Drugs

No. 07036987 TOBACCO CRITICA REVIEW Smoking is an ancient custom. The Greeks and Romans smoked pipes, using hemp, lavender and others leaves. The American Indians have been using tobacco, in pipes, for at least 1,000 years. This habit of tobacco smoking was reported by the fifteenth and sixteenth century explorers who visited South America, the first of whom was Christopher Columbus in 1492. The quality of tobacco plant was improved by the New World settlers along the east coast of the USA, in the states of now known as Maryland, Delaware, Virginia and the Carolinas. The introduction to Britain of the habit of smoking in pipes is attributed to Sir Walter Raleigh. By 1620, about 15,000kg of tobacco was imported into England, to be smoked by the rich in pipes or cigars. At the dawn of the 20th century, the most common tobacco products were cigars, pipe tobacco, and chewing tobacco. The mass production of cigarettes was in its infancy, although cigarette smoking was beginning to increase dramatically. In 1888, tobacco products were suspected of producing some adverse health effects, yet tobacco was also considered to have medicinal properties. Many scholars and health professionals of the day advocated tobacco’s use for such effects as improved concentration and performance, relief of boredom, and enhanced mood. By the dawn of the 21st century, in contrast, tobacco had become recognized as being highly addictive and one of the world’s most devastating causes of death and disease. Moreover, because of the rapid increase in smoking in developing nations in the late Student No. 07036987 20th century, the number of smoking-related deaths per year is projected to rise rapidly in the 21st century. For example, the World Health Organization (WHO) estimated that in the late 1990s there were approximately 4 million tobacco-caused deaths per year worldwide. This estimate was increased to approximately 5 million in 2003 and could reach 10 million per year by the 2020s. By the mid-21st century, a staggering 500 million of today’s cigarette smokers will have died prematurely because of their smoking. Although tobacco use is declining in many countries of Western Europe and North America and in Australia, it continues to increase rapidly in many countries in Asia, Africa, and South America. The primary cause of the escalation in the number of deaths and incidents of disease from tobacco is the large increase in cigarette smoking during the 20th century. Nowadays, tobacco products are manufactured with various additives to preserve the tobacco’s shelf life, alter its burning characteristics, control its moisture content, inhibit the hatching of insect eggs that may be present in the plant material, mask the irritative effects of nicotine, and provide any of a wide array of flavours and aromas. The smoke produced when tobacco and these additives are burned consists of more than 4,000 chemical compounds. Many of these compounds are highly toxic, and they have diverse effects on health. The primary constituents of tobacco smoke are nicotine, tar (the particulate residue from combustion), and gases such as carbon dioxide and carbon monoxide. Although nicotine can be poisonous at very high dosages, its toxic effect as a component of tobacco smoke is generally considered modest compared with that of many other toxins in the smoke. Carbon monoxide has profound, immediate health effects. It passes easily from the lungs into the bloodstream, where it binds to hemoglobin, the molecule in red blood cells that is responsible for the transfer of oxygen in the body. Carbon monoxide displaces oxygen on the hemoglobin molecule and is removed only slowly. Therefore, smokers frequently accumulate high levels of carbon monoxide, which starves the body of oxygen and puts an enormous strain on the entire cardiovascular system. Tobacco smoking is one of the strongest risk factors for various disorders such as lung cancers and cardiovascular disease (CVD). Further, former smokers remain at an increased risk for developing lung cancers and CVD even years after they stop smoking. These suggest that expression levels of some of the genes related to tobacco smoking may not return to levels similar to never smokers and could be permanently altered despite prolonged smoking cessation, thereby being involved in the development of lung cancers and CVD. The modification, aggregation, and deposition of proteins are a prominent part of many pathological processes and can play a direct role in tissue damage. Advanced glycation end products (AGEs) have been shown to play a role in the development of many of the pathological sequelae of aging and diabetes such as CVD and cancer growth and metastasis (S. Yamagishi, T. Matsui, K. Nakamura, 2007). Moreover, there are several papers to show that tobacco smoke is a source of toxic reactive glycation products. Further, recent epidemiological and prospective data have supported the concept of ‘metabolic memory’, a long-term influence of previous hyperglycemia on the development of CVD in diabetes. The data of the World Health Organization (WHO) indicate that 47% of men and 12% of women are smokers, and smoking is responsible for the death of about 3.5 million subjects every year, meaning about 10,000 death cases per day. In the year 2000, 4.83 million premature deaths in the world were attributable to smoking; 2.41 million in developing countries and 2.43 million in industrialised countries. Three hundred and eighty-four million of these deaths were in men. The leading causes of death from smoking were cardiovascular diseases (1.69 million deaths), chronic obstructive pulmonary disease (0.97 million deaths) and lung cancer (0.85 million deaths) (Ezzati and Lopez, 2003). The burning of tobacco at temperature of 830–900 _C, leads to the production of about 5000 already identified toxic substances. This heterogeneous mixture consists of a gaseous phase containing non-condensed gases and vapours, like carbon-monoxide, nitrogen oxides, nitrosamine, etc., and a solid phase, consisting of the products of pyrolysis like the nicotine, phenols, organic