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Cerebral Vascular Disease
Laboratory Tests
For the last 50 years, medical doctors have concentrated on controlling blood pressure as the primary method of preventing stroke. As you can see, there are several other mechanisms involved. Assessing the status of the blood clotting system through laboratory testing is central to assessing the risk of stroke in high-risk individuals. The following tests are typically used:
- Prothrombin time (PT) evaluates the time it takes for a clot to form after thromboplastin and calcium are added to the patient's plasma. Normal values are between 11-13 seconds. Prothrombin time is commonly used to monitor Coumadin therapy.
- The International Normalization Ratio (INR) standardizes prothrombin time to a control batch of thromboplastin (as the sensitivity of commercial thromboplastin reagents is variable) which allows comparisons between different samples and laboratories.
INR = (patient PT/control PT) × ISI
(International Sensitivity Index)
The target INR is 2.5 for those at risk for thromboembolic stroke, with a range of 2-3. A target of 2 with a range of 1.6-2.5 may be used in elderly patients to reduce the risk of hemorrhage. Some authorities, however, disregard age and recommend the higher target of 2.5.
The following may be predictive for the risk of stroke:
- Fibrinogen levels are useful because fibrinogen is converted into fibrin under the influence of thrombin. Fibrinogen is often elevated after acute trauma or illness, inflammation, and as a side effect of birth control pills.
- Triglyceride levels have been found to be a predictor of myocardial infarction, and elevated serum triglycerides have been specifically tied to the occurrence of atherothrombotic stroke and transient ischemic attacks.
- Homocysteine levels have been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke.
- C-reactive protein (CRP) is a sensitive marker of inflammation in the body. Inflammation may be a crucial factor in atherosclerosis and is considered to be a strong predictor of myocardial infarction and stroke (Di Napoli et al. 2001; Ridker 2001).
In addition, overall cardiovascular risk should also be assessed with the following laboratory tests:
- Total, HDL, and LDL cholesterol levels have been associated with cardiovascular risk for well over 40 years.
A comprehensive health assessment would also include measurements of the body's hormones, including DHEA, testosterone, estradiol, and progesterone (for women).
It is important to realize that conventional medicine uses blood tests as a diagnostic tool. Standard reference ranges are based on statistics that find the average value for all people taking the test, including both healthy and unhealthy people. The Life Extension Foundation recommends optimal ranges as a standard to measure wellness.
| Optimal Test Ranges |
| Blood Test |
Normal Reference Range |
Optimal Levels |
| Cholesterol |
Up to 199 mg/dL |
Between 180-200 mg/dL |
| LDL Cholesterol |
Up to 129 m g d /dL |
Under 100 mg/dL |
| HDL Cholesterol |
35-150 mg/dL |
55-150 mg/dL |
| Triglycerides |
Up to 199 mg/dL |
60-100 mg/dL |
| Glucose |
65-109 mg/dL |
70-99 mg/dL |
| Homocysteine |
5-15 micromol e /L |
Under 7.2 micromol e /L |
| Fibrinogen |
200-460 mg/dL |
200-300 mg/dL |
| DHEA |
Men: over 80 mcg/dL
Women: over 35 mcg/dL |
Men: 400-560 mcg/dL
Women: 350-430 mcg/dL |
| CRP |
Up to 4.9 mg/L |
Under 1.3 mg/L
Ideally under 0.5 mg/L |
Drug Strategies for Treatment and Possible Rehabilitation
In the 1960s, hypertension was identified as a treatable risk factor for stroke, and the decline in the incidence of and mortality from a stroke started when physicians began implementing aggressive antihypertensive therapies. In the 1970s, aspirin was first demonstrated effective in preventing strokes, although few physicians prescribe aspirin even to this day to reduce the risk of ischemic stroke. Cigarette smoking has been proven conclusively to be a major risk factor for stroke, and smoking cessation produces a significant risk reduction within 2 years.
Researchers now believe there are an immense number of mechanisms at work causing brain cell damage and death following a stroke. Each of these mechanisms represents a potential route for intervention, as well as prevention. Given the multidimensional nature of ischemic brain cell injury, stroke experts predict that no single drug will be able to completely protect the brain during a stroke. More likely, a combination of agents will be necessary for full recovery potential.
Most strokes culminate in a core area of cell death (infarction) in which blood flow is so drastically reduced that the cells usually cannot recover. This threshold seems to occur when cerebral blood flow is 20% of normal or less. Brain cells ultimately die as a result of the actions of calcium-activated proteases (enzymes which digest cell proteins), lipases (enzymes which digest cell membranes), and free radicals formed as a result of the ischemic cascade.
