How To Reverse Cardiovascular Disease Naturally

The Big Heart Disease Lie

The Big Heart Disease Lie is a book written by doctors who are members of the International Truth In Medicine Council they are also the authors of The Big Diabetes Lie. In this book you will be getting over 500 pages of scientifically proven, doctor verified information that you will not find anywhere else, not even bookstores.If you have high blood pressure or cholesterol, fatigue, shortness of breath, irregular heartbeat, swollen feet or ankles, chest pain, fainting, diabetes, asthma or allergies, pain, fatigue, inflammation, any troubling health issue, or simply want to discover the most powerful health and anti-aging program, then you really need to read this book. The book is a step by step guide that contains techniques scientifically verified and proven by doctors to reverse the symptoms of heart disease, and normalize blood pressure and cholesterol levels. These techniques have been used successfully by tens of thousands of people all over the world, and allowed them to take health into their own hands, ending the need for drugs, hospitals, doctors' visits, expensive supplements or grueling workouts. Read more here...

The Big Heart Disease Lie Summary


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An Overview Of Metabolic Syndrome A Precursor Of Diabetes Heart Disease And Stroke

(10) impaired circulation because of clogged arteries Individuals who have two or more of these symptoms are at higher risk of developing cardiovascular disease and type 2 diabetes (i.e., non-insulin dependent), especially if there is a family history of these illnesses. The symptoms of metabolic syndrome often occur concurrently because they arise from multiple, tightly-coupled biochemical abnormalities.2

Acute myocardial infarction

Interest in the therapeutic use of magnesium in patients with acute myocardial infarction comes from non-controlled studies carried out in Australia, Asia and Europe concerning a supposed decrease in arrhythmic events and an increase in survival in patients treated with magnesium.57,58 Epidemiological studies have also reported that the incidence of sudden death is greater in geographical areas characterized by soft water, which are relatively poor in calcium and magne-sium.59 An epidemiological perspective study has been carried out into the relation between plasma levels of magnesium and the incidence of coronary artery disease,60 and another study investigated the relationship between dietary magnesium and coronary artery disease.61 In the latter study, 13 922 middle-aged subjects were studied for a follow-up period of from 4 to 7 years. The risk of the onset of coronary artery disease was significantly higher in subjects with low plasma levels of magnesium and there was a...

Cardiovascular Disease

Over the past 25 years, the number of risk factors for coronary artery disease has increased dramatically. Systemic inflammation and abnormal lipoprotein metabolism are important contributors to the progression of atherosclerotic disease leading to plaque instability 13 . Even so, the vast majority of patients who experience an acute coronary event have no prior symptoms. Further complicating the diagnosis of acute coronary syndrome (ACS) is the frequent occurrence of patients who present symptoms of chest pain that can be attributable to other completely nonrelated events, such as acute gastroesophageal reflux disease. Given the serious life-threatening nature of ACS, an improvement in the early diagnosis of heart attacks would be a major medical advancement. Matrix metalloproteinases (MMPs) are promising IBs for early identification of high - risk patients. Pro - inflammatory cytokines stimulate the secretion of MMPs, and an increase in systemic MMPs has been documented in ACS and...

Lppla2 as a new marker for cardiovascular risk

The association of Lp-PLA2 with risk for CAD has been investigated in a number of different human populations. Data from large Caucasian population studies consistently report a positive association of plasma Lp-PLA2 mass or activity and risk for CAD. The West of Scotland Coronary Prevention Study (WOSCOPS)30 reported that, in men with increased plasma LDL-cholesterol levels (174-232 mg dL), plasma levels of Lp-PLA2 mass were significantly associated with development of CAD events. This association was independent of other traditional risk factors or markers of inflammation including C-reactive protein (CRP). More recently, in a prospective case-cohort study, the Atherosclerosis Risk in Communities study (ARIC), authors reported that circulating levels of Lp-PLA2 mass were associated with incident CAD in apparently healthy middle-aged men and women after adjustment for age, sex, and race.31 Similarly, in the monitoring of trends and determinants in cardiovascular disease study...

Potential Targets For Intervention In Acute Stroke

And preventing early stroke recurrence and progression of stroke (antithrombotics).3-5 Treatments directed to restoring circulation and neuroprotection that are applied soon after stroke can salvage the functionally silent but potentially viable tissue lying in the periphery of the core of ischaemia (the 'ischaemic penumbra').

Flavonoids and Cardiovascular Disease

Epidemiologic studies have found an inverse association between flavonoid intake and risk of cardiovascular disease.51 Mechanistically, most flavonoids can increase the resistance of LDL to oxidation in vitro however, ex vivo investigations of LDL oxidation in human studies have not proven consistent. There is a body of evidence showing that flavonoids have effects on other atherogenic mechanisms. For example, flavanols inhibit smooth muscle cell proliferation52 and flavanones reduce blood lipids.53 Flavonoid-rich grape juice, red wine, and coca are antithrombotic as they inhibit platelet aggregation and extend bleeding time.54 Animal and in vitro studies and human intervention trials are largely consistent in showing that flavonoids can improve endothelial function and may reduce blood pressure. In human intervention trials, black tea, cocoa, red wine, and soy flavonoids promote endothelial-dependent vasodila-tion and improve vascular dysfunction via actions on nitric oxide...

Links Between Wholefood Antioxidants and Heart Disease Cancer and Vision Loss

Antioxidant deficiencies have well-established links to the promotion of specific diseases. This is discussed more fully in other chapters. Antioxidant compounds are accumulated from the diet or synthesized in the body and prevent the chemical oxidation of proteins, lipids and other essential compounds. Industrialization has led to increased environmental pollutants in our air, food and water. Many of these pollutants have the capacity to deplete the body's antioxidant reserves. Antioxidant deficiencies resulting from dietary deficiencies and or increased environmental oxidant stress may be linked to the development of many diseases including heart disease, cancer and vision loss. Because fruits and vegetables remain the primary source of antioxidants, it is probable that the protective effects are due to the antioxidant activities associated with the fruits and vegetables we consume (Block et al., 1992). Compared with today's diet the Paleolithic diet was relatively rich in fruits...

Vitamin E and Cardiovascular Disease

Observational studies have associated lower rates of heart disease with higher vitamin E intake. These studies held promise that vitamin E was protective against coronary heart disease.95 A study of 87,245 female nurses suggested that high intake of vitamin E from diet and supplements was associated with between 30 percent and 40 percent lower incidence of heart disease and that this was due primarily to vitamin E supplementation rather than intakes from food.96 Similarly, a reduction in heart disease-related mortality was observed in men and women in a smaller Finnish study.97 Intervention studies were undertaken to investigate these relationships. The Women's Angiographic Vitamin and Estrogen (WAVE) trial98 found no effects from supplements providing 400 IU vitamin E and 500 mg vitamin C twice a day in 423 postmenopausal women. One of the larger studies, the Heart Outcomes Prevention Evaluation (HOPE) Study, followed 10,000 patients at high risk for heart attack or stroke over 4.5...

Effect of Flavonoids on Coronary Heart Disease

Kaempferol, myricetin, luteolin and apigenin. In the Zutphen Elderly Study (Hertog et al., 1993a), a flavonoid intake of greater than 30 mg day-1 was associated with a 68 reduction in mortality from CHD and an inverse but weaker relationship with the incidence of myocardial infarction. The major source of flavonoids in this population was black tea, followed by onions and apples, although minor ingredients such as parsley and thyme also made a contribution to the intake of flavones. Keli et al. (1996) found a dose-dependent inverse association between the mean intake of flavonoids over 15 years and the risk of stroke, after adjustment for known confounders. In this cohort, tea was again a major contributor to flavonoid intake and men who consumed 4.7 or more cups of tea had a lower incidence of stroke than men who drank less than 2.6 cups per day.

Treatment Of Myocardial Ischemia Pathophysiology Of Ischemic Heart Disease

Angina pectoris is caused by transient episodes of myocardial ischemia due to an imbalance in myocardial oxygen supply and demand that may result from an increase in myocardial oxygen demand, a decrease in myocardial oxygen supply, or sometimes from both (Figure 31-1). Among the pharmacological agents used in the treatment of angina are nitrovasodilators, p adrenergic receptor antagonists, Ca2+ channel antagonists, and antiplatelet agents. All approved antianginal agents improve the balance of myocardial oxygen supply and demand, increasing supply by dilating the coronary vasculature or decreasing demand by reducing cardiac work (Figure 31-1). Drugs used in typical angina function principally by reducing myocardial oxygen demand by decreasing heart rate, myocardial contractility, and or ventricular wall stress. By contrast, the principal therapeutic goal in unstable angina is to increase myocardial blood flow strategies include the use of antiplatelet agents and heparin to reduce...

The effect of wine on the risk of coronary heart disease

The incongruity between established dietary risk factors and death from CHD was highlighted by the reporting of the French paradox that is, why the French have a relatively low incidence of CHD while consuming a diet rich in saturated fat, mainly from butter and cream (Renaud and de Longeril, 1992). Epidemiological data from Denmark advanced this hypothesis by demonstrating a lower incidence of cardiovascular disease and stroke in subjects who consumed low or moderate amounts of wine (three glasses per day) (Gronbaek et al., 1995). A possible explanation for this effect is the relatively high consumption of phenolic compounds found in red wine

Rheumatic Heart Disease

Rheumatic heart disease (RHD) is the major sequela of rheumatic fever (RF) and develops 4-8 weeks after the first acute RF (ARF) episode in children or teenagers (3-19 years old). The disease results from autoimmune reactions triggered by an untreated S. pyogenes throat infection that leads to severe valvular damage in individuals who present genetic susceptibility. Recurrences of ARF play an important role in the worsening of valvular lesions due to high number of inflammatory cells and soluble mediators as well as the reactivation of autoreactive T cells 1,2 .

