYCLIDINE (PCP) <ul><li>Club drugs </li></ul><ul><li>Angel dust </li></ul><ul><li>Special K </li></ul><ul><li>Blockade of NMDA receptor </li></ul><ul><li>vivid dreams </li></ul><ul><li>hallucinations </li></ul>
  62. 63. KETAMINE & PHENCYCLIDINE (PCP) <ul><li>Powder forms – snorted ,smoked, ingested </li></ul><ul><li>Reinforcing in monkeys </li></ul><ul><li>Dependence not seen </li></ul><ul><li>Chronic exposure – schizophrenia like state </li></ul>
  63. 64. <ul><li>Drugs that Bind to Transporters of Biogenic Amines </li></ul><ul><li>Cocaine </li></ul><ul><li>Amphetamine </li></ul><ul><li>Ecstasy </li></ul>
  64. 65. cocaine <ul><li>alkaloid found in the leaves of Erythroxylon coca </li></ul><ul><li>Local anesthetic </li></ul><ul><li>recreational drug </li></ul><ul><li>Common form – crack cocaine </li></ul>
  65. 67. cocaine <ul><li>Iv use , inhalation – instant rush </li></ul><ul><li>blocks the uptake of dopamine , noradrenaline and serotonin through their respective transporters </li></ul><ul><li>block of the dopamine transporter (DAT) – reinforcing property </li></ul>
  66. 68. Effects of cocaine <ul><li>Psychostimulation </li></ul><ul><li>Increase arousal </li></ul><ul><li>Improved performance </li></ul><ul><li>Sense of self confidence </li></ul><ul><li>Alertness </li></ul><ul><li>Euphoria after higher dose </li></ul><ul><li>Chronic abuse – involuntary motor activity </li></ul><ul><li>- irritability </li></ul><ul><li>- risk of violence </li></ul><ul><li>- Megnan's symptom </li></ul>
  67. 69. Speedball <ul><li>Cocaine + heroin </li></ul><ul><li>Improved euphoria </li></ul><ul><li>Heroin reduces irritability in cocaine users </li></ul><ul><li>Faster onset </li></ul>
  68. 70. Tolerance ,dependence, withdrawal - cocaine <ul><li>Sensitization common in animal studies </li></ul><ul><li>In human – tolerance is seen </li></ul><ul><li>Withdrawal or cocaine crash </li></ul><ul><li>Depression </li></ul><ul><li>Dysphoria </li></ul><ul><li>Craving </li></ul><ul><li>Sleepiness </li></ul><ul><li>Bradycardia </li></ul>
  69. 71. Rx of cocaine addiction <ul><li>Withdrawal symptoms – no treatment </li></ul><ul><li>Enhancing GABAergic inhibition – prevents relapse of cocaine use – seen in animal studies </li></ul><ul><li>Topiramite </li></ul><ul><li>Baclofen </li></ul><ul><li>Modafinil </li></ul>
  70. 72. AMPHETAMINE <ul><li>indirect-acting sympathomimetic </li></ul><ul><li>reversing the action of biogenic amine transporters at the plasma membrane </li></ul><ul><li>interfere with the vesicular monoamine transporter (VMAT) </li></ul><ul><li>One of the CLUB DRUGS </li></ul>
  71. 73. AMPHETAMINE <ul><li>intravenous administration , pill, smoked </li></ul><ul><li>I ncrease arousal </li></ul><ul><li>Bruxism </li></ul><ul><li>S kin flushing </li></ul><ul><li>R educe sleep </li></ul><ul><li>Euphoria </li></ul><ul><li>Hallucination </li></ul><ul><li>Hypertensive crisis, stroke </li></ul><ul><li>Neurotoxic on long term use </li></ul>
  72. 74. MDMA = ecstasy <ul><li>Party drug or club drug </li></ul><ul><li>preferential affinity for the serotonin transporter ( SERT ) </li></ul><ul><li>marked intracellular depletion for 24 hours after a single dose </li></ul>
  73. 75. MDMA = ecstasy <ul><li>Available in tablet forms – 100mg </li></ul><ul><li>Acute effect </li></ul><ul><li>Feeling of energy </li></ul><ul><li>Altered sense of time </li></ul><ul><li>Enhanced perception </li></ul><ul><li>Tachycardia </li></ul><ul><li>Dry mouth </li></ul><ul><li>Higher dose – visual hallucinations, hyperthermia, panic attacks </li></ul><ul><li>Long term - neurotoxicity </li></ul>
  74. 76. references <ul><li>Goodman & Gillman's – the pharmacological basis of therapeutics- 11 th edition </li></ul><ul><li>Katzung – basic and clinical pharmacology </li></ul><ul><li>10 th edition </li></ul><ul><li>Lippincott ‘s illustrated reviews pharmacology – 4 th edition </li></ul><ul><li>en.wikipedia.org </li></ul><ul><li>Various internet sites </li></ul>
  75. 77. <ul><li>The </li></ul><ul><li>Addiction </li></ul><ul><li>Ends </li></ul><ul><li>Here…! </li></ul>