Stroke Prevention: Recent Advances in Treatment Strategies to Prevent the Recurrence of Stroke - Term Paper Example

INTRODUCTION Stroke Presentation Stroke, or cerebrovascular accident, is defined as the death of brain tissue due to the occlusion (ischemic stroke) or rupture (hemorrhagic stroke) of the supplying artery, usually the middle cerebral artery (MCA). This blood vessel supplies the outer surface of the frontal, parietal and temporal lobes near the sylvian fissure, as well as the basal ganglia, and thalamus. While the motor functions, together with somatic sensory, are initiated by the cerebrum, these are initiated by external stimuli relayed to and from the sensory organs by the thalamus, and are polished by the basal ganglia. Since these areas control senses and voluntary motor functions, the disease presents as sudden contralateral paralysis of the limbs (Purves, et al., 2004). If the ischemia occurs at the left part of the brain, dysphasia, defined as difficulty in speaking, is also presented, since the left hemisphere controls speech and language (Slater, 2011). CVA can result to varying degrees of motor deficits, depending on how much brain tissue is affected (Purves, et al., 2004). MCA is the most common location of cerebrovascular accident, with the highest incidence observed among those aged 70-90. Aside from the elderly, males are three times more at risk to be affected by MCA strokes than females. In the United States, more than 0.08% of the population have had MCA stroke. It must be noted that although stroke incidence decreased by 42% in richer countries, it doubled in poor- to middle-income nations. In fact, stroke incidence in poor- to middle-income countries is 20% higher than that in richer nations (Slater, 2011). According to Feng, Hendry and Adams (2010), the cumulative risks for recurrent stroke and death are increasing, from 8% and 25.5% in the first year to 18.1% and 41.3% respectively, within four years. 2. Pathophysiology In depth explanation of the disease’s pathophysiology is important in understanding the mechanisms of action of drugs to be discussed later. Ischemic stroke usually results from a thrombus from another vessel in the body getting dislodged and being stuck in an artery of the brain. Hemostasis normally occurs in response to a vascular injury to prevent excessive blood loss. However, in thrombus formation, blood clotting occurs even in the absence of injury. The process involves three components, the vascular wall, lined by endothelium, platelets, and the coagulation cascade (Mitchell, 2010) a. Endothelium Endothelial cells are vital in the study of stroke as they act to prevent or promote thrombus formation by synthesis of different substances that have affect either the platelets, coagulation, or fibrinolysis (Michiels, 2003; Galley and Webster, 2004; Pries and Kuebler, 2006). When injured, endothelial cells produce von Willebran factor (vWF), which promotes platelet binding to matrix elements of the endothelium (Ruggeri, 2007). If endothelial cells are non-damaged, they produce prostacyclin (PGI2) and nitric oxide that stimulate vasodilation and prevent platelet adhesion to the vascular walls. It also produces adenosine diphosphatase, which degrades adenosine diphosphate (ADP). Endothelial cells also produce tissue-type plasminogen activation, which forms plasmin, an active enzyme that denatures fibrin (Esmon, 2006). b. Platelets Platelets are anucleate, disc-shaped fragments originating from megakaryocytes in the bone marrow. They are important in thrombus formation, as they seal vascular defects, and concentrate activated coagulation factors. Platelet activation, adhesion and aggregation are principal processes in the pathogenesis of arterothrombosis. Through the platelet surface receptor glycoprotein Ib (GpIb), the platelet can bind to vWF. Platelets also release ADP and show negatively-charged phospholipids on their surfaces, thereby promoting platelet aggregation (Andrews and Berndt, 2004). Acting in concert with ADP and thrombin, thromboxane A2, which are produced by cyclooxygenases (COX) in the platelets, are also vital in platelet aggregation. ADP stimulates GpIIb-IIIa receptor on platelet membrane to bind with fibrinogen. Thrombin is especially important, because it converts fibrinogen into fibrin, which acts as a cement that stabilize the platelets (Mitchell, 2010). Aside from forming fibrin, thrombin is also pro-inflammatory by activating receptors on monocytes, dendritic cells, T cells, among others (Coughlin, 2005; Landis, 2007). c. Coagulation Thrombin is formed through a cascade of enzymatic reactions, known as the coagulation cascade. The cascade is