Desmoteplase

Last updated
Salivary plasminogen activator alpha 1
Desmoteplase 1A5I.png
Identifiers
Organism Desmodus rotundus
SymbolPLAT
Alt. symbolsBAT-PA; DSPA-5
ATC code B01
CAS number 145137-38-8
DrugBank DB04925
Entrez 112321404
HomoloGene 717
PDB 1A5I
RefSeq (mRNA) XM_024578803.1
RefSeq (Prot) XP_024434571.1
UniProt P98119
Other data
EC number 3.4.21.68
Chromosome Unplaced: 1.98 - 2.01 Mb
Search for
Structures Swiss-model
Domains InterPro

Desmoteplase is a novel, highly fibrin-specific "clot-busting" (thrombolytic) drug in development that reached phase III clinical trials. The Danish pharmaceutical company, Lundbeck, owns the worldwide rights to Desmoteplase. In 2009, two large trials (DIAS-3 and DIAS-4) were started to test it as a safe and effective treatment for patients with acute ischaemic stroke. After disappointing results in DIAS-3, DIAS-4 was terminated, and in December 2014 Lundbeck announced that they would stop the development of desmoteplase. [1]

Contents

Desmoteplase is a recombinant form of the alpha-1 isoform of DSPA (Desmodus rotundus salivary plasminogen activator).

Mode of action

Desmoteplase, a chemical found in the saliva of vampire bats, has the effect of catalysing the conversion of plasminogen to plasmin, which is the enzyme responsible for breaking down fibrin blood clots.

Discovery of desmoteplase

As early as in 1932, the saliva of the vampire bat (Desmodus rotundus) was known to lead to interference with the haemostatic mechanism of the host animal. [2] In 1991, the DNA coding of four plasminogen activators present in the saliva of the vampire bat was completed. Of the four, recombinant D. rotundus salivary plasminogen activator alpha 1 (rDSPAα1; desmoteplase) was investigated further. [3]

Chemical structure

The structure of desmoteplase is similar to rt-PA (alteplase), but it does not contain the plasmin-sensitive cleavage site and the lysine-binding Kringle 2 domain. As a result, desmoteplase, in comparison to rt-PA, has high fibrin selectivity (100,000- v. 550-fold increase in catalytic activity), an absence of neurotoxicity, and no apparent negative effect on the blood–brain barrier. Desmoteplase also has a half-life of about four hours; [4] rtPA has a terminal plasma half-life of about 5 minutes.

Desmoteplase in acute ischaemic stroke clinical trial program

The two phase II trials DIAS and DEDAS indicated that when intravenous (IV) desmoteplase was administered three to 9 hours after onset of ischaemic stroke symptoms, it was associated with a high rate of reperfusion and a low rate of symptomatic intracranial haemorrhage at doses up to 125 μg/kg. [5] [6] In the subsequent DIAS-2 trial, the same benefit could not be shown. This could be explained by the inclusion of a substantial number of patients with a mild stroke at baseline and small mismatch volumes associated with no vessel occlusion. [7] Post hoc analyses of the DIAS-2 data and the pooled data of the DIAS, DEDAS and DIAS-2 data showed that patients who had a proximal cerebral vessel occlusion or high-grade stenosis on baseline angiography, had a positive response for desmoteplase. [8]

In 2009, the DIAS-3 and DIAS-4 phase III trials started, each planning to enroll 400 patients worldwide who had had an acute ischaemic stroke. Participants are treated with desmoteplase as an intravenous bolus dose of 90 μg/kg within three to 9 hours after stroke symptom onset. Patients are selected with occlusion or high-grade stenosis (TIMI 0-1) in proximal cerebral arteries as assessed by magnetic resonance or computed tomography angiography. Wherever possible, additional perfusion-weighted imaging and diffusion-weighted imaging assessments will be done.

The outcomes of DIAS-3 and DIAS-4 studies should tell whether desmoteplase is a breakthrough treatment for acute ischaemic stroke. In June 2014, Lundbeck published a press release about the DIAS-3 study revealing neutral results in an intention-to-treat analysis. [9] The proportion of patients presenting good clinical outcome was comparable in the desmoteplase group (51.3%) and in the placebo group (49.8%). Notably, Lundbeck mentioned that, when analysing per protocol, desmoteplase showed an effect relative to placebo. Publication of the final results is still awaited.