Risks For Obesity Diabetes And Cardiovascular Disease 41 Obesity

Obesity is a major public health problem in the United States, with an increasing prevalence in both adults (37,38) and children (39). Obesity increases the risk of morbidity and mortality from associated diseases such as diabetes, hypertension, coronary heart disease, and cancer (40-42). Diets have been the traditional approach to dealing with excessive weight. Robert Atkins (43) popularized the use of the ketogenic diet to deal with weight gain. This type of ketogenic diet is a low-carbohydrate but high-protein formulation and consequently is fundamentally different from diets used for seizure control. The Atkins diet is based on the premise that control of insulin is essential for weight loss and associated beneficial effects in reduction of diabetes and cardiovascular risk. By reducing carbohydrate intake to a negligible level, the diet attempts to eliminate insulin fluctuations that might occur after a typical meal. It is important to note that while this diet does not limit...

Selenium in Cardiovascular Disease

There is strong evidence that meeting the RDA for selenium prevents Ke-shan disease. In relation to cardiovascular disease causes, epidemiological data shows an inverse relationship between blood selenium levels and increased rates of heart disease found in low-selenium areas.145 Prospective studies investigating the relationship between selenium intake or plasma levels and heart disease have been inconclusive, although two studies conducted in Finland found an association. However, selenium intake has been historically very low in Finland.146 In contrast, studies in populations with higher selenium intakes have found no association between selenium intake or plasma levels and cardiovascular disease.147 This has led some to speculate that only very low selenium levels have a relationship to risk of cardiovascular disease.148 As yet, controlled prevention trials to investigate selenium alone in prevention and therapy of cardiovascular disease have not been completed.

Human Intervention Trials on Effects of Antioxidant Supplements on Risk or Progression of Coronary Heart Disease

A number of studies show that vitamin E decreases the oxidative susceptibility of LDL. Animal investigations as well as human epidemiological data show that antioxidants decrease the risk or progression of coronary heart disease. Intervention trials will be now discussed aiming to assess the effects of antioxidant supplements on risk or progression of heart disease in various groups. A randomized, double-blind, placebo-controlled primary prevention trial (the ATBC study) was primarily aimed to determine whether daily supplementation with a-tocopherol, 3-carotene, or both would reduce the incidence of lung cancer and other cancers. A total of 29,133 male smokers (21 cigarettes a day for 36 years) 50-69 years of age were given a-tocopherol (50 mg per day) and or 20 mg synthetic 3-carotene for 5-8 years. Thirty-five fewer deaths from ischemic heart disease and 11 fewer deaths from ischemic stroke, but 22 more deaths from hemorrhagic stroke among men who received vitamin E supplements...

Cardiovascular Diseases

1 In 1900 heart disease killed 27,000 and strokes 21,000 U.S. population was about half of today's. A clearcut understanding of the exact pathological mechanism has not yet emerged. Cerebral blood flow, cardiac output, kidney and endocrine gland functions all appear to be normal, at least in the early stages of the disease. There has been no dearth of theories over the years regarding the etiology of the disease. A considerable pool of knowledge and understanding about the illness that, although not complete, has improved treatment. Much of it is due to better drugs and their proper utilization. For example, the benefits or even necessity of treating severe and even moderate hypertension was never seriously questioned. The risk factors of nontreatment were known for some time and are now well documented by large well-executed studies involving thousands of persons, primarily men. Cardiovascular complications ascribable to long-term untreated hypertension include congestive heart...

Other measures to reduce cardiovascular risk

Aspirin (section 2.9) in a dose of 75 mg daily reduces the risk of cardiovascular events and myocardial infarction. Unduly high blood pressure must be controlled before aspirin is given. Unless contra-indicated, aspirin is recommended for all patients with established cardiovascular disease. Use of aspirin in primary prevention, in those with or without diabetes, is of unproven benefit (see also section 2.9). Lipid-regulating drugs can also be of benefit in cardiovascular disease or in those who are at high risk of developing cardiovascular disease (section 2.12). Isolated systolic hypertension Isolated systolic hypertension (systolic pressure 160 mmHg, diastolic pressure 90 mmHg) is associated with an increased cardiovascular disease risk, particularly in those aged over 60 years. Systolic blood pressure averaging 160 mmHg or higher over 3 to 6 months (despite appropriate lifestyle interventions) should be lowered in those over 60 years, even if diastolic hypertension is absent....

Randomized Clinical Trials with Vitamin E in Cardiovascular Disease CVD

In the Finnish ATBC study (33-35), there was no effect of vitamin E on the incidence of fatal or nonfatal myocardial infarction (MI) (Table 17.1). An increased risk of hemorrhagic stroke and decreased risk of prostate cancer were identified with vitamin E but are of uncertain importance, given their absence in the Gruppo Italiano per lo Studio della Supravivenza nell'Infarto Miocardico (GISSI), Cambridge Heart Antioxidant Study (CHAOS), or Heart Outcomes Prevention Evaluation Study (HOPE). The Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study (36) randomized 520 men and women to vitamin E (91 mg d), 250 mg d slow release vitamin C, or both for 3 y. The rate of progression of IMT was unaffected by the consumption of any antioxidant(s) in women and by the taking of either antioxidant alone in men (Table 17.1). In the collaborative Primary Prevention Project (PPP), open-label, low-dose aspirin, and vitamin E treatments were a Abbreviations...

Myocardial infarction

TXA2 is thought to play a role in plaque instability, coronary vasoconstriction and, thus, in myocardial infarction. Myocardial ischemia is associated with enhanced release of eicosanoids into the coronary effluent. In contrast to non-ischemic conditions, there is a significant overflow of TXA2 as well as fatty acid peroxides and leukotrienes. Release of these substances may have deleterious effects on the course of ischemia, resulting in the facilitation of arrhythmia, tissue necrosis and exacerbation of ischemia probably because of local vasoconstriction and platelet plugging. Cyste-inyl leukotrienes were also shown to be potent coronary vasoconstrictors in isolated heart preparations. Eicosanoids in ischemic myocardium are synthesized not only by myocardial cells but also by invading platelets, neutrophils and macrophages 85 . Platelets from survivors of myocardial infarction are abnormally sensitive to aggregating agents and produce more TXA2 than controls 86 , Elevated TXB2...

Acute coronary syndromes

Acute coronary syndromes encompass a spectrum of conditions which include unstable angina, and myo-cardial infarction with or without ST-segment elevation. Patients with different acute coronary syndromes may present similarly definitive diagnosis is made on the basis of clinical presentation, ECG changes, and measurement of biochemical cardiac markers. Unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI) are related acute coronary syndromes that fall between the classifications of stable angina and ST-segment elevation myocardial infarction (STEMI). They usually occur as a result of atheromatous plaque rupture, and are often characterised by stable angina that suddenly worsens, recurring or prolonged angina at rest, or new onset of severe angina. Patients with unstable angina have no evidence of myocardial necrosis, whereas in NSTEMI, myocardial necrosis (less significant than with STEMI) will be evident. There is a risk of progression to STEMI or sudden death,...

Management of unstable angina and nonSTsegment elevation myocardial infarction

The glycoprotein IIb IIIa inhibitors eptifibatide and tirofiban (section 2.9) can be used (with aspirin and unfractionated heparin) for unstable angina or for non-ST-segment elevation myocardial infarction in patients at a high risk of either myocardial infarction or death. Revascularisation procedures are often appropriate for patients with unstable angina or non-ST-segment elevation myocardial infarction (NSTEMI) see section 2.9 for the use of antiplatelet drugs in patients undergoing coronary stenting. Prevention of cardiovascular events Patients with stable and unstable angina should be given advice and treatments to reduce their cardiovascular risk. The importance of life-style changes, especially stopping smoking, should be emphasised. Patients should take aspirin indefinitely in a dose of 75 mg daily. In patients with non-ST-segment elevation acute coronary syndrome, a combination of aspirin and clopidogrel (section 2.9) is given for up to 12 months most benefit occurs during...

Management of STsegment elevation myocardial infarction

Local guidelines for the management of myocardial infarction should be followed where they exist These notes give an overview of the initial and long-term management of myocardial infarction with ST-segment elevation. For advice on the management of non-ST-segment elevation myocardial infarction and unstable angina, see above. The aims of management of ST-segment elevation myocardial infarction are to provide supportive care and pain relief, to promote reperfusion and to reduce mortality. Oxygen, nitrates, and diamorphine or morphine can provide initial support and pain relief aspirin and percutaneous coronary intervention or thrombolytics promote reperfusion anticoagulants help to reduce re-occlusion and systemic embolisation long-term use of aspirin, beta-blockers, ACE inhibitors, and statins help to reduce mortality further. ACE inhibitors (section, and angiotensin-Il receptor antagonists (section if an ACE inhibitor cannot be used, are also of benefit to patients...

