IJCRR

IJCRR - 5(23), December, 2013

Pages: 31-36

Date of Publication: 16-Dec-2013

CEREBROVASCULAR ATTACK: NEW THERAPEUTIC AREAS OF INTEREST

Author: Partha S. Saha

Category: Healthcare

Abstract:Cerebrovascular attack (CVA) or stroke is one of the leading causes of adult disability in world. The current treatments of the stroke are preventive treatment, acute-phase stroke treatment and post-stroke rehabilitation. But the need of more sophisticated therapies and the drawbacks of the existing therapies in their usages call for the new therapies to replace them or develop them. This essay summarizes some of the major new therapeutic approaches, such as the use of statin agents, ACE-I, vitamins, minocycline, edaravone, other neuroprotective agents, stem cell therapy and hyperbaric oxygen therapy. It also describes new methods of implanting of Penumbra system for prevention of the stroke.

Keywords: Stroke, penumbra system, minocycline in stroke, edaravone in stroke, ReN001 stem cell therapy, hyperbaric oxygen therapy.

Full Text:

INTRODUCTION

Stroke, also known as a cerebrovascular attack (CVA), is the rapid loss of brain function(s) due to disturbance in blood supply to brain. This can be due to ischemia (lack of blood flow) caused by blockage (thrombosis, arterial embolism), or a hemorrhage (leakage of blood) [1]. As a result, the affected areas of brain cannot function, which might result in an inability to move one or more limbs on one side of the body, to understand or formulate speech, or to see one side of a visual field [2].

 A stroke is a medical emergency that can cause permanent neurological damage, complications, and even death. It is the leading cause of adult disability in the United States and Europe and the second leading cause of death worldwide [3]. Risk factors for stroke include old age, hypertension (high blood pressure), previous stroke or transient ischemic attack (TIA), diabetes, high cholesterol, cigarette smoking and atrial fibrillation. High blood pressure is the most important risk factor of stroke [2].

OBJECTIVE

Stroke is a major public health problem throughout the world. Stroke is usually considered as a disease of the elderly, but strokes can occur at any age and their consequences in terms of lost productivity are even greater in younger patients than that of older ones. Stroke is regarded as the third leading cause of death after heart disease and cancer, and it is a leading cause of disability as well. In addition, stroke is the single largest cause of adult disability in developed world. Over 150,000 people suffer a stroke each year in the UK, and over 700,000 people in the US.  The annual health and social costs of caring for disabled stroke patients is estimated to be in excess of £5 billion in the UK, with stroke patients occupying 25 per cent of long term hospital beds [3].

Current Therapies

Strokes can be classified into two major categories: ischemic and hemorrhagic, and the treatment of the stroke can be classified into three 

major categories - preventive treatment, acute-phase stroke treatment and the post-stroke rehabilitation.

The preventive treatment is aimed in reduction of associated risks of stroke earlier than its occurrence.  There are several ways by which preventive treatment can be done. Some of the treatment includes the use of the drugs, such as anticoagulants or antiplatelets, surgical procedures like Carotid Endarterectomy, Hemicraniectomy, Angioplasty, etc. Among these techniques, the most prevalent treatment therapy is through use of anticoagulants and antiplatelets. Several antiplatelet agents and anticoagulants interfere with the blood's clotting ability and thereby play a significant role in preventing stroke.

The acute-phase stroke treatment aims at arresting a stroke when it takes place. This therapy is done by using thrombolytics or clot-busting drugs, such as tissue plasminogen activator (tPA). Therefore, it is also known as thrombolytic therapy. This is the most promising treatment for the ischemic stroke till today.

Lastly, post-stroke rehabilitation therapies are effective for improving both functional and cognitive recoveries in a patient some weeks or months after the event of stroke. Transcranial infrared laser therapy, for example, reduces the infarct area and improves the intra-cerebral microcirculation.
Drawbacks of the current therapies

Among the preventive therapies, use of antiplatelet drugs or anticoagulant drugs involves increasing the incidence of the drug interaction in patients. On the other hand, the surgical preventive treatments are very costly and life-threatening.

The acute-phase treatment with thrombolytic drugs is more complex as it needs to be done in hospitals with professional intervention. In addition to that, to ensure best therapeutic effect of the dose, the thrombolytic drugs should be administered within a three-hour interval from the onset of symptoms. But in this short interval of time, only 3 to 5% of the patient can reach hospitals. Therefore, the disadvantage of this therapy can alone keep out patients to harvest maximum benefits out of this so-called ‘most promising’ treatment of ischemic stroke.

