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Aim of Learning Activity

  • To introduce issues relating to the prevention and treatment of ischemic brain damage

Key Concepts

  • Primary prevention of stroke
  • Drugs used in the Acute treatment of stroke
  • Tissue plasminogen activator mechanism of action
  • Anticoagulants and anti platelet drugs
  • Secondary prevention of are current stroke
  • Drug design and development process(in relation to stroke and neuroprotection)

Introduction

  • Stroke can be ischaemic (prevention of bloodflow) or haemorrhagic (bleed)
  • Stroke risk factors, modifiable and non-modifiable:
    • Hypertension, AF, smoking, diabetes, high cholesterol, age, gender, diet, excessive alcohol intake, obesity, lack of exercise, birth control pills
  • Primary prevention
    • Antihypertensives
      • Diuretics, ACEI (Lisinopril), AT1 antagonists (Losartan), Calcium antagonists (Nifedipine),B-adrenergic antagonists (Metoprolol)
    • Diabetes medications
      • Insulin, Biguanides, Sulfonylureas, Thiazolidinediones
    • Lipid lowering drugs
      • HMG-CoA Reductase Inhibitors – statins
    • Healthexercise/lifestyle
    • Quit smoking

Pharmacological treatment of haemorrhagic stroke

  • Essentially, there aren’t any
  • Primary bleed may cause swelling
    • Swelling can be reduced with mannitol
  • Surgery
  • Other (being trialled):
    • Reduce BP, free radical reduction, promote clotting, titration of BP, haematoma excavation
  • See the table showing potential future treatments for haemorrhagic stroke

Pharmacological treatment of ischaemic stroke

  • It is important to get to hospital ASAP because there is a progression of damage over time
    • Eg: MRI patient progression of damage:
      • 4 hours: small focus, 28 hours: increased area, 56 hours: even further
      • Note that although we need to restore brain bloodflow, you can get reperfusion injury.

Ischaemic stroke

  • Ischaemia leads to a lack of oxygen and thus a lack of ATP
    • Causes: a loss of ionic homeostasis across cell membranes
      • Changes in membrane potential (due to disruption of ion pumps)
      • This leads to waves of depolarisation and NT release
  • The ischaemic cascade
    • Effects:
      • Glutamate release
      • Enzyme induction
      • Free radicals
      • Membrane degradation
      • Depolarisation
      • Cell swelling
      • Mitochondrial damage
      • DNA damage
      • Inflammation
  • Moving train of overactivation of cells that is very hard to stop - glutamate release from cells spreads throughout the brain
  • Note the production of free radicals - when there are too many of these, you get oxiative stress which can activate inflammatory markers (e.g. TNFa). Can activate microglia (macrophages of brain) - continue the inflammatory process. We also get leucocyte infiltration into the brain, contributing to damage (leucocytes shouldn't be in brain).
  • Necrosis occurs at the beginning of stroke, apoptosis occurs over a longer period of time
  • Time course:
    • Excitotoxicity – due to glutamate/calcium is early and quick
    • Inflammation/apoptosis is later and slow
    • Over time, ability to ‘save’ brain tissue decreases, the longer the lesion remains, the greater the area of damage

Acute treatment of ischaemic stroke

  • Thrombolytics – recombinant tissue plasminogen activator (t-PA); clotbuster
  • Anticoagulants – warfarin, heparin
  • Antiplatelet drugs – aspirin, dipyridamole
  • Osmotic agents – mannitol

t-PA

See the graph - it shows you that the 3-4 hour time window after an ischaemic stroke.

  • Converts plasminogen into plasmin
    • Plasmin breaks down the fibrin matrix in clots and can restore blood flow
  • Shown to reduce lesion volume if given after 1.5 hours of 3 hours of onset, but not if any longer
  • Currently the only approved therapy
    • Reduces neurological damage if given within 3-4.5 hour window
      • More than 4.5 hours, increase risk of haemorrhage and potentially exacerbate brain injury (tPA can actually stimulate glutamate receptors in brain)
    • Only used in 1.5% of patients
      • Use is limited by delayed hospital presentation time (need early recognition: FAST)
      • Often patient doesn’t recognise the stroke/are asleep etc
  • Inclusion criteria
    • Ischaemic stroke with clearly defined onset time
    • Measurable neurological deficit
    • Neuro-imaging shows there is no haemorrhage
  • Exclusion criteria
    • Previous stroke/head trauma in 3 months
    • Major surgery in the last 14 days
    • History of haemorrhage, or current haemorrhage
    • High BP
    • GI bleed within 21 days
    • Arterial puncture
    • Seizure with stroke
    • Reduced coagulation factors
    • etc
  • Adverse events
    • t-PA is released by presynaptic neurons, broken BBB, microglia
    • Can exacerbate glutamate-caused injury – excitotoxicity and worsen neuronal damage by activating NMDA receptors. Hence we don't want to use it after the 3-4.5 hour time period.
  • Desmotoplase (DSPA)
    • The saliva of the vampire bat
    • Does not enhance toxicity
      • Has a larger time windows than t-PA (3-9 hours)
    • Currently being trialled