CYP Enzymes and Environmental Risk Factors for Cardiovascular Disease

Vascular cells express various CYPs including CYP1A1 and CYP1A2 36, 378 . CYP1A1 is the major enzyme that activates polycyclic aromatic hydrocarbons and CYP1A2 primarily activates aromatic amines 379-381 . Their variants are associated with altered enzyme inducibility and may differentially activate mutagens. CYP1A1*2A increases and CYP1A2*1F decreases the inducibility of the enzyme 382, 383 , which was suggested to explain the differences in susceptibility of individuals to smoking-related heart disease 384 . However, a recent study indicates that primarily the effects of CYP1A2 on oxidative stress 385 , lipid metabolism 386 , and inflammation 387 and to a lesser extent tobacco smoke-derived mutagens 384 promote CVD 388 . Additionally, in the same study, no association between CYP1A1 genotype and risk of MI regardless of smoking intensity was observed 388 . Thus, further studies are required to fully elucidate the potentially numerous mechanisms underlying smoking-associated risk for...

Atherosclerosis and Cardiovascular Disease

Atherosclerosis and myocardial infarction are leading causes of death worldwide. Atherosclerosis is a chronic inflammatory condition leading to plaque formation. Atherosclerotic plaques are characterized by the subendothelial accumulation of oxidized lipids and inflammatory cells, covered by a fibrous cap of modified smooth muscle cells and their extracellular matrix. As a prelude to atherosclerosis, macrophages internalize oxidatively modified low-density lipoprotein (oxLDL) and form foam cells, which accumulate as fatty streaks within the blood vessel wall, the first step toward the formation of an atherosclerotic plaque 90, 91 . Foam cell formation induces differences in protein expression. The role of Trx and TR in cardiovascular diseases, especially atherosclerosis and ventricular remodeling, is well established 92, 93 , and the peroxiredoxins are emerging as important enzymes in cardiovascular homeostasis. One of the proteins upregulated in foam cells is Prdx 1, mostly the...

Epidemiological Studies Showing Protective Effects of Antioxidants on Coronary Heart Disease in Humans

A number of studies (Table I) have investigated the relationship between plasma vitamin E concentrations or intakes and incidence of coronary heart disease. In 12 European populations of middle-aged men (40-59 years of age) with common plasma cholesterol (5.7-6.2 mmol liter) and blood pressure, both classical risk factors lacked significant correlation to ischemic heart disease mortality, whereas absolute levels of vitamin E showed a strong inverse correlation (r2 0.63, p 0.002). In all populations, cholesterol and diastolic blood pressure were moderately associated, but their correlation was inferior to that of vitamin E. Thus, in this study the cross-cultural differences of ischemic heart disease mortality are primarily attributable to the plasma status of vitamin E, which might have protective functions. In the study, vitamin C showed a moderate relation whereas vitamin A showed a weak relation to death from ischemic heart disease (Gey and Puska, 1989 Gey etal, 1991). A study of...

Effects of tea on myocardial infarction

The association between tea consumption and MI has been the subject of a number of epidemiological studies. Both inverse and converse relationships have been found in studies ranging from Saudi to Japan. The Boston Area Health Study reported that consumption at least one cup of black tea per day reduced the risk of suffering an MI by about a half, compared with that of habitual non tea-drinkers.13 The Zutphen Elderly Study claimed an inverse association between age-adjusted tea polyphenol intake and ischaemic heart disease, but not with MI incidence.23 Another study on Dutch populations, this time in Rotterdam, found that tea drinkers consuming more than 375 mL day had a lower relative risk of MI than non tea-drinkers.26

The Fenphen Story Serotonergic Mechanisms Determine Drug Induced Valvular Heart Disease

However, the situation changed abruptly in 1997 with a report by Heidi Connolly and co-workers of heart valve regurgitation in 24 women who had taken fenfluramine and phentermine for an average of 11 months (range 1-28 months).138 Echocardiograms demonstrated unusual valvular morphology and regurgitation in all patients. Both right-sided and left-sided heart valves were involved, and the five patients who underwent cardiac surgery had valvular heart disease (VHD) with histological features resembling changes seen in carcinoid syndrome (a mitogenic, serotonin-secreting tumor), or ergotamine-induced valve disease. Eight of the patients also had newly documented pulmonary hypertension. In a population-based study of the appetite suppressants that was reported simultaneously, Hershel Jick and colleagues found there were 11 cases of valvular disorders after the use of fenfluramine including cases of aortic regurgitation, mitral regurgitation, and combined aortic and mitral...

CoQ10 in heart disease

These findings and the observation of myocardial protection by CoQ10 during ischaemia provided the rationale for the therapeutic use of CoQ10 administration in heart disease. In the mid 1960s it was used for the first time by Yamamura in the treatment of congestive heart failure (Littarru et al., 1996).

Coronary Heart Disease

Coronary heart disease (CHD) is a multifactorial disease, for which the main established risk factors are raised serum cholesterol, raised blood pressure and smoking. The proportion of both men and women who are hypertensive steadily increases with age. Compared with men, serum cholesterol levels are lower in women up to the age of 50 years. After the menopause, levels of serum cholesterol in women exceed those of men. In women, therefore, the relative importance of CHD as a cause of death steadily increases with age, whereas in men, its importance declines after 55-64 years of age 181 . CHD accounts for 23 of deaths in women in the UK, and 30 of deaths in men, although rates have been falling since the late 1970s. Rates are low in Far East countries, such as Japan, and also declining 181,182 . Postmenopausal estrogen replacement has been shown to decrease lipoprotein (a) Lp(a) 183, 184 . The synthetic anti-estrogen, tamoxifen, has also been shown to beneficially alter serum lipid and...

Membrane Transporters In Therapeutic Drug Responses

PHARMACODYNAMICS TRANSPORTERS AS DRUG TARGETS Membrane transporters are the targets of many drugs. For example, neurotransmitter transporters are the targets for drugs used in the treatment of neuropsychiatric disorders. SERT (SLC6A4) is a target for the selective serotonin reuptake inhibitors (SSRIs), a major class of antidepressant drugs. Other neurotrans-mitter reuptake transporters serve as drug targets for the tricyclic antidepressants, amphetamines (including amphetamine-like drugs used in the treatment of attention deficit disorder in children), and anticonvulsants. These transporters also may be involved in the pathogenesis of neuropsychi-atric disorders, including Alzheimer's and Parkinson's diseases. Transporters that are nonneuronal also may be potential drug targets (e.g., cholesterol transporters in cardiovascular disease, nucleo-side transporters in cancers, glucose transporters in metabolic syndromes, and Na+-H+ antiporters in hypertension).

Nanobiotechnology and the assembling of hemoglobin with enzymes that remove oxygen radicals

Obstruction of arteries due to clots or other causes can result in stroke or heart attack (myocardial infarction). Being a solution, PolyHb can more easily perfuse partially obstructed vessels. However, if there is a prolonged lack of oxygen, reperfusion with PolyHb alone may give rise to damaging oxygen radicals, resulting in ischemia-reperfusion injuries. Thus, in a rat stroke model, after 60 min of ischemia, reperfusion with PolyHb resulted in a significant increase in the breakdown of the blood-brain barrier and an increase in brain water (brain edema) (Powandaand Chang, 2002). On the other hand, polyHb-SOD-CATdid not result in these adverse changes (Powanda and Chang, 2002).

Drug Administration and Drug Effectiveness

Perhaps for this reason, the modern practice of healing usually involves medicine, an agent or elixir given as treatment.1 The new millennium finds us rich in the knowledge of agents advanced in the art of harvesting or synthesizing remedies steadfast in the belief that cancer, heart disease, and neurodegeneration will eventually yield to these potions. Our skill in making medicine is far-reaching. Today, it would be difficult to find the person who has not personally experienced the healing force of antibiotics, vaccines, or modern chemotherapy. Unfortunately, it would be equally difficult to find the person who has not endured the premature death of a friend or relative due to unbeatable infection or cancer. So we continue to search for better therapeutics.

Incidence And Mortality

Cancer incidence refers to the number of new cases of cancer diagnosed in a given year, and the incidence rate is usually expressed as the number of new cancers diagnosed per year per 100,000 persons at risk. The cancer mortality rate is the number of deaths per year per 100,000 persons at risk. In the U.S., it is expected that over 1.3 million new cases of cancer will be diagnosed in 2003. In that same year, more than 550,000 deaths will occur due to cancer. The lifetime risk of developing cancer is approximately 44 for men and 39 for women, and 24 of men and 20 of women will die from cancer. Cancer is the second leading cause of death in the U.S., next to heart disease. Figure 1.1 shows the 10 leading causes of death and the percent of total deaths attributable to each cause in the year 2000. One sees that cancer accounts for approximately 23 of the total number of deaths and accounts for more deaths than the next five leading causes combined. In the quarter century between 1973 and...

Identifying effective drug treatments

The prescribing notes in the BNF provide an overview of the drug management of common conditions and facilitate rapid appraisal of treatment options (e.g. hypertension, p. 104). For ease of use, information on the management of certain conditions has been tabulated (e.g. acute asthma, p. 173). Information is also provided on the prevention of disease (e.g. malaria prophylaxis for travellers, p. 404). Cardiovascular risk prediction charts for the primary prevention of cardiovascular disease can be found in the glossy pages at the back of the BNF.

Brief Review Of Platelet Physiology

The participation of platelets in the reparative process that prevents blood loss from damaged vessels also makes these discoid-shaped blood elements key culprits in the development of acute coronary syndromes that are manifested clinically as unstable angina or acute myocardial infarction (MI). Platelet aggregation at the site of either atherosclerotic plaque rupture or vessel injury during a percutaneous intervention procedure may culminate in thrombosis that partially or completely occludes a coronary vessel.