promoted by the presence of a phospholipid surface, such as that provided by activated platelets, since they act as a canvass to which components of the cascade, or coagulation factors as they are usually known, are assembled (Hoffman and Monroe, 2007). These factors, II, XII, IX, and X, are then held together by calcium ions. To enable this process, these factors should first have γ-carbonyl groups on their glutamic acid residues. These moieties are added using a reaction that has vitamin K as a cofactor. All of these are initiated through activation by thromboplastin, a membrane-bound lipoprotein expressed at sites of injury (Monroe and Key, 2007). The process is tightly controlled by several processes. Heparin-activated antithrombin III binds and subsequently deactivates thrombin, as well as activated factors IXa, Xa, XIa, and XIIa. On the other hand, vitamin K-dependent proteins C and S also inactivate dactors Va and VIIIa. Upon activation of coagulation cascade, a fibrinolytic cascade is also initiated in order to control the size of the clot. This should produce plasmin, which breaks down fibrin and prevents polymerization (Cesarman-Maus and Hajjar, 2005). This protein is strictly controlled through inactivation by α2-plasmin inhibitor (Mitchell, 2010). The number of pathways that initiate and prevent thrombus formation implies that treating stroke should constitute modifying blood constituents, vessel wall and blood flow, in order to see significant clinical improvements in prevention of thrombus formation (Caplan, 2009). Thus, there drugs that prevent stroke should address these concerns in order to be effective. Aspirin 1. Mechanism of action Aspirin inhibits platelet cyclooxygenase (COX), the enzyme that produces thromboxane A2, which, in turn, promotes platelet aggregation and vascular constriction (Shimazawa and Hara, 2011). It also inhibits endothelium from producing PGI2, which has potent antiplatelet and vasodilator effects. 2. Effectiveness Aspirin is the first line of antiplatelet drugs. It results to 13% reduction (95% confidence interval [CI]: 4%-21%) (Shimazawa and Hara, 2011), and the number needed to treat for this drug is 26-28 in around 3-year treatment period (Antithrombotic Trialists’ Collaboration, 2002). In terms of public health, the effectiveness of this drug preventing the occurrence of stroke in the general public is below expected. This may be due to what is regarded as aspirin resistance, or the failure of aspirin to prevent thromboxane A2 production by platelets. There are two types of COX, COX-1 and COX-2, with the latter being significantly less sensitive to the effects of aspirin than COX-1. In addition, ADP, 5-HT, thrombin, and others are not inhibited by aspirin (Shimazawa and Hara, 2011). To increase the effectiveness of secondary stroke prevention, combination therapy of aspirin with other antiplatelet drugs was postulated. However, efforts to combine Combination therapy of aspirin and clopidrogrel did not improve the risk reduction by either drug alone (Caplan, 2004). Clopidogrel, together with ticlopidine, is a thienopyridine derivative, which prevents the binding of ADP to platelet P2Y12 receptor (Micieli and Cavallini, 2001), thereby inducing binding of the platelets with fibrinogen (Schnedier and Aggarwal, 2004). Ticlopidine has better effectiveness than aspirin, as it has resulted to a 23.3% relative risk reduction in stroke, myocardial infarction, or death. In effect, there is a 12% RRR in stroke or death, compared to aspirin (Shimazawa and Hara, 2011). On the other hand, clopidogrel was associated with an RRR of 8.7% (95% CI: 0.3%-16.5%) compared with aspirin for stroke, myocardial infarction or death. 3. Safety Safety of aspirin is also an issue, aspirin causes ulcer. Such antiplatelet drugs also have the risk of hemorrhage (Caplan, 2004). In fact, clinical trials have shown that it only resulted to an increase in hemorrhagic events (Bhatt, et al., 2005). The inhibition of prostaglandin synthesis decreases the rate of the production of mucus that lines the gastrointestinal wall, thereby allowing the acid in the stomach to cause gastrointestinal irritation and bleeding. The subpar effectiveness and poor safety profile of aspirin thus invoke scientists to develop new drugs for stroke prevention that are more safe and effective. CILOSTAZOL: THE NEW DRUG 1. Evidences of effectiveness a. Preventing platelet aggregation Cilostazol is an antiplatelet drug that inactivates AMP-dependent phosphodiesterase 3, thereby increasing the concentration of cyclic adenosine monophosphate (cAMP). In turn, this biomolecule inhibits platelet aggregation, thus preventing atherothrombosis (Sudo, et