Without neuroprotective agents, nerve and brain cells may be irreversibly damaged within several minutes. This knowledge is leading to unprecedented therapy development. Expanding knowledge regarding the nature of ischemic brain cell injury is leading researchers to focus on the development of calcium antagonists, glutamate antagonists, antioxidants, and other types of neuroprotective agents. The use of the drug Hydergine to treat acute stroke may be the most effective therapy to combine with t-PA to prevent permanent brain damage.
Those who have already suffered neurologic impairment caused by ischemic stroke may also consider the following drugs.
Hydergine
The most potent antioxidant that a hospital pharmacy normally stocks for the treatment of strokes is Hydergine. Insist that the emergency room doctor administer 10 mg of Hydergine sublingually and another 10 mg of Hydergine orally in liquid form. Hydergine is a powerful antioxidant that reduces free-radical damage. Hydergine will increase the amount of oxygen delivered to the brain, enhance the energy metabolism of brain cells, and protect brain cells against both the low- and high-oxygen environments that ischemic stroke victims often encounter (Marc-Vergnes 1974; Saletu et al. 1990).
Hydergine is used in Europe and the rest of the world as a treatment for stroke, but most emergency room physicians in the United States are reluctant to prescribe it because the FDA does not recognize its value in preventing brain cell death. Paralyzed stroke victims consume billions of healthcare dollars every year, and the reason most ischemic stroke victims are permanently paralyzed is that the FDA has stopped patients from being treated with medications to prevent brain cell death. Regrettably, some hospital formularies may not carry Hydergine or its generic equivalent.
Piracetam
Piracetam, a nootropic medication similar to pyroglutamate (an amino acid), would be useful in the treatment of ischemic stroke if it were approved in the United States for acute use. Piracetam appears to protect brain cells from injury and death during a stroke, thereby lessening the potential for permanent neurological damage. The recommended dosage for piracetam is 4800 mg taken orally. Piracetam is not currently available in the United States , but has been successfully used in Europe for 25 years as reported in the Journal of Pharmacopsychiatry (De Reuck et al. 1999). Piracetam may be obtained by prescription through selected compounding pharmacists throughout the United States . Non-FDA approved drugs, available in other countries, can often be legally prescribed in the United States when a licensed physician collaborates with a licensed compounding pharmacist to safely compound a substance for a particular patient (1938 Federal Government Compound Pharmacy Protection Act). Piracetam is also available from several offshore pharmacies.
A Belgian study indicated that piracetam may be very beneficial if administered within 7 hours after the onset of a stroke (De Deyn et al. 1997).
An article in the journal Stroke described a double-blind, placebo-controlled study of piracetam used to improve language recovery in post-stroke aphasia: 24 stroke patients were assigned to receive either placebo or 2400 mg of piracetam twice a day. After 6 weeks, the piracetam group showed improvement in six language functions, compared with only three in the placebo group. The authors concluded that piracetam as an adjunct to speech therapy improves the recovery of several language functions (Kessler et al. 2000).
A review of three studies of piracetam in ischemic stroke, however, did not find sufficient evidence to support routine use. The authors concluded that more clinical trials are needed (Ricci et al. 2000).
Nimodipine
Nimodipine is a European drug especially recommended for head trauma victims. Nimodipine (brand name Nimotop) is a calcium channel blocker specific to the central nervous system. It prevents movement of calcium into the cells of blood vessels, thereby relaxing the vessels and increasing the supply of blood and oxygen. It dramatically improves cerebral blood flow. Nimodipine is an FDA-approved drug used to prevent and treat problems caused by a burst blood vessel around the brain, but it has been ignored by most neurologists treating victims of stroke and other age-related neurological diseases.
An article by Pantoni et al. (2000a) described a 26 week, multinational, double-blind, placebo-controlled study of nimodipine in patients with multi-infarct dementia. This study failed to show a significant effect of nimodipine on cognitive, social, or global assessments. However, a lower incidence of cerebrovascular and cardiac events was observed in the nimodipine-treated patients in comparison with the placebo group. A subgroup analysis found that those patients with subcortical vascular dementia performed better on the majority of neuropsychological tests and functional scales in comparison with patients on placebo (Pantoni et al. 2000b).