Clinical Pharmacology 31 Dose Response Studies in Humans

Studies in healthy volunteers and in patients with stable coronary artery disease confirmed that an abciximab bolus dose of 0.25 mg kg was sufficient to block at least 80 of GP libAIIIa receptors and virtually abolish ADP-induced platelet aggregation (44, 45). Although the onset of action of abciximab is immediate, the above effects were reported at 2 hours after administration. Concomitant with a decrease in receptor blockade to below 80 at 4 to 6 hours, the degree of platelet inhibition began to wane gradually. Since it is likely to take more than 8 hours for an injured atherosclerotic blood vessel to undergo passivation (24), that is, to become nonthrombogenic and nonplatelet-reactive, it was suspected that the duration of platelet inhibition achieved with a single bolus dose might not be therapeutically adequate. A bolus dose followed by a continuous infusion proved to be more effective in producing sustained platelet inhibition. Studies conducted in patients with stable coronary...

On the Possible Role of Inflammation in Obesity and Type 2 Diabetes in Schizophrenia

Obesity is also linked to cardiovascular disease, both conditions occurring frequently in patients with schizophrenia. This is due to the impact of nutrient excess on the vascular endothelial cells. A major function of these cells is to activate nitric oxide synthase to produce the potent, but short-lived, vasodilator nitric oxide. The insulin receptor system-phosphoinositol-3-kinase pathway is a major factor in the control of nitric oxide synthesis in most tissues so that nutrient excess that reduces the activity of this pathway rapidly leads to a reduction in nitric oxide synthesis. Thus, the decrease in nitric oxide, combined with the accumulation of fat in the coronary circulation as a consequence of increased fat synthesis, provides a link between cardiovascular disease, diabetes obesity and inflammation 40 .

Evaluating adverse effects

There is a profound need to recognize the importance of adverse events. In the USA, adverse drug reactions (ADRs) have been found to be involved with large numbers of deaths, with fatal ADRs ranking as the fourth to sixth leading cause of death after heart disease, cancer, and stroke, and similar to pulmonary disease and accidents 23 . A recent Swedish study showed that fatal drug reactions account for approximately 3 of all deaths in the general population 24 . In hospitals, analgesics are associated with the single largest number of adverse effects, with opioids particularly a concern 25 . As well as the human dimension, adverse events are expensive. Studies of the cost of gastrointestinal bleeding due to NSAIDs across countries are consistent, and in the UK the estimate was a conservative 250 million (410 million euros) a year 26 .

Risk factors for chronic disease The metabolic syndrome MetS

The metabolic syndrome (MetS) is a combination of medical disorders integrated to have a useful description of related cardiovascular risk factors which also predict the risk of developing diabetes. Although there have been arguments against the use of a minimalistic view for these diseases, there is currently a unifying definition for the MetS (Fig. 3.1). According to this (Alberti et al., 2006), obesity and insulin resistance appear to be the causative factors in the development of the MetS. General features include obesity, insulin resistance (correlated with the risk of Type 2 diabetes and CVD), atherogenic dyslipidemia (increased triglycerides and HDL cholesterol), elevated BP, elevated C-reactive protein (CRP proinflammatory state), and a prothrombic state, associated with coagulation and fibrinolytic proteins. Scientific effort has been done to clarify associations between MetS factors, and after decades of effort, some facts can be stated FIGURE 3.1 General features of MetS....

Month Efficacy Results

Six months of follow-up revealed that the reduction in ischemic complications achieved with abciximab was sustained. At 6 months, the composite endpoint of death, MI, or any revascularization was reduced by 11.6 , from 25.8 with placebo to 22.8 with abciximab and low-dose heparin (P 0.07), and by 13.6 , to 22.3 , with abciximab and standard heparin (P 0.04) the composite endpoint of death, MI, or urgent revascularization was reduced by 43 , from 14.7 with placebo to 8.4 with abciximab (P 0.001). Abciximab significantly decreased both the 6-month incidence of myocardial infarction, from 9.9 to 5.2 , and the 6-month rate of urgent revascularization, from 6.7 to 3.3 . In contrast to the EPIC trial, however, abciximab did not reduce the need for non-urgent target vessel revascularization at 6 months.

O Enzymes Blood Clotting Factors

Alteplase is used to improve ventricular function following an acute myocardial infarction, including reducing the incidence of congestive heart failure and decreasing mortality. The drug is also used to treat acute ischemic stroke after computed tomography (CT) or other diagnostic imaging has ruled out intracranial hemorrhage. rtPA is also used in cases of acute pulmonary thromboembolism and is being investigated for unstable angina pectoris.

Matrix metalloproteinases and their inhibitors in brain injury and repair

MMPs appear to play a key role in the patho-genesis of central nervous system (CNS) disorders, contributing to blood-brain barrier (BBB) eruption, brain edema, immune cell infiltration, myelin degradation and glial-scar formation. Increased activity of MMPs has recently been reported in experimental animal models of demyelinating diseases as well as in multiple sclerosis (MS) patients. Similarly, increased levels of MMPs, and in particular MMP-2 and -9, have been detected in experimental cerebral ischemia as well as in stroke patients. Modulation of MMP TIMP profiles seems to be associated also with bacterial and viral meningoencephalitis. Additionally, though results are still controversial, MMPs seem to be involved in the deposition of p-amyloid protein in Alzheimer's diseases (AD).

Vitamin E studies in the elderly

There is also growing interest in the potential for vitamin E to reduce cardiovascular disease (CVD) risk CVD is the leading cause of death. There are data indicating that vitamin E's beneficial effects on monocyte function may be one mechanism by which vitamin E prevents CVD (Devaraj et al., 1996 Lander, 1997 Martin et al., 1997).

Cardiovascular System

The cardiovascular effects of muscarinic receptor antagonists are of limited clinical application. Atropine may be considered in the initial treatment of patients with acute myocardial infarction in whom excessive vagal tone causes sinus or nodal bradycardia. Dosing must be judicious doses that are too low can cause a paradoxical bradycardia excessive doses will cause tachycardia that may extend the infarct by increasing O2 demand. Atropine occasionally is useful in reducing the severe bradycardia and syncope associated with a hyperactive carotid sinus reflex. Atropine will protect the SA and AV nodes from the effects of excessive ACh in instances of poisoning with anti-cholinesterase pesticides.

Apparent Diffusion Coefficient MRI

Measurement of tissue water diffusion has proven to be remarkably versatile for characterizing tissue structure, as well as tissue changes due to pathology or the effects of therapy. Diffusion MRI has been well studied in the clinical evaluation of ischemic stroke 150 . In oncology, the application of diffusion MRI has focused on the image-based measurement of tumor ADC to detect early changes associated with treatment response 151 . ADC-MRI has been applied with some preliminary success in preclinical and clinical research as an imaging biomarker of treatment response in cancers of the brain 152,153 . head and neck 154 . cervix 155 . breast 156 . and prostate 157 . A related MRI technique, diffusion tensor imaging (DTI), has been used for noninvasive characterization of tissue anisotropy, structural integrity, and connectivity in myocardium 158 and white matter tracts in the brain 159 . In particular, the latter application has been useful in preoperative planning for brain tumor...

MMPs In Cerebral Ischemia

MMP-9 activity was observed after 12 h, peaking by 24 h.45'46 In these studies, unlike MMP-2 and MMP-9, TIMP-1 was identified at comparable levels in both control and ischemic tissue. Rats injected with MMP-9 neutralizing monoclonal antibody exhibited significantly reduced infarct size,45 implicating the potential therapeutic significance of MMP inhibitors in reducing brain injury after stroke.45 In brain autopsies of patients who died between less than 2 h and several years after a stroke, MMP-9 activity was markedly elevated in the infarcted tissue at 2 days post-infarction and remained elevated in tissues from patients who died months after the event. A significant increase in MMP-2 activity was observed only in patients who died 4 months or later after the event.47 Studies conducted in our laboratory have demonstrated a positive correlation between MMP-2 and MMP-9 levels in the CSF of patients following stroke, and the size of the peri-infarct edema.48,49

Abciximab Alone Versus Abciximab Plus Low Dose Plasminogen Activator

In an ongoing multicenter trial, patients with acute MI and ST-segment elevation are being randomized to receive either an intravenous bolus dose of abciximab, 0.25 mg kg, or placebo. After undergoing angiography 60 to 90 minutes after initial therapy, patients then are crossed over to a bolus injection of whichever agent was not administered initially. If TIMI (thrombolysis in myocardial infarction) 3 flow is not evident on a second angiogram obtained 10 minutes after crossover therapy, patients are then randomized to adjunctive low-dose tPA or placebo. Preliminary data from 26 patients have revealed that 31 of patients achieved TIMI 3 flow and 50 of patients achieved TIMI 2 or 3 flow after treatment with abciximab alone (79).

Mechanisms Of Induction Of Apoptosis

Focal cerebral ischemic stroke results in the neurodegeneration of cortical and other brain tissue and loss of function (31,32). Cessation of blood flow to the brain, whether permanent or transient, results in pannecrosis (infarction) to those areas that are truly ischemic. The penumbral areas surrounding the anoxic and aglycemic core are susceptible to a variety of toxicities created by ischemia that include overexposure to glutamate, oxygen radicals, and cytokines. Recent evidence indicates that, especially in the penumbra, delayed cellular death (apoptosis) by caspase activation (see Sec. IX) and DNA fragmentation can be a major contributor to the total infarcted tissue (33-39). In an intraluminal thread

Toxicity Adverse Effects And Contraindications

Epi may cause restlessness, throbbing headache, tremor, and palpitations these effects rapidly subside with rest, quiet, recumbency, and reassurance. More serious reactions include cerebral hemorrhage and cardiac arrhythmias. The use of large doses or the accidental, rapid intravenous injection of Epi may result in cerebral hemorrhage from the sharp rise in blood pressure. Ventricular arrhythmias may follow the drug's administration. Epi may induce angina in patients with coronary artery disease. Use of Epi generally is contraindicated in patients receiving nonselective b receptor blocking drugs, since its unopposed actions on vascular a1 receptors may lead to severe hypertension and cerebral hemorrhage.

