BAT’s Saliva can Save BAT’s Patient Hanish P. Kodali
Desmoteplase• In 1932, Saliva of the Vampire bat (Desmodus rotundus) was known to lead to interference with the haemostatic mechanism of the host animal.• It has some highly potent plasminogen activators, specialized in rapid lysis of fresh blood clots.• In 1991, DNA coding of four plasminogen activators was done, and recombinant D. rotundus salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated.
Mechanism of Action• Protease - only subtrate protein- Plasminogen.• Fibrin is a must co-factor.• BBB permeation via Transendothelial Translocation- LRP- mediated transcytosis.• Oxygen & Glu Deprivation exacerbated passage .
Advantage of DSPA over tPA• Longer half life (4 hours)• Doesn’t contain the plasmin-sensitive cleavage site and the lysine-binding Kringle 2 domain.• Doesn’t promote kainate- or NMDA-mediated neurotoxicity in vivo.
Clinical Trials1. Desmoteplase in Acute Ischemic Stroke (DIAS)2. Dose Escalation of Desmoteplase in Acute Ischemic Stroke (DEDAS)3. Study of Desmoteplase (International Nonproprietary Name [INN]) in Acute Ischemic Stroke (DIAS-2)4. Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (DIAS-3)5. Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (DIAS-4)
1. Desmoteplase in Acute Ischemic Stroke (DIAS)
2. Dose Escalation of Desmoteplase in Acute Ischemic Stroke (DEDAS)
2. DEDAS Patient Selection Criteria• Inclusion Criteria - scoring 4 to 20 on the National Institute of Health Stroke Scale (NIHSS) - showing a perfusion-diffusion mismatch on MRI of 20 % - enrolment within a 3 h to 9 h time window after symptom onset. - 18-85 years of age• Exclusion Criteria - Participation in any interventional trial in the previous 30 days. - Women in the childbearing age. - Any history of intracranial hemorrhage, subarachnoid hemorrhage, neoplasm, arteriovenous malformation or aneurysm. - Conditions that, according to the judgment of the investigator, might impose an additional risk to any individual stroke patient when receiving study medication (this applied to patients on platelet-function inhibitors as well). - MRI exclusion criteria: Evidence of ICH, Evidence of SAH, Signs of extensive early infarction on DWI assessed by evidence of involvement of >1/3 of the middle cerebral artery (MCA) territory. No perfusion deficit, Internal carotid artery (ICA) occlusion ipsilateral to stroke lesion without additional ipsilateral MCA, anterior cerebral artery (ACA) or posterior cerebral artery (PCA) occlusion. Any intracranial pathology that would interfere with the MRI assessment of acute ischemic stroke.
3. Desmoteplase (International Nonproprietary Name [INN]) in Acute Ischemic Stroke (DIAS-2)
• Main selection criteria• Inclusion criteria- Informed consent• Age 18–85 years• Treatment within 3–9 h of the onset of stroke symptoms• Score of 4–24 points on the National Institutes of Health stroke scale (NIHSS) with clinical signs of hemispheric infarction (eg, hemiparesis) that are suggestive of ischaemic stroke• A distinct penumbra (at least 20%), measured by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI) or perfusion CT, in the territory of the middle cerebral artery, anterior cerebral artery, or posterior cerebral artery with a hemispheric distribution• Exclusion criteria –• Patients not able to receive study medication within 60 min of completing diagnostic imaging screening• Rapidly improving neurological symptoms such that the rate of improvement is projected to give the patient an NIHSS score of <4 at randomisation• Prestroke modified Rankin scale (mRS) score of more than 1 point (indicating previous disability)• Consciousness level greater than 2 points on question 1a of NIHSS• History or clinical presentation of intracranial haemorrhage, subarachnoid haemorrhage, arteriovenous malformation, aneurysm, or cerebral neoplasm• Suspected acute occlusion of the vertebral or basilar artery• Current use of oral anticoagulants and a prolonged prothrombin time (international normalised ratio >1·6)• Use of heparin, except for low-dose subcutaneous heparin, in the previous 48 h and a prolonged partial thromboplastin time that exceeded the upper limit of the normal range of the local laboratory• Use of inhibitors of glycoprotein IIb–IIIa within the past 72 h; use of single oral inhibitor of platelets (clopidogrel or low-dose aspirin) before entry into the study was permitted• Baseline blood glucose concentration less than 50 mg/dL or greater than 300 mg/dL; patients with blood glucose concentrations between 200–300 mg/dL could be included only if the blood glucose concentration decreased to less than 200 mg/dL after treatment with antidiabetic drugs and before the study medication was given• Uncontrolled hypertension, defined as systolic blood pressure >185 mm Hg or diastolic blood pressure >110 mm Hg on at least two separate occasions at least 10 min apart, or blood pressure that required aggressive treatment to reduce it to within these limits• Hereditary or acquired haemorrhagic diathesis• Another stroke or a serious head injury within the previous 6 weeks• A history of stroke in a patient with diabetes, unless blood glucose concentration was within the range indicated above
Comparison of baseline characteristics: DIAS/DEDAS versus DIAS-2
Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke (DIAS-3) & (DIAS_4)Patient InvolvementPatients are randomized to either: Desmoteplase Score 90 μg/kg bodyweight, IV, single bolus over 1 - 2minutes on 1st day or Placebo IV, single bolus over 1 - 2 minutes on 1st day. Follow up with a Modified RankinScale and National Institutes of Health Stroke Scale (NIHSS) Score is done in 90 days.
References• "Hawkey C. Inhibitor of platelet aggregation present in saliva of the vampire bat Desmodus rotundus. Br J Haematol.1967;13(6):1014-20.".• "Schleuning WD. Vampire Bat plasminogen activator DSPA-alpha-1 (desmoteplase): a thrombolytic drug optimized by natural selection. Haemostasis. 2001;31(3-6):118-122.".• "Paciaroni M, Medeiros E, Bogousslavsky J. Desmoteplase. Expert Opin Biol Ther. 2009;9(6):773- 778.".• "Hacke W, Albers G, Al Rawi Y, et al. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73.".• "Furlan AJ, Eyding D, Albers G. W, et al. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37(5):1227- 1231.".• "Hacke W, Furlan AJ, Al Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009(2):141- 150.".• National Institute of Neurological Disorders and Stroke. NINDS CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) information page. Available from http://www.ninds.nih.gov/disorders/cadasil/CADASIL.htm. Accessed October 13, 2009. Hacke W, Kaste M, Bluhmki E, et al, for the ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317–29.