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new Trends for acute stroke treatment

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Stroke recent

  1. 1. The Recent Therapy for Acute Stroke Dr. Doha Rasheedy Lecturer of Geriatrics& Gerontology CME 5-12-2013
  2. 2. In fact clinical management of stroke, with the exception of thrombolytic therapy is based primarily on supportive care.
  3. 3. Reperfusion therapy: 1. Thrombolytics (plasminogen activators) (direct fibrinolytics) 2. Sonothrombolysis 3. Laser thrombolysis 4. Endovascular thrombectomy Neuroprotective therapy: 1. ↓excitatory neurotransmitters 2. ↓reperfusion injury Neuronal regeneration therapy: (neurogenesis) 1. gene therapy, 2. neurotrophic factors 3. neural stem cells (NSCs).
  5. 5. Intravenous thrombolytics Intravenous rt-PA within 3 h • is the only treatment approved by the FDA • was proven clinically effective in multiple randomized clinical trials for acute ischemic stroke. • The effectiveness of t-PA is time-dependent; treatment beyond 4.5 hours from stroke onset does not result in improved clinical outcome. • alteplase has been shown in animal and tissue culture models to be neurotoxic, which may exacerbate ischemic damage after successful recanalization.
  6. 6. Indications within 3 hours(AHA/ASA) 2007: 1. Diagnosis of ischemic stroke causing measurable neurologic deficit 2. Neurologic signs not clearing spontaneously 3. Neurologic signs not minor and isolated 4. Symptoms not suggestive of subarachnoid hemorrhage 5. Onset of symptoms less than 3 hours hours before beginning treatment 6. No head trauma or prior stroke in past 3 months 7. No MI in prior 3 months 8. No GI/GU hemorrhage in previous 21 days 9. No arterial puncture in noncompressible site during prior 7 days 10. No major surgery in prior 14 days 11. No history of prior intracranial bleed 12. Systolic blood pressure under 185 mm Hg, diastolic blood pressure under 110 mm Hg 13. No evidence of acute trauma or bleeding 14. Not taking an oral anticoagulant, or if so, INR under 1.7 15. If taking heparin within 48 hours, a normal activated prothrombin time (aPT) 16. Platelet count of more than 100,000/μL 17. Blood glucose greater than 50 mg/dL 18. No seizure with residual postictal impairments 19. CT scan does not show evidence of multilobar infarction (hypodensity over one-third hemisphere) 20. The patient and family understand the potential risks and benefits of therapy
  7. 7. 2009, AHA/ASA • revised to expand the window of treatment from 3 hours to 4.5 but excluded those patients 1. Patients older than 80 years 2. All patients taking oral anticoagulants are excluded regardless of the international normalized ratio (INR) 3. Patients with baseline NIHSS score > 25 4. Patients with a history of stroke and diabetes
  8. 8. The National Institutes of Health Stroke Scale (NIHSS) • 0 to 3 -------->minor, • 4 to 7 -----mild, • 8 to 15 ----- moderate • >15 ----- severe • scores between 8 and 20 are more likely to benefit from reperfusion and are less likely to have hemorrhagic transformation, making them better candidates for treatment.
  9. 9. Intra-arterial Thrombolysis • Recanalization rate after intra-arterial delivery is 60% - 70%, while it is 30% to 40% for intravenous delivery. • Patients with moderate-to-severe ischemic strokes usually have an occlusion of large cerebral arteries (internal carotid artery [ICA], vertebrobasilar arteries and M1 MCA) or a large clot burden. • up to 6 h following stroke • intravenous thrombolysis, about 6% of patients intra cerebral hemorrhage while IA 10%.
  10. 10. sequenced intravenous and intra-arterial thrombolysis • IV t-PA at 0.6 mg/kg followed by 22 mg IA via a 2-h infusion or until thrombolysis. • The recanalization rate was 79.3% in compared to 55.9% in the intra arterial thrombolysis alone group. • Significant ICH in (20.7%) while in (11.8%) in the intra arterial thrombolysis alone group.