Pharmacogenetics And Ethical Considerations

Often provides some prediction of future patient health and risk of disease e.g., cholesterol level and risk of heart disease. All such information, not just genetic information, must be handled with sensitive and steps taken to ensure confidentiality. A detailed review of these issues is provided in the recent report of the Nuffield Council of Bioethics (http pharmacogenetics latestnews.asp) (Melzer et al. 2003).

Pharmacogenetics Moving From Research To The Clinic

It is anticipated that regulatory authorities will increasingly expect to see this type of application of scientific advances, such as pharmacogenetics, being employed in the assessment of new medicines. The FDA Critical Path White paper, issued 14 March 2004 entitled Innovation or stagnation Challenge & opportunity on the critical path to new medical products sets out this vision and expectation for clinical drug development. Regulatory authorities are under increasing public opinion scrutiny to understand safety risk, particularly in the wake of the recent voluntary withdrawal of the widely used pain-killer and anti-inflammatory inhibitor drug, Vioxx (rofecoxib) by Merck in September 2004 due to cardiovascular risk concerns. Pharmacogenetics is about assessing individuals and must be a core component of the strategy to explore safety signals of clinical concern observed in patients following drug administration. Regulatory authorities are likely to be a key driving force in bringing...

Adrenergic Receptor Agonists

B Adrenergic receptor agonists play a major role only in the treatment of bronchoconstriction in patients with asthma (reversible airway obstruction) or chronic obstructive pulmonary disease (COPD). Minor uses include management of preterm labor, treatment of complete heart block in shock, and short-term treatment of cardiac decompensation after surgery or in patients with congestive heart failure or myocardial infarction. The chronotropic effect of b agonists is useful in the emergency treatment of arrhythmias such as torsades de pointes, bradycardia, or heart block (see Chapter 34).

Therapeutic Uses Pharmacokinetics

Dobutamine (dobutrex, others) is indicated for the short-term treatment of cardiac decompensation post cardiac surgery or in patients with congestive heart failure or acute myocardial infarction. An infusion of dobutamine in combination with echocardiography is useful in the noninvasive assessment of patients with coronary artery disease stressing the heart with dobuta-mine may reveal cardiac abnormalities in selected patients.

Platelet pharmacology

Some of the clinical complications attributed to increased platelet activity include acute myocardial infarction, stroke (hemorrhagic and thrombotic), unstable angina, reocclusion following coronary thrombolysis, occlusion during thromboplasty and coronary restenosis and tumor metastasis (8, 10, 12-15, 30, 47). In addition to these clinical situations, platelets are known to contribute to atrial fibrillation, pulmonary embolism, and left ventricular dysfunction in a highly significant manner. In this regard, inhibitors of platelet function have proven effective in the secondary prevention of clinical vascular complications in patients with cardiovascular and cerebrovascular disease (80-87). The encouraging results obtained with low to moderate doses of aspirin, a known inhibitor of cyclooxygenase, in patients with coronary artery disease have prompted the use of antiplatelet drugs in the secondary prevention of cardiovascular events associated with coronary artery disease. A recent...

Materials and Methods

Three studies have examined the relation of blood ascorbate levels to CVD, with two finding significant associations (Table 7.1). Using the broadest definition of CVD 9 th revision of the International Classification of Disease (ICD-9), codes 390-459 , Simon et al. (10) found that 30- to 75-y-old participants in the second National Health and Nutrition Examination Survey (NHANES II) with saturated ( 1.1 mg dL) or normal (0.5-1.0 mg dL) compared with marginal (60 y old, Sahyoun et al. (13) found that participants with plasma ascorbate 1.0-1.5 mg dL vs. 0.9 mg dL had a decreased risk of heart disease mortality participants with levels 1.6 mg dL also had an increased risk although it was not significant. Although this study adjusted for a number of confounders, adjustment was not made for smoking. Two other studies examining CHD mortality in middle-aged men (14) and elderly men and women (15) found no significant association with plasma ascorbate. Another study examining the relation of...

Individuals with Bipolar Disorder at Risk for Metabolic Disorders

Intrinsic neuroendocrine features of BD may lead to somatic metabolic dysfunction. In both the depressive and manic phases of BD, there is a positive association with chronic stress and elevated cortisol 23 . These abnormalities, along with frequent hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, could potentially contribute to the higher prevalence of MetS. Chronically elevated glucocorticoids from HPA hyperactivation impedes glucose uptake by insulin, which in turn promotes metabolic dysfunction and cardiovascular disease 24 . Dysregulation of the HPA axis is also associated with obesity and elevated levels of leptin, a hormone that mediates central regulation of body mass, suggesting that the obesity may be due to inefficient leptin signaling and decreased feelings of satiety 23 . Another consequence of elevated cortisol is increased activity of lipoprotein lipase, which increases the amount of adipose tissue 25 . Elevated cortisol secretion also causes IR in...

Adverse Effects And Precautions

CARDIOVASCULAR SYSTEM b receptor blockade may cause or exacerbate heart failure in patients with compensated heart failure, acute myocardial infarction, or cardiomegaly. Nonetheless, chronic administration of b receptor antagonists is efficacious in prolonging life in the therapy of heart failure in selected patients (see below and Chapter 33). The bradycardia caused by b antagonists may cause life-threatening bradyarrhythmias in patients with partial or complete AV conduction defects. Particular caution is indicated in patients who are taking other drugs, such as verapamil or various antiarrhythmic agents, which may impair sinus-node function or AV conduction.

Menstrual Irregularities and Bipolar Disorder

PCOS is one of the most common endocrine disorders occurring in reproductive-aged endocrine disorder with an estimated prevalence of between 4 and 6 38 . It is characterized by chronic anovulation and hyperandrogenism 39 . Chronic ano-vulation can lead to menstrual abnormalities and infertility. Hyperandrogenism can manifest as hirsutism (excess hair growth on the face), acne, and male-pattern balding. Metabolic consequences of PCOS include obesity and IR, which may lead to type-2 diabetes mellitus and cardiovascular disease (CVD) 39-42 , and underscores the relationship between reproductive abnormalities and IR in women. PCOS is associated with overweight or obesity in approximately 50 of women with the disorder 43 . Even if they are normal weight, individuals with PCOS tend to have a higher proportion of abdominal body fat 44, 45 , which is a risk factor for both IR 46 and CVD 47 . Lipid abnormalities have also been found at high rates among women with PCOS, including low...

Vitamin E Supplement

The prospective, randomized, placebo-controlled Alpha-Tocopherol, Beta Carotene Cancer Prevention Study (n 29,133 876 new lung cancer diagnosis and 1415 other cancer diagnoses) showed no effect of vitamin E supplementation (25 mg d) on the incidence of lung cancer in male smokers (12). However, in this trial, there was a beneficial effect of vitamin E use against prostate cancer (34 lower incidence) and colorectal cancer (17 lower incidence). Importantly, a potential adverse effect of vitamin E use was observed in these male smokers, i.e., a 5 increased incidence of hemorrhagic stroke (12). In this same cohort, there was a nonsignificant increased risk of fatal coronary heart disease in smokers ingesting vitamin E supplements (+33 ) (13). In the Heart Outcomes Prevention Evaluation Study (n 9541 1511 primary cardiovascular events), a high dosage of vitamin E (180 mg d for 5 y) had no effect on risk of cardiovascular mortality or all-cause mortality in high-risk patients (14). There...

Nitric Oxide And Focal Ischemia

Defining the role of NO in cerebral ischemia provides the rationale for new protective strategies based on modulation of NO production in the postischemic brain (92). At present, the only effective treatment of acute ischemic stroke is prevention of risk factors. There is currently no medical therapy that can be recommended for routine use in patients with acute ischemic stroke. Therefore, therapies to reduce mortality and to improve neurological outcome are needed. Heavy studies are performed to develop drugs that will prevent neurodegeneration following acute ischemic stroke. For this purpose, animal models have been produced that mimic the neuropathological consequences of stroke. These models have several advantages and disadvantages (93). Reversible or irreversible focal ischemia models like stroke in humans are useful for investigations of molecular mechanisms of stroke and also for the development of neuroprotective drugs. damage, whereas knockout mice lacking the iNOS gene are...

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Recently, ephedra preparations have been sold with misleading names alluding to the drug ecstasy (MDMA) (Blumenthal and King 1997). Several deaths have resulted from cardiac toxicity because hypertension and cardiac arrhythmia are chief problems with higher doses of ephedrine. Use of ephedra is thus contraindicated in people with existing high blood pressure. Cases have been reported of intracerebral hemorrhage and vasculitis in association with ephedrine (Forman et al. 1989 Kaye and Fainstat 1987 Wooten et al. 1983). The risk of cerebral hemorrhage is even greater when combining ephedrine with other catecholamine stimulants such as the over-the-counter stimulant phenyl-propanolamine (Stoessl et al. 1985). Pseudoephedrine may be safer than ephedrine in some respects (Porta et al. 1986). In a large sample (n 100,000) of pseudoephedrine users, there were no reports of cerebrovascular disorders within 15 days after administration. The incidence of myocardial infarction, seizures, and...

