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Future directions in stroke treatment
Published in Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees, Stroke in Practice, 2017
Christos Tziotzios, Jesse Dawson, Matthew Walters, Kennedy R Lees
Preclinical evidence suggests a differential safety and efficacy profile of alternate thrombolytic agents, and among these, desmoteplase (a highly fibrin-specific thrombolytic agent originally isolated from the saliva of the vampire bat) has undergone extensive evaluation in stroke patients using a longer time window.91011 A large trial of this agent in highly selected patients within nine hours of hemispheric stroke is underway.
Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Desmoteplase is third-generation plasminogen activator, a non-t-PA variant. Desmodus salivary plasminogen activators (DSPAS) is a group of four enzymes isolated from common vampire bat, Desmodus rotundus and desmoteplase is one among them, called DSPAα1 or Bat-PA (Kratzschmar et al., 1991). It is a single-chain 50 kDa protein which could be produced in both CHO cell lines and insect cells by recombinant techniques. It has an extended terminal half-life when compared with other thrombolytic enzymes such as t-PA (Hildebrand et al., 1996). DSPAα1 contains a single kringle domain quite similar to the kringle 1 domain of t-PA but it is devoid of any lysine binding site. Apart from kringle domain, it also contains a signal peptide, an epidermal growth factor (EGF) domain, a serine protease domain, and a finger domain. Also the protease domain lacks plasmin cleavage site. The bimolecular rate constant of plasminogen activation was 13000 for DSPAα1 and 72 for t-PA in the presence of fibrin versus fibrinogen (fibrin selectivity), proving it to be highly fibrin specific (Bringmann et al., 1995). Tranexamic acid is a synthetic lysine analog that can inhibit desmoteplase, therefore possible for managing any bleeding complications, occurring during the usage of the enzyme (Niego et al., 2008). The canine model of arterial thrombosis showed desmoteplase to be better in thrombolysis compared to t-PA (Mellott et al., 1992). Intravenous administration directly into brain causes excitotoxic injury leading to brain damage in case of t-PA, whereas desmoteplase does not encourage excitotoxic injury and thus proves to be a better therapeutic for ischemic stroke (Reddrop et al., 2005). DSPAα1 definitely has therapeutic advantages over t-PA and preclinical studies have already showed better specificity and selectivity towards fibrin. Most thrombolytic drugs have a time window of less than 3–4.5 h. However, desmoteplase is supposed to demonstrate better clinical advantages by extending the therapeutic window of patients with ischemic stroke. Desmoteplase in acute ischemic stroke (DIAS) trial; a phase II trial showed that the administration of this drug within 3–9 h after the onset of the symptoms of stroke has got a clinical benefit with use of DSPAα1 (Hacke et al., 2005). However, the DIAS-2 failed to prove any significant advantage of the drug within 3–9 h time window after onset of stroke (Hacke et al., 2009). According to DIAS 3 and DIAS 4 trials, acceptable safety profile was observed for DSPAα1, but no evidence to extend therapeutic window up to 9 h for ischemic stroke was found (Albers et al., 2015; Kummer et al., 2016). Satisfactory reperfusion efficacy was shown by desmoteplase after 3 h since onset of AIS; however, more studies with well-designed clinical trials are needed to be evaluated for the effectiveness of the drug to improvise the therapeutic window in treating AIS patients (Li et al., 2017). Although intracranial hemorrhages are low for desmoteplase, it did not showed any neurological improvement or survival rate improvement (Hacke et al., 2009; Albers et al., 2015; Kummer et al., 2016).