  11. 11. New thrombolytics: • desmoteplase, (r-DSPAα1), a recombinant protein derived from the saliva of bat. • The advantages of r-DSPA α 1 include increased fibrin selectivity as well as absence of neurotoxic effects. • has a long half-life, enabling it to be given as a single bolus
  12. 12. Reteplase • third-generation thrombolytic. • longer half-life • better penetration into a thrombus. • high rate of recanalization + acceptable risk for bleeding complications. • early reocclusion similar to rt-PA. dt platelet activation. So, combination of thrombolysis with platelet-inhibiting agents may offer an advantage.
  13. 13. Tenecteplase • high-level fibrin selectivity • long half-life • increased thrombolytic potency on platelet- rich clots. • It is only approved for use in acute myocardial infarction.
  14. 14. Direct Fibrinolytics • Newer drugs that do not depend on the availability of plasminogen are being evaluated in the setting of acute stroke treatment. offers selectivity to plasmin formation at the site of the clot and theoretically reduces systemic hemorrhagic risk. • V10153 • Microplasmin • Alfimeprase
  15. 15. Mechanical thrombus disruption • Sonothrombolysis • Laser thrombolysis
  16. 16. Sonothrombolysis the use of high frequency sound waves to penetrate the skull and disrupt the clot, increasing exposure of fibrin to plasmin. It accelerates enyzymatic fibrinolysis by increasing penetration of drug molecules into the clot Using: transcranial Doppler ultrasound probe . the CLOTBUST phase II trial showed that the combination of alteplase plus 2 hours of continuous transcranial Doppler (TCD) increased recanalization rates, producing a trend toward better functional outcomes compared with alteplase alone.
  17. 17. Laser thrombolysis • Endovascular photoacoustic Laser Therapy • Transcranial Laser Therapy
  18. 18. Transcranial Laser Therapy • This noninvasive technique uses near-infrared wavelengths applied to the scalp within 24 h of symptom onset. • The mechanism is incompletely understood but may involve increased mitochondrial adenosine triphosphate production. • NEST-1 (phase 2) and NEST-2 (phase 3) confirmed the safety of transcranial laser therapy, although efficacy was not found in NEST-2. Pooled analysis of NEST- 1 and NEST-2 revealed a significantly improved success rate in patients treated with laser therapy. Further phase 3 testing is planned and may create a new paradigm for the treatment of acute ischemic stroke
  19. 19. The endovascular photoacoustic recanalization device (EPAR) is a mechanical clot-fragmentation device based on laser technology. The photonic energy is converted to acoustic energy at the fiberoptic tip through creation of microcavitation bubbles, causing emulsification of the thrombus which is a mechanical thrombolysis and not a direct laser-induced ablation. • Recanalisation rate in phase 1 was 41% (14 out of 34 patients). 11 (61%) had good-to-complete recanalization,,16 patients the treatment was incomplete. • Technical difficulties with the device occurred in four patients. • There was one fatal device-related adverse event caused by aneurysmal dilatation. • Symptomatic ICH occurred in two patients (6%)
  20. 20. Mechanical thrombectomy • Merci retriever device • The penumbra device
  21. 21. Mechanical Thrombectomy Two FDA-approved devices are available. For : • large-vessel intracranial occlusions within 8h of onset. and • Occlusion ineligible for or refractory to IV t-PA The Merci retriever: Designed for placement distal to the thrombus, retrieval allows en bloc thrombus removal (Fig. 1). The penumbra device (Fig. 2), by contrast, works proximally to disrupt and aspirate the thrombus.