Side effects and their management

Overall, NSAIDs have a good safety record but, due to the enormous quantities prescribed, they account for a large proportion of serious adverse drug events. In 1985, from all reported adverse drug reactions, NSAIDs accounted for 25 percent in men and 30 percent in women. The elderly account for approximately 40 percent of NSAID prescriptions and are at greater risk of side effects.19 In a recent retrospective study conducted by Gallelli et al.,20 NSAIDs were found to be responsible for 55.2 percent of the episodes of adverse drug reactions overall. Diclofenac and aspirin were the drugs most frequently involved, while the skin was the system most susceptible to NSAID-induced adverse drug reactions (43 percent). Withdrawal of NSAID therapy resulted in resolution of side effects in 86 percent of episodes. NSAID side effects may present with a life-threatening event. As well as the elderly, those at higher risk include patients who are hypovolemic, immunocompromised or taking...

Imaging of Ongoing Apoptosis with 99mTcAnnexin A5

The possibility of imaging vulnerable plaques using 99mTc-annexin A5 has been extensively investigated in animals and patients by Narula's group (Kologdie et al. 9 , Johnson et al. 19 , and Kietsaler et al. 20 ). Recently, we compared 99mTc-annexin A5 accumulation in plaques with the histological findings in a rabbit model of spontaneous atherosclerosis (myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits WHHLMI rabbits ), which develop lesions similar to human atherosclerosis 4 , to further investigate the relationship between 99mTc-annexin A5 accumulation and plaque vulnerability. 99mTc-annexin A5 was injected into the auricular vein in WHHLMI and control rabbits, and SPECT was performed. The aorta in WHHLMI was clearly imaged 3 h after administration, and a significantly higher level of 99mTc-annexin A5 (5.6 times) was detected in the excised aorta of WHHLMI than in that of the control (P 0.0001). The excised tissues were subjected to autoradiography....

Supplementation and Drug Interactions

The anticoagulants aspirin and warfarin (Coumadin) are commonly prescribed to patients at risk of heart attacks or stroke. High-dose vitamin E can magnify the anti-clotting effects of these drugs and increase the possibility of clinically significant bleeding (78). Bleeding with anticoagulant drug use occurs more frequently in older patients and in patients at risk of vitamin K deficiency due to antibiotic therapy or fat malabsorption syndromes (92). Thus, high-dose vitamin E therapy might be contradicted in these patient populations. p-Hydroxyl-p-methyl glutarate-CoA reductase inhibitors (statins) in combination with niacin are often the initial therapy prescribed for dyslipidemia to reduce LDL cholesterol and raise high density lipoprotein (HDL) cholesterol. A recent clinical trial examining the efficacy of different lipid-altering and or antioxidant strategies on coronary artery disease indices demonstrated that when statin niacin therapy was combined with antioxidant use...

Functional Imaging Pain And Depression

Lead to urinary retention, constipation, tachycardia, blurred vision, and delirium. Antihistaminergic effects include sedation, increased appetite, and weight gain. Orthostatic hypotension results from blockade of a1-receptors and could contribute to the increased risk of fall-related hip fractures among patients receiving TCAs.26,27,28 Tricyclics also have type 1 antiarrhythmic properties in that cardiac conduction is prolonged by inhibition of sodium channels. These antiarrhythmic effects could, in part, account for the increased risk of sudden cardiac death and myocardial infarction in patients treated with TCAs.29,30 The use of TCAs in combination with methadone, which increases the QTc interval, has been associated with an increased risk of death related to accidental overdose.31,32 Tricyclics also increase the risk of seizure by inhibiting chloride channels.

Rb PET Relative Perfusion Imaging

82Rb is produced from a Sr-82 Rb-82 generator which can be eluted every 10 min. 82Rb PET imaging has been widely used in the clinical setting in North America 9 . 82Rb has high diagnostic ability compared to standard single photon emission computed tomography (SPECT) myocardial perfusion imaging in patients with coronary artery disease 11, 26, 27 . The use of attenuation correction plays an important role in this good diagnostic accuracy. Beanlands et al. 12 evaluated perfusion PET diagnostic accuracy using pooled data from 14 studies with 1460 patients. The mean sensitivity was 89 , with a range of 83 -100 , and specificity was 89 , with a range of 73 -100 . Recent advances in PET CT are expected to lead to further improvements in diagnostic accuracy.

The Antioxidant Controversy

The bottom line of all these complex reactions is that ROS and RNS, while common in biological systems and often playing critical roles in the processes of life, can be dangerous. They are essential and yet, because of the way life evolved here on earth, they can also be lethal. Damage that radicals and reactive species can inflict on critical biomolecules must be repaired or damaged cells replaced (from stem cells) in order for organisms to continue to function. ROS and RNS-generated damage increases with age and damaging processes, such as underlying chronic inflammation, accumulated exposure to environmental injury from radiation, or xenobiotics. Simultaneously, the ability to repair or remove damaged biomolecules declines as well.55 This imbalance between radical induced damage and the radical defense and tissue repair mechanisms has been proposed as the mechanism leading inevitably to development of age-related diseases such as cardiovascular disease, cancers, and...

Introductory Remarks And Scope Of The Chapter

The biological significance and pharmacological effects of members of the endogenous defence against oxidative insults have been reviewed excellently by others, and will not be discussed at length. Thus, the importance of the vitamins E and C as well as the ubiquinols and carotenoids in disease prevention has become widely recognized and is supported by a host of clinical and epidemiological studies. It should be pointed out, though, that the beneficial effects of antioxidant vitamins on, for example, carcinogenesis, atherosclerosis and coronary heart disease suggested by epidemiological studies have still to be confirmed conclusively in controlled trials (Barber and Harris, 1994 Burr, 1994 Elinder and Walldius, 1994 Rautalahti and Huttunen, 1994 van Poppel et al., 1994). The enzyme systems that are devoted to detoxification of reactive and potentially pathological oxygen metabolites (superoxide dismutase, glutathione peroxidase, catalase, etc.) have also been thoroughly treated by...

Dietary Sources Supplements and Recommended Intake of Vitamin E

As an upper limit for supplemental vitamin E intake, the FNB published a dose for adults of 1 g d a-tocopherol (i.e., 1500 iu RRR- or 1100 iu all-rac-a-tocopherol) this dose is considered safe, showing no apparent side effects (6). In human intervention studies, various doses of vitamin E up to 3600 iu d have been used (21). Nevertheless, conclusive evidence from long-term studies regarding biological effects and safety of chronic intake of pharmacologic doses of vitamin E are lacking. In the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study (22) with Finnish smokers consuming 50 iu d vitamin E for 6 y, an increase in mortality from hemorrhagic stroke was observed however, other intervention studies did not report such an adverse effect (23,24). It was suggested that pharmacologic doses of vitamin E are contraindicated in persons with blood coagulation disorders because vitamin E might exacerbate defects in the blood coagulation system due to its inhibitory effects on...

Therapeutic Potential

The WNT FZD signaling system is broadly expressed in both the developing and the adult organism and its involvement in several disease states makes it a suitable target for therapy. Indeed, some forms of human disease are directly linked to mutations in FZD, as exemplified by the FZD4 - dependent familial exudative vitreoretinopathy - 99 - Broad expression and a large number of receptor and ligand isoforms provide both possibilities and pitfalls for drug development. Despite the current lack of understanding of specificity of WNT-FZD interaction and the underlying signaling mechanisms, this receptor system has important therapeutic potential. Developing drugs that selectively attack FZDs and WNT-i nduced signaling positively and negatively could be very useful for the treatment of conditions such as cancer, neurological disorders, osteroporosis, and cardiovascular disease 93, 100-103 - to name but a few. WNT Frizzled signaling might also play a major role in the future use of stem...

Epidemiological Studies of Cholesterol and AD

Initial interest in cholesterol and Alzheimer's disease stemmed from a lengthy historical backdrop. One of the first studies linking cholesterol to AD stemmed from an observation that senile plaques were quite prevalent in the brains of non-demented patients who had died from coronary heart disease 21 , a population known to possess elevated cholesterol levels. Additional studies soon followed demonstrating that the ApoE4 allele of the ApoE cholesterol transporter was a major risk factor for AD 13-16 . Is there a clear association between cholesterol and Alzheimer's disease Although a few studies have observed an association between elevated cholesterol, dementia and AD 22,23 , the majority of cross-sectional studies typically report no association or lower levels of cholesterol in patients with AD compared to controls or VaD patients 24-30 . In two longitudinal population-based studies, higher midlife cholesterol levels were reported to be associated with an increased risk of AD...

From Animal to Human

Animal models are being extensively used to develop biomarkers to assess NCE efficacy in humans. Biomarkers are indicators of normal biological or disease-associated processes and can be used to assess pharmacological responses to NCEs. Examples of common biomarkers are body temperature for fever, blood pressure for stroke risk, serum cholesterol for cardiovascular risk, blood sugar for diabetes, and cognition for Alzheimer's and other neurodegenerative disorders (Day et al., 2008). In colorectal cancer, apoptosis signaling proteins are being developed as prognostic biomarkers (Hector & Prehen, 2009).