Anticoagulants

  • Used to reduce further clot formation in the brain and other parts of the body
    • Heparin (IV) – broken down if taken orally
      • Combines with Antithrombin III and inhibits formation of thrombin
      • Thus prevents formation of fibrin – the thrombus framework
    • Warfarin (oral)
      • Competitive inhibitor for vitamin K and thus lowers the levels of prothrombin and other clotting factors
      • Thus thrombin can’t be formed and fibrin matrices not created
  • Indications
    • Ischaemic stroke or TIA
    • Hypertension
    • Cardiac disease
    • Diabetes
    • Heart valves
  • Adverse effects
    • Risk of haemorrhage
  • Contraindications
    • Haemorrhagic stroke

Antiplatelet agents

  • Used to reduce risk of clot formation
    • Aspirin – cyclo-oxygenase inhibitor
    • Dipyridamole – phosphodiesterase inhibitor
  • Inhibiting these enzymes prevents platelet activation
  • Indications
    • TIA
    • Previous ischaemic stroke
    • Hypertension
  • Many (80%) of ischaemic stroke patients that survive are prescribed aspirin unless contraindicated e.g. hypersensitivity
    • Treatment may be life-long
    • Reduces the risk of further strokes by 10-20%

Osmotic agents

  • Reduce oedema and relieve intracranial pressure
    • Mannitol (iv infusion)
      • Raises serum osmoliarty
      • Plasma osmotic pressure is increased relative to CSF
      • Water follows osmotic gradient and drains from tissue into the blood
  • Indications
    • 10% of stroke patients develop oedema
    • Can be dangerous, thus treatment is important

Secondary preventative measures

  • Reduces risk factors
    • Control blood pressure, lower blood cholesterol, prevent further clots, vitamins and antioxidants – good nutrition, mild exercise



Drug developments – potential stroke treatments

  • Many compounds are trialled, very few make it to clinical trials, fewer even, to commercial release
    • Costs hundreds of millions of dollars per drug, and many fail
    • Notice also that toxicology at the end of the trial may reveal that the drug is unsafe, then you've wasted all your money.
  • Potential targets are the common injury pathways
    • Excitotoxicity – increased levels of glutamate causing excessive receptor activation and increased intracellular calcium activating apoptosis
    • Oxidative stress – increased level of free radicals
    • Neuroinflammation – activation of microglia, release of ROS and cytokines
    • Apoptosis – programmed cell death. Enzyme inhibitors can target apoptosis
  • All these targets are part of the ischaemic cascade
  • Drug targets
    • Glutamate – NMDA antagonists (problem = affect normal brain activity)
    • Depolarisation – sodium channel blockers (problem = affect normal brain activity, and Na channels in heart etc)
    • Increased intracellular Ca2+ - Ca2+ channel blockers
    • Free radicals – antioxidants or scavengers
    • Inflammation – inhibitors
    • Anti-apoptosis
  • Testing involves tissue studies, animals studies etc
    • Need to simulate global ischaemia and focal ischaemia
    • Neuroprotection of antioxidants in H2O2 insult has been shown in tissue studies
    • The next stage is to try it in an animal brain with an MCA occlusion. The size of the injury is shown to be smaller with MK-801 (a glutamate receptor antagonist). Hence we've shown beneficence, but the effects of the glutamate blocker on off-targets is negative


  • Use various methods of occlusion including clips, thread and injection of clots
    • All trials failed clinically – did not show improvement in neuroprotection
  • Stroke therapy academic industry roundtable (STAIR) recommendations (this committee is made of clinicians who got together to solve the problem of stroke studies costing a lot of money but ending up failing). This is a set of criteria needed for anyone doing experimental studies in stroke.
    • Adequate dose-response and serum concentration studies
  • Time-window studies to confirm efficacy
    • Physiological monitoring
    • Randomised, blinded studies
    • Infarct volume and functional tests
    • Small rodent studies with middle cerebral artery occlusion
    • Should provide cortical and subcortical protection
    • Time and duration of drug administration should be appropriate to action and clinical use **Should be efficacious as a monotherapy

SEE THE LIST IN LECTURE SLIDE

NXY -059

  • Free radical scavenger
    • Shown to neuroprotective in rodents and primates; many research groups found this very exciting
    • Clinical trial 1: SAINT 1 – stroke acute ischaemic NXY-059 treatment
      • Modest improvements vs placebo
    • Clinical trial 2: Saint II
      • No clinical efficiacy “Back to the drawing board”