  22. 22. Merci: The device is placed distal to the clot (top), engages the clot (middle), and then pulls the clot back into the guide catheter (bottom Penumbra: (Bottom) Model of Penumbra aspiration catheter and separator proximal to intraluminal thrombus
  23. 23. • revascularization in (54%) with retriever alone and in (69%) after additional therapy (IA t-PA as bridging therapy • (9.0%) ------------ICH
  24. 24. Percutaneous Angioplasty • Intracranial angioplasty and stenting is technically possible only in the larger segments of the Circle of Willis – that is, vertebral and basilar arteries, intracranial ICA and the M1 segment of the MCA. • Partial or complete recanalization could be achieved in 91% of patients treated with direct PTA versus 64% treated with thrombolytic therapy alone. ICH was seen in 3% versus 19%, and good outcome occurred in 73% versus 50% of the patients, respectively. • PTA may also be particularly useful in the cases of atherothrombotic disease, in which the residual stenosis may reduce flow sufficiently to lead to rethrombosis
  25. 25. Neuroprotection
  26. 26. • Deprivation of oxygen supply to the brain tissue leads to activation of the ischemic cascade with a series of molecular mechanisms being activated. • There is depletion of adenosine triphosphate and consequent high levels of lactate and unbuffered hydrogen ions. • These hydrogen ions facilitate the generation of ferrous iron-mediated free radicals that result in astroglial injury. Ischemic insult
  27. 27. • Failure of energy dependent mechanisms including ion pumps leads to deterioration of membrane ion gradients, opening of selective and unselective ion channels, and equilibration of most intracellular and extracellular ions (anoxic depolarisation). • Thus potassium ions leave the cell, sodium, chlorine and calcium enter and many excitatory neurotransmitters (glutamate, aspartate) are released in potentially toxic concentrations
  28. 28. • Calcium activates phospholipases which hydrolyse membrane-bound glycero- phospholipids to free fatty acids and these in turn facilitate free radical peroxidation of other membrane bound lipids. Calcium similarly activates both proteases that lyse structural proteins as well as nitric oxide synthase that initiates free radical . • The intracellular entry of calcium is made largely possible by the activation of two types of receptors: Voltage gated (L-type) and/or several N-methyl-D-aspartate (NMDA
  29. 29. Reperfusion insult • Despite the good outcome generally associated with reopening a blood vessel, additional brain injury may result when reperfusion occurs. • When white blood cells reenter a previously hypoperfused region via returning blood, they can occlude small vessels, producing additional ischemia. Leukocytes release toxic products that can lead to free radical and cytokine formation. • Agents that prevent white blood cells from adhering to vessel walls, limit formation of free radicals, or promote neuronal repair may protect the brain from additional injury during reperfusion. • Neuroprotective agents that work primarily during reperfusion may have a longer window of therapeutic effect than drugs that work earlier in the ischemic cascade.
  30. 30. Neuro-protective agents • limits acute injury to neurons in the ischemic penumbra. • Many of these agents modulate neuronal receptors to reduce release of excitatory neurotransmitters, which contribute to early neuronal injury. • Other neuroprotective agents prevent potentially detrimental events associated with return of blood flow.
  32. 32. N-methyl-D-aspartate receptor antagonists • Dextrorphan, a noncompetitive NMDA antagonist, hallucinations and agitation; hypotension, which limited its use • Selfotel, a competitive NMDA antagonist>>>> studies terminated dt ↑ mortality. • aptiganel HCl (Cerestat)>>>> concerns regarding benefit-to-risk ratios • glycine-site NMDA antagonists (↓hallucination) A large efficacy trial using the agent GV150526 on 1367 patients was completed in 2000. Although the drug was reported to be safe and well tolerated, no improvement was observed in any of the 3-month outcome measures
  33. 33. Magnesium • It may reduce ischemic injury by increasing regional blood flow, antagonizing voltage- sensitive calcium channels, and blocking the NMDA receptor. • the Intravenous Magnesium Efficacy Study phase III no benefit (window gap 12hours) • Field Administration of Stroke Therapy - Magnesium Phase III (FAST-MAG) not finished (2/2014) but administer mg within 1 hour
  34. 34. Nalmefene • a narcotic receptor antagonist that reduces levels of excitatory neurotransmitters contributing to cellular injury in early ischemia. • early studies suggest that the drug may have more benefit in patients younger than 70 years • Phase III CT>>>>> no clinical benefit was found, No further trials are planned.
  35. 35. Lubeluzole • The drug may block sodium channels in cells. In addition, it may reduce the release of nitric oxide, Clinical stroke research with this drug has been abandoned.