Methods for Assessment of Oxidative Damage in Vivo

Assessment of the in vivo effect of dietary phenolic compounds can be very difficult. Recently, we have studied the effects of antioxidant polyphenolics in beverages such as red wine on LDL oxidation (Abu-Amsha et al., 1996). Since oxidative damage to low-density lipoproteins has been linked to the development of atherosclerosis and heart disease, the rich flavonoid content of red wine has led to its appeal as possibly being beneficial against heart disease. While a number of in vitro studies clearly show strong antioxidant effects of red wine phenolics against LDL oxidation (Frankel et al., 1993 Abu-Amsha et al., 1996 Puddey and Croft, 1997), several human intervention trials have given conflicting results (Fuhrman et al., 1995 Sharpe et al., 1995 De Rijke et al., 1996). This may arise from the fact that alcohol itself is a pro-oxidant and the overall effects of a beverage may be due to a balance between its pro-oxidative and antioxidant components (Puddey and Croft, 1997). In...

Technical considerations

Figure 20.8 Two eight-contact electrodes placed for angina pain. The electrodes are central to slightly leftward and span from C7 to T3. Note the sternal wires from previous coronary bypass surgery in inferior aspect of film. Figure 20.8 Two eight-contact electrodes placed for angina pain. The electrodes are central to slightly leftward and span from C7 to T3. Note the sternal wires from previous coronary bypass surgery in inferior aspect of film.

Approaches To Evaluating Whether There Is Increased Value For Use Of Biomarker Measurements In Preclinical Studies

Approaches to ascertaining the value of knowledge of an analyte serum concentration in assessing drug-induced tissue injury might be phrased more generally at the outset. Will the knowledge of the serum concentration of an analyte add value by helping to identify individual patients that may be at increased risk for developing a progressive organ-directed disease As mentioned earlier, certain oncological agents are associated with nephrotoxicity 14 and therefore should be used only with caution in patients at risk for renal dysfunction. Similarly, caution is advised in prescribing thiazolidinedione antidiabetic agents to patients with preexisting hepatic or congestive heart disease. Improved sets of sensitive markers for these and many other examples of underlying predispositions for drug-induced morbidity that can be routinely measured to better identify patients at risk and similarly be useful for monitoring for any early dose-related onset of such toxicity would be extremely...

Pharmacological Actions And Side Effects

An intramuscular dose of 10 mg nalbuphine is equianalgesic to 10 mg morphine, with similar onset and duration of analgesia. Nalbuphine depresses respiration as much as morphine. However, it exhibits a ceiling effect such that increases in dosage beyond 30 mg produce no further respiratory depression or analgesia. in contrast to pentazocine and butorphanol, 10 mg nal-buphine given to patients with stable coronary artery disease does not increase cardiac index, pulmonary arterial pressure, or cardiac work, and systemic blood pressure is not significantly altered these indices also are relatively stable when nalbuphine is given to patients with acute myocardial infarction. Nalbuphine produces few side effects at doses of 10 mg or less sedation, sweating, and headache are most common. At much higher doses (70 mg), psychotomimetic side effects (e.g., dysphoria, racing thoughts, and distortions of body image) can occur. Nalbuphine is metabolized in the liver and has a t 2 in plasma of 2-3...

Tricyclic Antidepressants

Unfortunately, the adverse effects of the TCAs may limit their utility (Table 5-7). Amitriptyline and imipramine have more troublesome side effects than the secondary-amine TCAs (e.g., nortriptyline and desipramine). TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign pros-tatic hypertrophy.

Crystallization Induced Asymmetric Transformation in the Synthesis of L768673

Compound 4 is an inhibitor of the slowly activating delayed rectifier K(+) current which repolarizes the cardiac ventricular cell membrane. As a result, the refractory period of the spontaneously contracting heart muscle is prolonged and the cardiac action potential is delayed. This helps to reduce the potentially fatal cardiac ventricular fibrillation which can result from ischaemic heart damage, leading to myocardial infarction.

Flavonoids and Chronic Disease

Research with cell cultures and animal models suggests flavonoids may play a role in promoting human health and reducing the risk of some chronic diseases. Flavonoids have been purported to have a beneficial effect on cardiovascular disease, cancer, neurodegenerative diseases, diabetes, and osteoporosis as well as having antibacterial, anticarcinogenic, antiinflammatory, diuretic, and immunostimulatory actions. Observational studies have associated

Ketogenic Diet In Adults

Both partial and generalized seizures responded favorably. All patients noted constipation and bloating, and women reported menstrual irregularities. Cognitive improvement was observed, similar to what has been reported in children. Seven patients noted improved cognition and mood, whereas 2 patients reported worsened concentration. Cholesterol and triglyceride levels increased, with an increased ratio of cholesterol to high-density lipoprotein (HDL). One patient with long-standing high cholesterol discontinued the diet after 5 mo and 5 mo later experienced a myocardial infarction. Although it is doubtful that the KD was responsible for this adverse event, it must be asked whether the diet contributed to this cardiovascular morbidity. A standard set of laboratory studies was performed prior to beginning the diet. This included a complete blood count, renal and electrolyte evaluation, liver function tests, fasting lipid panel, and serum vitamin B12, folic acid, carnitine, and selenium...

Cytoprotective Therapy

Some circumstances might explain the lack of efficacy in clinical trials, such as species differences and incompatibility of animal stroke models to the human condition. Neuroprotective drugs have been administered with different therapeutic windows, in some instances beyond the 24 h after stroke onset. Therefore, probably a neuroprotectant could not be demonstrated to be an efficient drug. Heterogeneity of stroke patients enrolled in clinical trials may dilute the positive effects of neuroprotection. Outcome measures and follow-up periods used are probably not able to detect the efficacy of the therapeutic intervention, especially in patients with mild stroke. Finally, the neuroprotective agent may act only in one step of the ischaemic cascade, without arresting entirely the other biochemical mechanisms triggered by ischaemia.

Therapeutic Prospects

Effects of CB1 antagonists however to overcome the difficulty of such limiting effects, the development of novel CB1 blockers not penetrating in the brain is highly required. LH-21 (Table 7.1) is an example of neutral CB1 antagonist that exhibits some anorexigenic effect in rats. Indeed, it has been reported that LH-21 failed to ameliorate hepatic damage or to improve insulin secretion whereas rimonabant did it (Pavon et al., 2006, 2008). However, blocking peripheral CB1 receptors could play a role in pathologies not directly related to obesity, such as hepatic fibrosis, chronic inflammatory conditions, diabetes, and cancer. Alternative applications of novel high selective peripheral CB1 antagonists and lower doses of CB1 antagonists should be taken into account to avoid central psychotropic side effects, or to overcome psychotropic side effects limitations. Both efficacy and side effects increase with dose, but the 2-year RIO-EUROPE study suggests that doses lower than that normally...

Antithrombotic Therapy

Two recent studies have addressed the efficacy of aspirin (160-300 mg day) administered within a few hours of stroke onset.47,73 In these trials, aspirin reduced the rate of recurrent strokes. A small reduction in the rate of death or disability with aspirin was observed at 6 months, and an excess of extracranial bleeds did not outweigh this benefit.47 Considering together the results of the two trials, aspirin produces a small reduction of about 9 per 1000 patients treated for the combined outcome of death or non-fatal recurrences during the first weeks after stroke.5 The results of the first trial of intravenous abcixi-mab administered no longer than 24 h after stroke onset have recently been published.74 Abciximab is a monoclonal antibody directed against the platelet glycoprotein IIb IIIa receptor, producing blockade of the glycoprotein Ib IIIa receptor, reduction of ADP-induced platelet aggregation, and prolongation of the bleeding time.75 Doses of abciximab were similar to those...

Secondary Stroke Prevention

Include the identification and modification of risk factors. In most instances, data on the potential benefits of risk-factor management for secondary stroke prevention have been extrapolated from studies focused on primary prevention. In the last few years, however, a body of evidence has shown that antihypertensive therapy decreases recurrences by one-third among subjects who have already suffered a first stroke.99-101 Cigarette smoking increases the risk of stroke 1.5-fold and should be intensely discouraged.102 Although specific evidence regarding the benefits of secondary stroke prevention is still lacking, it has been suggested that statins may reduce the incidence of first stroke by 30 in patients with symptomatic coronary artery disease or hypercholesterolaemia, and a similar efficacy might be expected to occur in patients with prior stroke.103 Nevertheless, there is still a large gap between the benefits of risk-factor control in reducing recurrences as reported by several...

Reteplase a recombinant plasminogen activator

Key words Acute myocardial infarction, thrombolytic therapy, recombinant Abstract Thrombolysis is now standard therapy for the treatment of acute myocardial infarction. However, evidence suggests that earlier treatment and more rapid and complete recanalization of infarct-related coronary arteries may lead to greater survival benefits than achieved by current therapies. Furthermore, first- and second-generation thrombolytics can be associated with side effects, such as bleeding complications, and often require prolonged infusion or complex dosing regimens to optimize clinical outcome. Reteplase, a novel recombinant plasminogen activator (thrombolytic), is a deletion variant of native, human t-PA that has been designed to provide a longer half-life plus more specific and rapid lysis of coronary thrombi, using a bolus dosing regimen. Clinical studies comparing reteplase with the current standard thrombolytic agents have demonstrated that reteplase has a highly favourable pharmacological...

Preliminary Clinical Trials of BMSC Transplantation for CNS Disorders

Based on the above observations obtained from animal experiments, some preliminary clinical testing has already been started 34-39 . Thus, Bang et al. 34 intravenously injected autologous BMSCs into 5 patients with severe neurological deficits due to ischemic stroke at 5 to 9 weeks after the onset, and they concluded that autologous BMSC infusion was a feasible and safe therapy that may improve functional recovery. On the other hand, Sykova et al. 37 injected unmanipulated bone marrow cells, through an intra-arterial or intravenous route, in 20 patients with spinal cord injury in the acute or chronic stage. Yoon et al. 38 isolated autologous bone marrow mononuclear cells from 35 patients with spinal cord injury, and directly injected them into the injured spinal cord in the acute or chronic stage. They found an improvement of neurological function in patients who were treated in the acute or subacute stage 38 . Saito et al. 36 intrathecally infused autologous BMSCs into a 35-year-old...