Like acute-phase therapy, the post-stroke rehabilitation therapies also need the professional intervention of physicians, rehabilitation nurses, vocational therapists, and mental health professionals. Moreover, they are involved with the use of sophisticated instrument which is never a cost-effective way. Moreover, patients do not get cured fully.

Therefore, the existing therapies have several drawbacks of their usage which call for the new therapies to replace them or develop them.

New Therapeutic Approaches

Use of Statin agents, ACE-I, vitamins for prevention of the stroke

Atherosclerosis, a major risk factor for stroke, was first realized as an inflammatory disease. This insight helped to make suggestion regarding its therapeutic agents, such as statins, vitamins and angiotensin-converting enzyme inhibitors (ACE-I) as they have certain anti-inflammatory activities. These agents reduce inflammation by stabilising atherosclerotic plaque or by other protective mechanism. Here, the statins like atorvastatin lower the risk factor of stroke. ACE-I, on the other hand, lowers the risk of vascular outcomes and related complications in high-risk patients, especially those with diabetic and non-diabetic renal diseases. In addition to that, vitamin C, beta carotene and vitamin E are the sources of the antioxidant nutrients. These antioxidants reduce the atheroma formation by inhibiting oxidation of LDL, which is an important step for atherosclerotic process [4].

The Penumbra System

To prevent the damage caused in the penumbral region, timely revascularization and the establishment of the reperfusion are mostly essential. The Penumbra System is an embolectomy device which is designed for removing thrombus in acute ischemic stroke. The  

device functions through 2 mechanisms - aspiration and extraction. The device is composed of three parts: a reperfusion separator, catheter, and thrombus removal ring. For aspiration, the reperfusion catheter is used along with the separator and an aspiration source to separate the thrombus and aspirate it from the occluded vessel. If residual thrombus still remains after revascularization with aspiration, the thrombus removal ring is used to directly removal of the thrombus. Overall, it is an effective device to reduce the neurologic deficit, stroke-related mortality and morbidity, and also to improve clinical outcomes [5]. It was approved by FDA in 2007 [6].

On July, 2013, Penumbra Inc. has launched a next-generation clot-extraction device, namely 5MAX™ ACE. This device uses aspiration technology as a primary tool to revascularize the clots more effectively than any other devices which use aspiration approach [7]. A Direct Aspiration First-Pass Technique (ADAPT) - a simple and effective technique using a large bore aspiration catheter to recanalize the vessel in AIS- when optimized with 5MAX™ ACE showed superior clinical outcomes as a first-line approach. In this way, it is now possible to remove complete thrombus without causing distal embolism- which is regarded as the highest state-of–art in reperfusion technology [7, 8].

Use of Minocycline for the treatment of the stroke

Minocycline is a protease inhibitor which was found to be useful in treatment of stroke in preclinical state of a preclinical stroke model. Being a promising anti-inflammatory, it has shown its effectiveness as a potential vascular-protective agent.  Moreover, it has also shown a significant success in dropping bleeding effects during tissue plasminogen activator (tPA) trial. Overall, this drug has already shown a great success to be used as an adjunctive therapy to tPA in stroke. It is to be noted here that since it shows no adverse effect in the fibrinolytic activity of tPA, the impact of reperfusion homorrhage is highly reduced; however, it was observed in some other experimental models [9].

Significance of Neuroprotection in Ischemic Stroke treatment

Neuroprotection is regarded as “any strategy, or combination of strategies, that antagonizes, interrupts, or slows the sequence of injurious biochemical and molecular events that, if left unchecked, would eventuate in irreversible ischemic injury” [10].

It is considered that some of the important mechanisms, such as activity of the excitotoxic neurotransmitters, production of the free radicals in neurons and apoptotic signalling of them can give a complete picture to draw conclusion about the mechanisms of the neuronal cell death in the brain even in the stroke condition [11]. In the preclinical condition, the neuroprotective agents have their own merits and demerits. Some of these types of the neuroprotective agents are the glutamate antagonists, GABA agonists, nitric oxide signal regulators, glutamate antagonists, etc. Use of the neuroprotective agents for the use of inhibiting neuronal cell death is a matter of recent concern and some of these protective therapies, which are considered to be used shortly, are the therapeutic hypothermia, hyperacute magnesium therapy, high-dose human albumin therapy, etc. The effectiveness of these therapies, even in their combinations, is also being studied [12].