al., 2000). In cats, it has been shown to increased cAMP levels, thereby causing antithrombosis in cerebral ischemia, increased cerebral blood flow and vasodilation (Shimazawa and Hara, 2011). Since clinical trials, such as Thompson, et al., 2002, have shown the effectiveness of cilostazol in improving symptoms of intermittent claudication in patients with peripheral artery disease, it has been recommended as the first-line drug for intermittent claudication (Norgren, et al., 2007). b. Stimulation of vasodilation Aside from preventing platelet aggregation, various animal and cell culture studies have shown that it also dilates blood vessels, prevents vascular smooth muscle proliferation, and protects the vascular wall and endothelium (Ikeda, Sudo and Kimura, 2006). This is made possible by the variety of pro-atherothrombotic substances such as arachidonic acid, ADP, epinephrine, collagen, thrombin, and high shear stress (Shimazawa and Hara, 2011). c. Preventing stroke recurrence In addition, the drug also confers greater protection against stroke by inhibiting lipopolysaccharide-induced apoptosis (Kim, et al., 2002) and neutrophil adhesion to endothelial cells (Park, et al., 2006). 2. Safety features a. Neuroprotective effects The drug may also have neuroprotective effects, since 34, 35 showed significant reduction in cerebral infarct size after middle cerebral artery occlusion and subsequent 24-hour reperfusion. Several mechanisms of action have been suggested. First, cilostazol acts as an antioxidant that collects hydroxyl radicals, mediating its anti-inflammatory and anti-apoptotic effects. In addition, decrease in the production of tumor necrosis factor-α (TNF- α), inhibition of poly(ADP-ribose) polymerase activity (Lee, et al., 2008), and stimulation of metallothionein-1 and -2 in ischemic brain areas (Wakida, et al., 2006) have been implicated as well. b. Reduction of the risk for hemorrhage It was shown to be significantly better than placebo in lowering the incidence of recurrent and secondary cerebral infraction without increased recurrence of cerebral hemorrhage (Shinohara, et al., 2008). RRR was noted to be 40.3% (Gotoh, et al., 2000). In fact, cilostazol has been shown to reduce extent of hemorrhagic transformation during MCA occlusion and reperfusion in mouse brain, by reducing blood-brain barrier disruption during these vascular events (Nonaka, et al., 2009). Similarly, the drug does not seem to increase the bleeding time (Wilhite, et al., 2003). 3. Usefulness in the presence of comorbidities Since many of the stroke victims present with other chronic diseases as well, it is important to determine whether a drug can be used in various conditions of the patient. According to Shinohara, et al. (2008), cilostazol is also effective in those with lacunar infarction, as well as those with diabetes and hypertension 4. Comparison with other drugs Cilostazol resulted to a significantly greater risk reduction (25.7%) for stroke, transient ischemic attack, angina pectoris, myocardial infarction, and heart failure, as compared to aspirin (Shinohara, et al., 2010). When compared with aspirin, Cilostazol resulted to a relative risk reduction (RRR) of 38.1%, which was greater than that of clopidogrel which was at 8.7% (Shimazawa and Hara, 2011), ticlodipine that had an RRR of 21% (Antithrombotic Trialists’ Collaboration, 2002). In addirion, Cilostazol is more cost-effective, as its numbers needed to treat is around 20 for 3 years (Shinohara, et al., 2008). CONCLUSION Stroke is a debilitating disease with an acute onset, caused either by the occlusion or severing of arteries supplying the brain. Because of there is a significantly increased risk of stroke for those who had a past medical history of brain ischemia, it is important to prevent its reoccurrence. One of the drugs currently used to do this is aspirin, which acts on cyclooxygenase to prevent the formation of thromboxane A2. However, studies have shown its lack of effectiveness and issues with safety. Cilostazol is one of the relatively new drugs that have better effectiveness and safety profiles than aspirin. References Andrews, R. and Berndt, M., 2004. Platelet physiology and thrombosis. Thromb Res, 114, p. 447. Antithrombotic Trialists’ Collaboration, 2002. 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Cilostazol reduces ischemic brain damage partly by inducing metallothionein-1 and -2. Brain Res., 1116, pp. 187–193 Wilhite, D. B., Comerota, A. J., Schmieder, F. A., Throm, R. C., Gaughan, J. P., Rao, A. K., 2003. Managing PAD with multiple platelet inhibitors: the effect of combination therapy on bleeding time. J Vasc Surg, 38, pp. 710–713. Read More