Pharmacological management of cerebral ischemia in the elderly
Published in Expert Opinion on Pharmacotherapy, 2021
Adithya Kannan, Mychael Delgardo, William Pennington-FitzGerald, Enoch X. Jiang, Brandon R. Christophe, E Sander Connolly
Few thrombolytic agents aside from alteplase have shown promise recently. Desmoteplase, a plasminogen activator that functions similarly to tPA and is highly fibrin-specific, demonstrated encouraging results in early trials for extending the safety window beyond 4.5 hours. The safety and efficacy of the novel thrombolytic were tested in two double-blind, randomized placebo-controlled phase III trials, the DIAS-3 and DIAS-4. The former enrolled 492 patients and found that while the drug was safe, it did not improve the probability of a favorable outcome (modified Ranking Score (mRS) of 0–2) at 90 days compared to placebo. The latter was terminated based on these results [14,15]. Three phase III trials assessing the efficacy of promising thrombolytics against standard of care treatment of AIS with alteplase are currently in the recruiting stage. Two will focus on tenecteplase, a modified tissue plasminogen activator which has replaced alteplase in the thrombolytic treatment of myocardial infarction (MI), and has shown to have a similar safety profile and improved incidence of reperfusion and functional outcomes in recent clinical trials [16–19]. The third will look at urokinase, a serine protease present in humans [20].
Investigational drugs for ischemic stroke: what’s in the clinical development pipeline for acute phase and prevention?
Published in Expert Opinion on Investigational Drugs, 2022
Maria Giulia Mosconi, Maurizio Paciaroni, Walter Ageno
Clinical stroke research is also investigating other fibrinolytic agents in clinical trials for the treatment of acute ischemic stroke. Of these, desmoteplase is a plasminogen activator derived from the saliva of the vampire bat Desmodus rotundus. It has a higher fibrin specificity, a longer half-life and lower neurotoxicity, compared to alteplase [75]. Some clinical trials have been conducted to assess desmoteplase, but phase 3 studies did not suggest its superiority. Presently, there are no active or planned studies on desmoteplase [76–81].
Recent advances in targeted delivery of tissue plasminogen activator for enhanced thrombolysis in ischaemic stroke
Published in Journal of Drug Targeting, 2018
Masumeh Zamanlu, Mehdi Farhoudi, Morteza Eskandani, Javad Mahmoudi, Jaleh Barar, Mohammad Rafi, Yadollah Omidi
The third generation of thrombolytic agents combines the advantages of fibrin specificity with higher half-life and significantly greater recanalization rates. There are several third generation agents with desirable therapeutic impacts, including: mutants tPA and scuPA, chimeric type of tPA/scuPA such as Amediplase (a recombinant single chain glycoprotein of 365 amino acid residues composed of kringle-2 domain of human tPA fused to the serine protease domain of prourokinase); conjugates of tPA with monoclonal antibody (mAb) specific to fibrin, platelets or thrombomodulin; and tPA originated from other animals (e.g. vampire bat tPA) or bacteria (Staphylococcus aureus) such as Staphylokinase [57]. Another example is reteplase (Retavase™ produced by Chiesi) that is a recombinantly produced tPA in E coli. It is a non-glycosylated form of human tPA containing 357 of the 527 amino acids of the original tPA, which has approximately 15 min half-life and shows improved penetration into clots [58]. Tenecteplase (BL-115; TNKase™ developed by Genentech) is a glycoprotein (527 amino acids) with two substitutions (i.e. threonine 103 with asparagine and asparagine 117 with glutamine) within the kringle 1 domain, and a tetra-alanine substitution (i.e. amino acids 296–299) in the protease domain – produced in Chinese hamster ovary (CHO) cells with a long half-life (over 20 min) [59]. Pamiteplase (YM-866; Solinase™ developed by Astellas Pharma, Japan) is a modified tPA with deleted kringle 1 domain and a point mutation (arginine 274 to glutamine), at which it becomes resistant to the plasmin-mediated cleavage and half-life of up to 45 min [57,59]. Desmoteplase is a vampire bat (Desmodus rotundus) saliva-derived analogue of human tPA, which can break down fibrin of blood clots. Many physiological and biochemical properties of desmoteplase appear to be similar to that of the tPA, while it shows higher circulating half-life of 4 h. This agent has shown promising outcomes in laboratory phase and proceeded towards clinical trials to be examined upon its safety and efficacy in human subjects [53,60–63].