Use of Edaravone for Acute of the stroke

Since 2001, in Japan, the edaravone has been marketed by Mitsubishi Pharma. This was being used an antioxidant. But later on, it was found to have effectiveness in treating acute brain ischemia and cerebral infraction, along with different mechanism of the neurological recovery. The mechanism that is involved with the activity of the edaravone in causing the neurological recovery is the ability to take away the hydroxyl radicals and thus inhibiting the hydroxyl dependent and independent lipid peroxidation. This is the reason that it can act as a potent antioxidant in protecting 

against oxidative stresses and neuronal cell deaths [12].

The edaravone is effective for both acute ischemic stroke (AIS) and acute haemorrhage stoke (AHS). According to an investigator, “a clinical trial has shown that the administration of edaravone alone within 72h of the onset of AIS significantly reduced the infarct volume and produced sustained benefits during a 3-month follow-up period”. He observed the effects of edaravone on AHS and found that “in an AHS model, rats treated with edaravone immediately after a hemorrhage showed a stronger reduction in brain water content and quicker functional recovery compared with rats treated with edaravone at 2h or 6h after hemorrhage” [13]. Most recently, Kono et al. has concluded through a clinical research on ischemic stroke patients older than 80 years of age that edaravone may be used as a partner for combination therapy with tPA; this may enhance recanalization and reduce hemorrhagic transformation [14]. On the other hand, safety and efficacy of multi-doses Edaravone injection is being trailed at phase II level [15].

ReN001 Stem cell therapy

Recently, stem cell therapy has proven effective to address the rehabilitation of post-stroke patients. ReN001 is a standardised, clinical and commercial-grade cell therapy product which is capable of treating all eligible patients. In short, it involves a neural cell line (CTX), cell selection technologies, cell-expansion procedures for selected cells and quality testing procedure. An extensive pre-clinical testing has shown to improve functional deficits associated with stroke disability, and it also indicated that the therapy is safe, with no adverse effects. A ground-breaking first-in-man clinical trial with ReN001 is proceeding in the UK under the name of PISCES (Pilot Investigation of Stem Cells in Stroke) study, which is being coordinated by ReNeuron Group. This is the world's first fully regulated clinical trial with neural stem cell. Based on the results already shown by the on-going study, the authority has already submitted an application for commencing a multi-site Phase II clinical trial to inspect the efficacy of ReN001 stem cell therapy on patients disabled by an ischaemic stroke [16]. Undoubtedly, the report of PISCES study indicates so far that ReN001 stem cell therapy is an effective treatment, but it is only useful for the patients who are in third treatment stage, not for any other two classifications [16].

Hyperbaric oxygen therapy (HBO₂T)

Hyperbaric oxygen (HBO) has proved itself effective in treating acute and sub-acute focal cerebral ischemia in several animal models [reviewed in 17]. Observing its apparent promise in treating different diseases, the scientists have been practising hyperbaric oxygen therapy or HBO₂T to cure or treat several diseases. This therapy involves placing one or more patients in an enclosed chamber and supplying with 100% oxygen in a pressure-regulated manner for respiration for a stipulated period of time, once or twice daily. In 2010, a clinical trial was organized by Bennett et al. to assess the effectiveness and safety of HBO₂T. Due to adoption of less number of randomized controlled trials, the study could not show consistent evidence of its efficacy [18]. However, in this year, FDA has already warned on the potential health risks that are associated with the HBO₂T.

Yet, certain groups of medical practitioners are still hopeful over the value. In tune with this, again in this year itself, Lim et al. observed the neuroprotective effect of HBO in attenuating microgliosis and pro-inflammatory cytokinine TNF-α expression [19]. This suggests again the need of performing a well set-up clinical trial to find its true effectiveness in treating stroke, at least as a rear-liner in stoke treatment.

CONCLUSION

Many substances or agents are still in pipeline for the treatment of the stroke. With the advancement of molecular biology and bio-therapeutics, newer agents are emerging day to day with strong promises to treat stroke. The days are not far when the patients from each phase of stroke will be able to get full range of effective treatments to come round all in all.