After the disappointing results in DIAS-3, the DIAS-4 trial was terminated. [10] In December 2014 Lundbeck announced they would stop the development of desmoteplase and the company made a write-down of 309 million Danish crowns. [1]

Significance of the time window

Current standards of treatment allow for IV rt-PA up to 4.5 hours in ischaemic stroke. After this time window, the benefit is typically thought to be outweighed by the risk of brain haemorrhage. [11] Interarterial approaches are thought to be useful up to six hours. Nevertheless, CT-perfusion scans and MRI-perfusion versus MRI-diffusion demonstrate that even after six hours a significant ischaemic penumbra of brain tissue may be salvageable. Some approaches to this involves mechanical removal of clot (for example the Merci device, the penumbra device and removable stents like Solitaire). [12] [13]

If desmoteplase can extend the IV treatment window to 9 hours, this would allow a much larger percentage of ischaemic stroke patients to receive active thrombolytic treatment – including patients who were delayed in getting to the hospital and neurological assessment. This could make a substantial difference in stroke outcomes. A 9-hour treatment window could also have a major impact on the treatment of "wake-up" strokes - where a patient awoke with symptoms, and is not sure whether the stroke occurred within the past 4.5 hours.

Related Research Articles

<span class="mw-page-title-main">Vampire bat</span> Species of bat

Vampire bats, members of the subfamily Desmodontinae, are leaf-nosed bats currently found in Central and South America. Their food source is the blood of other animals, a dietary trait called hematophagy. Three extant bat species feed solely on blood: the common vampire bat, the hairy-legged vampire bat, and the white-winged vampire bat. Two extinct species of the genus Desmodus have been found in North America.

<span class="mw-page-title-main">Ischemia</span> Restriction in blood supply to tissues

Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism. Ischemia is generally caused by problems with blood vessels, with resultant damage to or dysfunction of tissue i.e. hypoxia and microvascular dysfunction. It also implies local hypoxia in a part of a body resulting from constriction. Ischemia causes not only insufficiency of oxygen, but also reduced availability of nutrients and inadequate removal of metabolic wastes. Ischemia can be partial or total blockage. The inadequate delivery of oxygenated blood to the organs must be resolved either by treating the cause of the inadequate delivery or reducing the oxygen demand of the system that needs it. For example, patients with myocardial ischemia have a decreased blood flow to the heart and are prescribed with medications that reduce chronotrophy and ionotrophy to meet the new level of blood delivery supplied by the stenosed vasculature so that it is adequate.

<span class="mw-page-title-main">Thrombolysis</span> Breakdown (lysis) of blood clots formed in blood vessels, using medication

Thrombolysis, also called fibrinolytic therapy, is the breakdown (lysis) of blood clots formed in blood vessels, using medication. It is used in ST elevation myocardial infarction, stroke, and in cases of severe venous thromboembolism.

<span class="mw-page-title-main">Tissue-type plasminogen activator</span> Protein involved in the breakdown of blood clots

Tissue-type plasminogen activator, short name tPA, is a protein involved in the breakdown of blood clots. It is encoded in the human by the PLAT gene. It is a serine protease found on endothelial cells, the cells that line the blood vessels. As an enzyme, it catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for clot breakdown. Human tPA has a molecular weight of ~70 kDa in the single-chain form.

<span class="mw-page-title-main">Stroke</span> Death of a region of brain cells due to poor blood flow

A stroke is a medical condition in which poor blood flow to the brain causes cell death. There are two main types of stroke: ischemic, due to lack of blood flow, and hemorrhagic, due to bleeding. Both cause parts of the brain to stop functioning properly.

Mechanical thrombectomy, or simply thrombectomy, is the removal of a blood clot (thrombus) from a blood vessel, often and especially endovascularly as an interventional radiology procedure called endovascular thrombectomy (EVT). It thus contrasts with thrombolysis by thrombolytic medications, as either alternative or complement thereto. It is commonly performed in the cerebral arteries as treatment to reverse the ischemia in some ischemic strokes. Open vascular surgery versions of thrombectomy also exist. The effectiveness of thrombectomy for strokes was confirmed in several randomised clinical trials conducted at various medical centers throughout the United States, as reported in a seminal multistudy report in 2015.

<span class="mw-page-title-main">Alteplase</span> Thrombolytic medication

Alteplase, sold under the brand name Activase among others, is a biosynthetic form of human tissue-type plasminogen activator (t-PA). It is a thrombolytic medication used to treat acute ischemic stroke, acute ST-elevation myocardial infarction, pulmonary embolism associated with low blood pressure, and blocked central venous catheter. It is given by injection into a vein or artery. Alteplase is the same as the normal human plasminogen activator produced in vascular endothelial cells and is synthesized via recombinant DNA technology in Chinese hamster ovary cells (CHO). Alteplase causes the breakdown of a clot by inducing fibrinolysis.