  36. 36. Clomethiazole • a gamma-aminobutyric acid agonist, decreases excitatory neurotransmission by increasing activity of inhibitory pathways. • A large phase III trial was then performed in 1198 patients, focusing on patients with large strokes, which were defined by the presence of higher cortical dysfunction, limb weakness, and visual field disturbances. • The results were negative, with 42% of the clomethiazole group and 46% of the placebo group showing a good outcome.
  37. 37. Calcium channel blockers • Studies of calcium channel blockers did not show efficacy in stroke treatment. The most recent clinical trial, which assessed the usefulness of oral nimodipine given within 6 hours of symptom onset, was terminated early after analysis of the first 439 patients predicted no beneficial effect of the drug
  38. 38. High-dose human albumin treatment • In animal models of focal cerebral ischemia, albumin infusion at the doses ranging from 0.6-2.5 g/kg are neuroprotective. • Apart from functioning as a haemodiluent, albumin induces systemic mobilization of polyunsaturated fatty acids and help to replenish polyunsaturated fatty acids lost from neural membranes. • A phase III trial investigated albumin versus placebo given within 5 hours of symptom onset (In preclinical studies, albumin appears to have both antioxidant properties and the ability to increase blood flow to the penumbra. The trial, however, was stopped early for futility
  39. 39. Therapeutic Hypothermia Effects: 1. ↓brain damage from ischemia by preventing disruption of the brain-blood barrier. 2. ↓the basal metabolic rate and counteracts the ischemic cascade in the penumbra. 3. Hypothermia might enhance the effects of neuroprotective drugs 4. extends the therapeutic window for systemic thrombolysis or endovascular reperfusion techniques.
  40. 40. • (32°C to 34°C). • including endovascular cooling catheters placed in the vena cava and surface cooling methods such as ice-water immersion techniques. • Still unanswered are questions such as the ideal depth of cooling, duration of hypothermia, rate of re-warming, and whether cooling before reperfusion therapy is essential. • Studied alone or combination with caffeine+ alcohol
  41. 41. Free-radical scavenger • Edaravone. • NXY-059
  42. 42. Free-radical scavenger Edaravone • The Japanese Guidelines for the management of stroke 2009 suggest edaravone for the treatment of acute ischemic stroke as a grade B recommendation. Therefore, edaravone is now widely used to treat acute ischemic stroke in Japan. • It is currently only approved in Japan. • Clinical trial data show that administration of edaravone within 72 h of ischemic stroke onset significantly reduces infarct volume, extend the narrow therapeutic time window of t-PA in rats. • long-term treatment with edaravone suppressed the progression of disuse muscle atrophy and improved leg locomotor function to a greater extent than did short-term treatment
  43. 43. Free-radical trapping NXY-059 • SAINT I showed promise 90 days outcome using modified Rankin score • SAINT II did not show any difference between the treatment and control arms
  45. 45. Prevention of Reperfusion Injury • Enlimomab • Hu23F2G • Tetracycline antibiotics • Antiplatelet antibodies • Citicoline: membrane stabilization • GSK249320
  46. 46. Enlimomab • Monoclonal antibodies can block an intercellular adhesion molecule (ICAM) on the endothelium to prevent adhesion of white blood cells to the vessel wall. • Trial was –ve: • Treated subjects were found to have higher mortality rates and worse outcomes than subjects in the placebo group. A marked increase in fevers occurred in patients who received enlimomab. Elevated temperatures had previously been found to worsen stroke outcome.
  47. 47. human antileukocytic antibody, Hu23F2G, • A phase III trial was then done by using a human antileukocytic antibody, Hu23F2G, no clinical benefit was seen with Hu23F2G on any of the planned measures. No further studies with this agent are planned,
  48. 48. Tetracycline antibiotics • A phase I dose-finding trial using minocycline to treat ischemic stroke (6-h window) was completed. • In addition to providing potential neuroprotection, minocycline also appears to decrease levels of matrix metalloproteinase-9, which has been associated with recombinant tissue plasminogen activator (rtPA)–associated cerebral hemorrhage.