References:

1. Sims NR, Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochimica et Biophysica Acta. 2009; 1802 (1): 80–91.
2. Donnan GA, Fisher M, Macleod M, Davis SM. Stroke. Lance. 2008; 371 (9624): 1612–23.
3. Feigin VL. Stroke epidemiology in the developing world. Lancet. 2005; 365(9478): 2160–1.
4. Gorelick PB. Stroke Prevention Therapy Beyond Antithrombotics : Unifying Mechanisms in Ischemic Stroke Pathogenesis and Implications for Therapy. Stroke .2002; 33:862-875.
5. Bose  A, Henkes H, Alfke K, Reith W, Mayer TE, Berlis A, Branca VS. The penumbra system: a mechanical device for the treatment of acute stroke due to thromboembolism.  American Journal of Neuroradiology. 2008; 29:1409- 1413.
6. Penumbra stroke system being used to treat acute stroke patients by our neuro-endovascular service, 2011. A physician’s newsletter from the Departments of Neurology and Neurological Surgery at the University of Miami Miller School of Medicine. [Last accessed: 26th Oct. 2013] http://neurosurgery.med.miami.edu/documents/NeuroFocus_Spring_2011.pdf
7. Penumbra, Inc. (2013). Penumbra, Inc. launches 5MAX™ ACE—the newest clot extraction device to treat acute ischemic stroke patients. Available:

http://www.penumbrainc.com/site.asp?release_id=48andview_pr=1andcontent_id=66andcategory=news_eventsandmenu_id=0andtemplate=8 [Last accessed 26th Oct. 2013].

8. Turk AS, Spiotta A, Frei D, Mocco J, Baxter B, Fiorella D, Siddiqui A, Mokin M, Dewan M, Woo H, Turner R, Hawk H, Miranpuri A, Chaudry I. Initial clinical experience with the ADAPT technique: A direct aspiration first pass technique for stroke thrombectomy. J Neurointerv Surg. 2013 [Epub ahead of print].
9. Fagan SC, Jennifer LW, Nichols FT, Edwards DJ, Pettigrew LC, Wayne MC,  Hall E, Switzer JA,  Ergul A, and David C. Minocycline to Improve Neurologic Outcome in Stroke (MINOS) Stroke. American Heart Association .2010; 41:2283-2287.
10. Ginsberg MD. Neuroprotection for ischemic stroke: Past, present and future Neuropharmacology. 2008; 55: 363-389.
11. Weinberger JM. Evolving therapeutic approaches to treating acute ischemic stroke. Journal of the Neurological Sciences. 2006; 249:101–109.
12. Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A. Research and development of the free radical scavenger edaravone as a neuroprotectant. Yakugaku Zasshi. 2004;124 (3): 99–111.
13. Kikuchi K, Kawahara K, Miyagi N, Uchikado H , Kuramoto T , Morimoto Y, Tancharoen S , Miura N , Takenouchi K , Oyama  Y.  Edaravone: A new therapeutic approach for the treatment of acute stroke. Medical Hypotheses. 2010; 75:583–585.
14. Kono S, Deguchi K, Morimoto N, Kurata T, Yamashita T, Ikeda Y, Narai H, Manabe Y, Takao Y, Kawada S, Kashihara K, Takehisa Y, Inoue S, Kiriyama H, Abe K. Intravenous Thrombolysis with Neuroprotective Therapy by Edaravone for Ischemic Stroke Patients Older than 80 Years of Age. J Stroke Cerebrovasc Dis. 2013 Oct; 22(7):1175-83.
15. ClinicalTrials.gov (2013). Compound edaravone injection for acute ischemic stroke. Available: http://clinicaltrials.gov/ct2/show/NCT01929096?term=edaravoneandrank=6 [Last accessed 26th Oct. 2013].
16. ReNeuron. ReN001 for Stroke. 2013. Available at: www.reneuron.com. [Last accessed: 17th Oct. 2013].
17. Nighoghossian N, Trouillas P. Hyperbaric oxygen in the treatment of acute ischemic stroke: an unsettled issue. J Neurol Sci. 1997; 150(1):27-31.
18. Bennett  MH,  Wasiak J, Schnabel A, Kranke P, French C. Hyperbaric Oxygen Therapy for Acute Ischemic Stroke. Stroke. 2010; 41:185-186
19. Lim SW, Wang CC, Wang YH, Chio CC, Niu KC, Kuo JR. Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy. J Surg Res. 2013 ;184(2):1076-84.