Dias or DIAS may refer to:

<span class="mw-page-title-main">Cerebral infarction</span> Medical condition

Cerebral infarction is the pathologic process that results in an area of necrotic tissue in the brain. It is caused by disrupted blood supply (ischemia) and restricted oxygen supply (hypoxia), most commonly due to thromboembolism, and manifests clinically as ischemic stroke. In response to ischemia, the brain degenerates by the process of liquefactive necrosis.

Ancrod is a defibrinogenating agent derived from the venom of the Malayan pit viper. Defibrinogenating blood produces an anticoagulant effect. Ancrod is not approved or marketed in any country. It is a thrombin-like serine protease.

Tenecteplase, sold under the trade names TNKase, Metalyse and Elaxim, is an enzyme used as a thrombolytic drug.

<span class="mw-page-title-main">Désiré Collen</span> Belgian chemist, physician

Désiré, Baron Collen is a Belgian physician, chemist, biotechnology entrepreneur and life science investor. He made several discoveries in thrombosis, haemostasis and vascular biology in many of which serendipity played a significant role. His main achievement has been his role in the development of tissue-type plasminogen activator (t-PA) from a laboratory concept to a life-saving drug for dissolving blood clots causing acute myocardial infarction or acute ischemic stroke. Recombinant t-PA was produced and marketed by Genentech Inc as Activase and by Boehringer Ingelheim GmbH as Actilyse, and is considered biotechnology's first life saving drug.

<span class="mw-page-title-main">Anterior cerebral artery syndrome</span> Medical condition

Anterior cerebral artery syndrome is a condition whereby the blood supply from the anterior cerebral artery (ACA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the medial aspects of the frontal and parietal lobes, basal ganglia, anterior fornix and anterior corpus callosum.

<span class="mw-page-title-main">Acute limb ischaemia</span> Occurs when there is a sudden lack of blood flow to a limb

Acute limb ischaemia (ALI) occurs when there is a sudden lack of blood flow to a limb, within 14 days of symptoms onset. It is different from another condition which is more chronic called critical limb ischemia (CLD). CLD is the end stage of peripheral vascular disease where there is still some collateral circulation (alternate circulation pathways} that bring some blood to the distal parts of the limbs. While limbs in both acute and chronic limb ischemia may be pulseless, a chronically ischemic limb is typically warm and pink due to a well-developed collateral artery network and does not need emergency intervention to avoid limb loss.

<span class="mw-page-title-main">Reperfusion therapy</span>

Reperfusion therapy is a medical treatment to restore blood flow, either through or around, blocked arteries, typically after a heart attack. Reperfusion therapy includes drugs and surgery. The drugs are thrombolytics and fibrinolytics used in a process called thrombolysis. Surgeries performed may be minimally-invasive endovascular procedures such as a percutaneous coronary intervention (PCI), which involves coronary angioplasty. The angioplasty uses the insertion of a balloon and/or stents to open up the artery. Other surgeries performed are the more invasive bypass surgeries that graft arteries around blockages.

<span class="mw-page-title-main">Hematophagy</span> Ecological niche involving feeding on blood

Hematophagy is the practice by certain animals of feeding on blood. Since blood is a fluid tissue rich in nutritious proteins and lipids that can be taken without great effort, hematophagy is a preferred form of feeding for many small animals, such as worms and arthropods. Some intestinal nematodes, such as Ancylostomatids, feed on blood extracted from the capillaries of the gut, and about 75 percent of all species of leeches are hematophagous. The spider Evarcha culicivora feeds indirectly on vertebrate blood by specializing on blood-filled female mosquitoes as their preferred prey. Some fish, such as lampreys and candirus; mammals, especially vampire bats; and birds, including the vampire finch, Hood mockingbird, Tristan thrush, and oxpeckers, also practise hematophagy.

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A migrainous infarction is a rare type of ischaemic stroke which occurs in correspondence with migraine aura symptoms. Symptoms include headaches, visual disturbances, strange sensations and dysphasia, all of which gradually worsen causing neurological changes which ultimately increase the risk of an ischaemic stroke. Typically, women under the age of 45 who experience migraine with aura (MA) are at the greatest risk for developing migrainous infarction, especially when combined with smoking and use of oral contraceptives.

A cerebroprotectant is a drug that is intended to protect the brain after the onset of acute ischemic stroke. As stroke is the second largest cause of death worldwide and a leading cause of adult disability, over 150 drugs tested in clinical trials to provide cerebroprotection.

References

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