Problems with the Evaluation of Wholefood Antioxidant Consumption Studies

Evaluation of in vivo study outcomes is complicated by many factors that are difficult to objectively address. Given the low baseline incidence of heart disease, cancer and macular degeneration, large long-term interventional studies may be required to fully appreciate whole-food effects on these diseases. Furthermore, the same whole-food products can differ widely in their antioxidant content because of environmental influences and food processing techniques, so surveys of antioxidant intake may not reflect true intake levels. Possible genetic differences influencing human antioxidant status have not been investigated but may also be found to play a role in explaining why individual effects of whole-food antioxidants vary. One of the greatest problems surrounding the study of whole-food effects on in vivo antioxidant capacity has been the lack of assays for complete quantification of plasma antioxidant capacity.

Hydrophilic Analogues

Water-soluble tocopherol analogues have also been made in order to utilize their efficient scavenging properties, but alter their distribution, especially in connection with treatment of oxidative stress during myocardial infarction. Trolox (312), the most well-known example, has a distribution coefficient (log D) of -1.02 (octanol water, pH 7.4). It has been found to reduce infarct size in dogs subjected to myocardial ischaemia followed by reperfusion (Mickle et al., 1989). The hydrophilic (log P -0.60) quaternary ammonium analogue MDL 73404 (313) has been found to have cardioselective distribu

MicroRNAs in Human Disease

The expanding inventory of human miRNAs along with their highly diverse expression patterns and high number of potential target mRNAs suggest that miRNAs are involved in a wide variety of human diseases. One is spinal muscular atrophy (SMA), a paediatric neurodegenerative disease caused by reduced protein levels or loss-of-function mutations of the survival of motor neurons (SMN) gene.116 A mutation in the target site of miR-189 in the human SLITRK1 gene was recently shown to be associated with Tourette's syn-drome,117 while another recent study reported that the hepatitis C virus (HCV) RNA genome interacts with a host-cell miRNA, the liver-specific miR-122a, to facilitate its replication in the host.118 Other diseases in which miRNAs or their processing machinery have been implicated include fragile X mental retardation (FXMR) caused by absence of the fragile X mental retardation protein (FMRP),119,120 DiGeorge syndrome,121 human immunodeficiency virus (HIV) replication and coronary...

Diabetes and Pre Diabetes in the General Population

Diabetes type 1 is a very different disorder that is predominantly genetically inherited and in which obesity is not an important risk factor. Worldwide there are substantial regional variations with Africa having the lowest prevalence. In Europe, prevalence will increase from around 6 in 2008 to 8 in 2025 in the 20-79 age group and in some regions will increase to over 10 2 . The worldwide prevalence of DM was 5.1 in 2003 and will rise to 6.3 by 2005. In the UK it is estimated that by 2010 DM will be diagnosed in 7 of men and 5 of women 3 . In addition, impaired glucose tolerance (IGT) will rise from 8.2 in 2003 to 9 in 2005. The sheer relevance of these data is encapsulated in the single statistic that in 2007 3.8 million deaths will be due to DM globally 4 . Complications of DM are of concern on many levels in that peripheral vascular disease (amputation risk is increased by 15-40 times compared with the general population), retinopathy and cardiovascular disease are mostly also...

Questions to Be Answered Before the Clinical Application of BMSC Transplantation

Third, it is essential to develop techniques to track the fate of the transplanted cells in the host CNS continuously and noninvasively in order to guide further advances in neurotransplantation research and its future clinical applications. A cell-tracking technique would also be important as a biologically relevant endpoint in the clinical situation (see above). Recent studies have suggested that magnetic resonance (MR) imaging, nuclear imaging, and optical imaging could be suitable candidates for cell-tracking. In previous animal experiments, the donor cells were identified on MR imaging by labeling with an SPIO agent 59-61 . MR imaging can image intact, opaque organisms in three dimensions with good spatial resolution, but it requires long imaging times and consequently slows data acquisition because of the low sensitivity. More importantly, the magnetic nanoparticles that label the donor cells cannot label all the cells during their proliferation. Nuclear imaging can detect...

The Immunobiology of Vascularized Allografts

Although the early survival of allogeneic transplants has increased dramatically in recent years, the incidence of chronic rejection has not decreased appreciably (20). Chronic rejection occurs in all types of solid-organ transplants. In heart transplants, it is characterized by progressive coronary artery disease (21,22) in lung transplants, as bronchiolitis obliterans (5,23). Liver allografts appear to be less affected by chronic rejection, but when it does occur, biliary epithelium is lost leading to hyperbilirubinemia and graft failure (24). Chronic allograft nephropathy is the general term used to describe a slow deterioration of renal allograft function that is characterized histologically by interstitial fibrosis, tubular atrophy, widespread arterial intimal fibrosis, and global glomerulosclerosis (25,26). In many respects, the tissue damage seen during chronic rejection mirrors the pathophysiologic processes seen in other non-transplant-associated disorders (5,26).

Oxidized Lipid and Atherosclerosis

Oxidation of lipoproteins plays a significant role in atherogenesis. That knowledge offers an opportunity to test effects of antioxidants as inhibitors of atherogenesis, which can be done in experimental animals. They can also be studied as inhibitors of lipoprotein oxidation or reducers of risk of cardiovascular disease.

Secretion Aggregation

Fuster V, Badimon L, Badimon JJ, Chesebro JH The pathogenesis of coronary artery disease and the acute coronary syndromes. Part 1. New Eng J of Med 326 242,1992 2. Fuster V, Badimon L, Badimon JJ, Chesebro JH The pathogenesis of coronary artery disease and the acute coronary syndromes. Part 2. New Eng J of Med 326 310,1992

Dilemma about Antioxidants

Lifestyle may be one of the determinants of the picture presented to the investigators. Heart disease and cancer are generally described as lifestyle disease but the research approach focuses on only one aspect of lifestyle. Slattery et al. (1995) examined dietary antioxidants and plasma lipids in participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study and found that higher intake of dietary antioxidants is associated with other lifestyle factors such as physical activity and nonsmoking. In Britain, plasma concentrations of antioxidants are related to social class, being higher in the better educated and more affluent (Gregory et al., 1990). If protective levels of antioxidants such as carotenoids, tocopherols, and others are part of a life-long behavioural pattern, we cannot expect too much if we influence one aspect of risk by dietary supplements without addressing other behaviours.

[30 Using Genetically Engineered Mice to Study Myocardial Ischemia Reperfusion Injury

Evidence exists in the literature supporting a role of reactive oxygen species in the pathophysiology of ischemic heart disease. Most of the evidence is based on the fact that free radical scavengers and or antioxidants reduce the severity of ischemic injury. However, the pathogenesis of ischemic injury is multifactorial, and many factors, in addition to the oxygen free radicals, for example, lipids, calcium, and many other mediators, play a crucial role in the development of ischemic heart disease leading to congestive heart failure.4 To derive more conclusive evidence of the role of free radicals in ischemic heart disease and to demonstrate whether the

Targeting the MAPK Pathway in Other Diseases

In a mouse animal model of myocardial injury, inhibition of both p38 and fibroblast growth factor (FGF) increased mitosis in cardiomyocytes, reduced scarring and wall thinning and improved cardiac function (Engel et al. 2006). While the p38 inhibitor alone did not improve cardiac function, it did increase cardiomyocyte mitosis. These findings raise the possibility that the p38 MAPK pathway may be targeted, potentially in combination with other treatments, to promote recovery following a heart attack. Consistent with these preclinical obser vations, the p38 inhibitor SB-681323 (GlaxoSmithKline) is in phase-II studies for patients with coronary heart disease.

Brain To Body Central Nervous System Effects On The Immune System

Although the relationship between stress and immunity is quite complex, more acute and or mild stressors, in general, tend to be associated with activation of immune responses, whereas more chronic and intense stressors tend to be associated with activated innate immune system elements and impaired acquired immune system responses. The health relevance of these stress-related immune changes has been demonstrated in studies that have shown an association between chronic stress and increased susceptibility to the common cold, reduced antibody responses to vaccination, and delayed wound healing (Cohen et al. 1991 Glaser et al. 1992 Kiecolt-Glaser et al. 1995). In addition, stress, as well as depression, has been linked to increased morbidity and mortality in infectious diseases (e.g., HIV infection), neoplastic diseases (including breast cancer and malignant melanoma), diabetes, and cardiovascular disease (Evans et al. 2005 Fenton and Stover 2006 Leserman et al. 1999 Raison and...

Neuroprotection In Ischemia

Finally, as noted above, growth factors may have significant uses in cerebral ischemia, and their combination with more conventional neuroprotec-tive agents may represent another therapeutic breakthrough, as they may enhance neuronal repair after stroke. The addition of a reperfusing agent to this package may also be advantageous for the reason noted above.123

Typeii Diabetes Mellitus

Reaven (1988) suggested that insulin resistance might be a common denominator for obesity, Type-II diabetes hypertension and hyperlipidaemia (metabolic syndrome) and should be treated rigorously to avoid coronary heart disease, the most common cause of morbidity and mortality in Type-II diabetes mellitus. However, it still remains to be proven that effective blood glucose control will reduce the mortality of the disease (Turner and Holman, 1990).

Your Heart and Nutrition

Your Heart and Nutrition

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