Studies on the use of nimodipine on thrombotic and ischemic stroke have shown mixed results (Chua et al. 2001). In one study, low-dose nimodipine therapy was shown over high-dose therapy to positively affect systolic and diastolic blood pressure (Ahmed et al. 2000). However, in a second study, higher dose nimodipine was more effective than lower dose therapy (240 versus 120 mg per a day) in reducing cerebrospinal fluid calcium, thereby improving cerebral blood flow (Bereczki et al. 2000).
There is a delayed response to nimodipine therapy. Nimodipine is recommended for at least 21 days in subarachnoid hemorrhage, and its beneficial effects in migraine prophylaxis usually become apparent after 1 or 2 months of therapy. This delayed benefit may be the reason why nimodipine has not been found to be effective in several clinical studies.
Nimodipine is highly recommended as long-term therapy for thrombotic stroke patients because of its well-known effect on increasing cerebral blood flow and because of its tolerance in most individuals. The most common side effect is hypotension. Rapid elimination rates correspond to a half-life of 1-2 hours which necessitates frequent dosing (e.g., every 4 hours). The recommended dose of nimodipine is 30 mg, three times a day.
Aminoguanidine
Aminoguanidine is being studied for use in stroke because of its action as an inducible nitric oxide synthase inhibitor (Fasbender et al. 2000).
Aminoguanidine is one of the most widely used drugs in Europe . It works by preventing crosslinks caused by glycosylation (a chemical reaction between blood sugar and protein). Animal studies have found that aminoguanidine can prevent diabetic atherosclerotic blood vessel aging and molecular crosslinking in cells throughout the body. Aminoguanidine also prevents destructive crosslinking of collagen and elastin fibers in the brain, which is a primary cause of mental degeneration in the elderly.
An article in Brain Research described a study of aminoguanidine in a rat model of middle cerebral artery occlusion. Daily injections of aminoguanidine (100 mg/kg) began 6 hours after the occlusion. Treatment resulted in a slowing of the growth of ischemic lesions. Interestingly, serial measurements of nitric oxide and nitric oxide synthase activity found no difference between the treatment and placebo groups which suggested that the neuroprotective effects of aminoguanidine may be due to mechanisms other than nitric oxide metabolism (Cash et al. 2001).
An earlier study in the journal Brain Research also used aminoguanidine in a rat model of middle cerebral artery occlusion. The authors found that treatment for a longer period of time (more than 2 days) decreased the volume of ischemic injury. The average reduction was 21% at 3 days and 30% at 4 days (Zhang et al. 1998).
An article in the journal Stroke described a study of aminoguanidine used to treat rats with induced cerebral artery occlusion. Aminoguanidine administered 15 minutes after the onset of ischemia resulted in a significant reduction of infarct volume. Protection was also measured when aminoguanidine was administer e d 1 or 2 hours after the onset of ischemia (Cockroft et al. 1996).
Aminoguanidine and piracetam are European drugs that are not approved for general use in the United States by the FDA. They can, however, be purchased from offshore pharmacies for personal use and may be obtained by physician prescription through compounding pharmacists. The Life Extension Foundation maintains a list of offshore pharmacies that ship European drugs to United States citizens. This list is available by calling the Life Extension Foundation at (800) 226-2370.
Carnosine
Since it is difficult for Americans to obtain aminoguanidine, a nutrient called carnosine should be considered. Carnosine has demonstrated potent anti - glycosylation properties and protects brain cells by additional mechanisms. Carnosine is a peptide made from the amino acids beta-alanine and L-histidine. Several researchers have proposed that carnosine may be of benefit in protecting against stroke. Carnosine acts to regulate the metabolism of zinc and copper, which play a major role in the modulation of central nervous system excitability (Horning et al. 2000; Suslina et al. 2000; Trombley et al. 2000).
In a study in Brain Research Bulletin, rats were subjected to 45 minutes of reduced blood flow (ischemia) to the brain. The result was massive injury that caused 67% of the animals to die. In a group pretreated with carnosine, only 30% died in response to the ischemic injury, and a significant protective effect was shown to in cell membranes and cerebral enzyme levels. The scientists that conducted the study concluded that "carnosine protects against oxidative injury and thereby increases the survival of the animals" (Stvolinsky et al. 2000).
Based on extrapolations from this study and previous reports, the risk of acute death from a stroke in someone taking carnosine every day might be reduced by more than 50% and the chances of significant neuronal impairment that could cause paralysis would also be lowered. The volume of published data on carnosine shows multiple benefits, including antioxidant, anti - glycating, aldehyde quenching, and metal chelating actions.
To derive benefit from carnosine, enough must be consumed to saturate the carnosinase enzyme to make free carnosine available to the body. This dose is typically 1000 mg a day. |