  49. 49. Citicoline • Citicoline may reduce ischemic injury by stabilizing membranes and decreasing free radical formation. • A large international trial, the International Citicoline Trial on acUte Stroke (ICTUS), enrolled 2298 patients with moderate-to-severe strokes within 24 hours of stroke onset. • Unfortunately, this trial did not show efficacy for citicoline compared with placebo
  50. 50. GSK249320 • a monoclonal antibody that blocks myelin- associated glycoprotein, a molecule inhibiting axon outgrowth. • A dosage-finding study showed that the drug was well tolerated and additional trials are in progress
  52. 52. Neurogenesis Enhanced by Gene Therapy • Recent studies have shown that a single injection of adenoviral brain derived neurotrophic factor into the lateral ventricle substantially augmented the recruitment of new neurons into both neurogenic and non-neurogenic sites in the adult rat brain. • Matsuoka et al reported recently that adenovirus- mediated intraventricular gene transfer of FGF-2, which increased FGF-2 level in brain tissues and the cerebrospinal fluid (CSF), is more effective in promoting neurogenesis after ischemia than continuous infusion of FGF-2 peptide, which increased FGF-2 level only in the CSF
  53. 53. Neurogenesis Enhanced by Growth Factors • Fibroblast growth factor-2 and epidermal growth factor (EGF) act as mitogens for adult stem and progenitor cells. • The infusion of EGF into the lateral ventricle of adult mouse forebrain for 6 consecutive days resulted in a substantial increase in cellular proliferation and in the total number of subependymal cells.
  54. 54. Fiblast • a basic fibroblast growth factor. • In a phase II safety trial, Fiblast was administered IV for up to 24 hours in acute stroke patients. • Safe but transient leucocytosis may occur • . A large trial was begun to evaluate the efficacy of Fiblast in stroke patients presenting within 6 hours of symptom onset. However, the trial was terminated because of poor risk-to-benefit ratios.
  55. 55. Adult stem cell therapy in stroke • Stem cell therapy for ischaemic stroke focuses on a regenerative strategy required to restore not only neural elements, but also supporting structures such as blood vessels. • Human NSCs delivered intravenously or stereotactically surrounding the lesion have been shown to survive, migrate towards the lesion and differentiate (mainly neurones and astrocytes), while improving functional recovery in rodent models of stroke.
  56. 56. • In order for stem cells to produce successful neuroregeneration, several conditions must be met: 1. they must be able to produce multiple types of neurons and glia. 2. the new cells must be able to migrate to the site of injury. 3. and they must be able to integrate with existing circuitry by initializing and maintaining appropriate functional connections with neighboring cells.
  57. 57. • studies showed an amplification of endogenous neurogenesis following global ischemia, but did not show any replacement of the CA1 pyramidal cells that are lost in ischemia. • One of the drawbacks of endogenous neurogenesis as a therapy for stroke is that the new cells have limited capabilities to migrate to the site of injury. • Granulocyte colony stimulating factor (G-CSF) has arisen as a potential therapy to allow for the migration of endogenous stem cells to the site of ischemic injury.
  58. 58. • There is currently a phase I trial planned using a commercially developed (foetally derived) NSC line delivered by stereotactic injection in patients with ischaemic stroke (ReNeuron, UK)
  59. 59. Unresolved issues in the translation of stem cell therapy. • (1) choice of cell type, • (2) cell numbers to be given, • (3) optimum timing of treatment, • (4) optimum route of delivery. IV IA IC • (5) optimum tracking of cells after delivery.
  60. 60. • Iv : many of the injected cells end up being caught in peripheral organs such as the liver, spleen and lungs • IA delivery is more invasive, infusing cells directly into the artery that is perfusing the ischemic tissue. The benefit of this method is that it allows the cells to bypass any peripheral organs and go directly to the site of injury. Some concerns with this method of delivery are the potential for the injected cells to form microvascular occlusions, thus worsening the ischemia. • Finally, direct intra-cerebral injection is highly invasive and carries many risks, such as initial human studies showing adverse side effects such as seizures, subdural hematoma and worsening of motor function
  61. 61. Stem cells for neuroprotection • studies have revealed that iv exogenous stromal stem cells in rodents provided multiple benefits, including reduced stroke volumes, improved functional outcomes, and an extended time window for treatment—up to 48 h following stroke onset.