Stroke burden is substantially increasing but current therapeutic drugs are still far from ideal. Here we highlight the vast potential of staphylokinase as an efficient, fibrin-selective, inexpensive, and evolvable thrombolytic agent. The emphasis is escalated by new recent findings. Staphylokinase nonimmunogenic variant was proven noninferior to alteplase in a clinical trial, with decreased risk of intracranial hemorrhage and the advantage of single bolus administration. Furthermore, our detailed kinetic analysis revealed a new staphylokinase limiting bottleneck whose elimination might provide up to 1000-fold higher activity than the clinically approved alteplase. This knowledge of limitations unlocks new possibilities for improvements that are now achievable by the community of protein engineers who have the required expertise and are ready to transform staphylokinase into a powerful molecule. Collectively, the noninferiority and safety of nonimmunogenic staphylokinase together with the newly identified effectivity limitation make staphylokinase a perfect candidate for further exploration, modification, and advancement to make it the next-generation widely accessible thrombolytic drug effectively treating stroke all around the world, including middle- and low-income countries.
- MeSH
- cévní mozková příhoda * farmakoterapie MeSH
- fibrin MeSH
- fibrinolytika * terapeutické užití MeSH
- kinetika MeSH
- lidé MeSH
- metaloendopeptidasy metabolismus terapeutické užití MeSH
- tkáňový aktivátor plazminogenu terapeutické užití MeSH
- trombolytická terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Several plasminogen activators (PAs) have been found effective in treating different thromboembolic diseases. However, administration of conventional thrombolytic therapy is limited by a low efficacy of present formulations of PAs. Conventional treatments using these therapeutic proteins are associated with several limitations including rapid inactivation and clearance, short half-life, bleeding complications or non-specific tissue targeting. Liposome-based formulations of PAs such as streptokinase, tissue-plasminogen activator and urokinase have been developed to improve the therapeutic efficacy of these proteins. Resulting liposomal formulations were found to preserve the original activity of PAs, promote their selective delivery and improve thrombus targeting. Therapeutic potential of these liposome-based PAs has been demonstrated successfully in various pre-clinical models in vivo. Reductions in unwanted side effects (e.g., hemorrhage or immunogenicity) as well as enhancements of efficacy and safety were achieved in comparison to currently existing treatment options based on conventional formulations of PAs. This review summarizes present achievements in: (i) preparation of liposome-based formulations of various PAs, (ii) development of PEGylated and targeted liposomal PAs, (iii) physico-chemical characterization of these developed systems, and (iv) testing of their thrombolytic efficacy. We also look to the future and the imminent arrival of theranostic liposomal formulations to move this field forward.
- MeSH
- aktivátor plasminogenu urokinasového typu aplikace a dávkování terapeutické užití MeSH
- fibrinolytika aplikace a dávkování terapeutické užití MeSH
- lidé MeSH
- liposomy chemie ultrastruktura MeSH
- metaloendopeptidasy aplikace a dávkování terapeutické užití MeSH
- nanostruktury chemie ultrastruktura MeSH
- plasmin aplikace a dávkování terapeutické užití MeSH
- streptokinasa aplikace a dávkování terapeutické užití MeSH
- tkáňový aktivátor plazminogenu aplikace a dávkování terapeutické užití MeSH
- tromboembolie farmakoterapie MeSH
- trombolytická terapie metody MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Příspěvek se zabývá popisem vývoje alfimeprázy - nové, fibrinolyticky účinné látky, nového potenciálního léčiva k terapii akutní ischemické mrtvice, okluze katétru a akutní periferní arteriální okluze. Alfimepráza rozpouští krevní sraženinu rychleji než v současnosti používaná léčiva díky specifickému mechanizmu účinku, přímo degraduje fibrin.
This article describes the continuing investigation of alfimeprase, a novel direct-acting thrombolytic agent for its indications - the treatment of acute peripheral arterial occlusion, stroke, and catheter occlusion. Alfimeprase dissolves blood clots faster than current therapies, degrades fibrin directly.