acids, aldehydes, ketons and aromatic, polycyclic hydrocarbons. In addition, during cigarette smoking a considerable amount of free radicals (FR) are also liberated (Pryor et al., 1983), estimated as 2 · 1014 radicals/cigarette. It is known that the oxidative stress derives from a disequilibrium between the oxidant and antioxidant components, which may be of enzymatic and non-enzymatic type. Such a disequilibrium may be due to an excessive increase of FR and/ or reduction of the defensive mechanisms, and it is a potent accelerator of aging. The FR may favour aging through their damaging actions on various substrates, which have fundamental biological functions, and favouring pathological processes by pathogenetic stimulation. The smoke contains two different population of FR in the gaseous and solid phases, respectively (Church and Pryor, 1985). The solid phase contains relatively stable FR, while the gaseous one contains small FR of oxygen, carbon and sulphur, high concentration of nitric oxide, and particularly reactive aldehyde moieties. Other important FRs are the H2O2 and O2, the major source of which in smoke are the polyphenols. These latter FR have a synergistic action with the nicotine, and are considered as important mediators of the vascular insults at the endothelial level. The smoke is able to cause tissue oxidative damage at various levels (Park et al., 1998), and contributes significantly to the appearance of endothelial dysfunctions (Nagy et al., 1997), and to the alterations which induce the arteriosclerosis process (Lakier, 1992). As a matter of fact, one can observe in smokers an increase of lipid peroxidation products (Smith et al., 1993), particularly important is the increase of oxidized LDL (Sanderson et al., 1995), accompanied by a decrease of HDL-cholesterol levels; the negative effects are evident also in hypercholesterolemic patients (Schuitemaker et al., 2002). In smokers is also evident a marked reduction of the endothelium-dependent vasodilatation (Celermajer et al., 1994; Heitzer et al., 1996; Pepine et al., 1998). It has been recently shown that the alteration of endothelial vasoregulatory activity is independent from the number of smoked cigarettes (Barua et al., 2002), as this activity was similar in subjects who smoked 1 package of cigarettes per week or per day (or less). Another important aspect of the oxidative stress induced damages in smokers regards nuclear and mitochondrial DNA. Several in vitro studies have shown that smoke is able to increase the frequency of DNA breaks (Leanderson and Tagesson, 1992; Park et al., 1998). During oxidative stress reactions, the reduction of several antioxidant defensive systems also plays an important role. Indeed, it is known that the serum of smokers is poor in ascorbic acid (Schectman et al., 1989), which is the most potent water-soluble vitamin with antioxidant effect. A synthesis of the literature shows that compared with non-smokers, on overage, active smokers have greater than 25% lower circulating concentrations of ascorbic acid, acarotene, b-carotene, and cryptoxanthin. The differences observed between smokers and non-smokers seem to be due to an acute effect of smoking (Alberg, 2002). At tissue levels, homogenized preparations of the endothelial cells taken from the coronary arteries of smokers who underwent a surgery of aorto-coronary by pass displayed a decrease of both vitamin C and E, and an increase of the products of lipid peroxidation (Mezzetti et al., 1995), and these values were inversely correlated to the extent of the with coronary stenosis. It has also been demonstrated recently that after smoking only a single cigarette, the nitrate and nitrite concentrations which are the indicators of both the circulating levels of NO and plasma concentrations of several other antioxidants, decrease rapidly (Tsuchiya et al., 2002; Zhang et al., 2006), and they return to the normal range only after about 60 min after the cessation of smoking. These transient changes may partially contribute to coronary vasoconstriction, which is routinely observed after smoking. There is no doubt that smoke is an important risk factor for numerous pathologies, in particular for cardiovascular, neoplastic and respiratory diseases, which are the main causes of death in the industrialized countries, where smoking habit is also largely diffuse. Among smoking-induced damages at cardiovascular system level, one can distinguish immediate (or acute) effects and long-term (or chronic) ones. The acute ones can be observed immediately after smoking, while the chronic ones are correlated to a series of complex hemorheological modifications, as well as to alterations of the vascular walls subsequent to a chronic smoke exposure. The acute effects are caused mainly by nicotine, which is absorbed very rapidly and enter the circulation; it stimulates directly the sympathetic nervous system, increasing the secretion of catecholamine from the medullar area of the surrenal glands (Cryer et al., 1976; Black, 1990), stimulates the cerebral cortex and the hippocampus, the chemoreceptors of the aorta and the carotid arteries. The produced effects are vasoconstriction, reduced oxygen tension, increase of the arterial blood pressure and the cardiac frequency, the contractibility of the myocardium and the cardiac output. Endothelial damage is the first event in the pathogenesis of atherosclerosis. In laboratory rats the exposition to cigarette smoke leads to morphological alterations of endothelium which appears irregular with membrane disturbances, evidenced by the formation of blebs or microvillous-like projections (Pittilo, 2000). A lot of studies provided evidences that cigarette smoke can alter vascular endothelium not only morphologically but also functionally. It is known that in young adults the smoking affect endothelium-dependent arterial dilation through inhibition of nitric oxide synthase. Some authors (Bernhard et al., 2005) set out to explain the mechanisms by which cigarette smoke constituents affect vascular endothelial integrity. They showed that cigarette smoke contains metals (like Cd and Pb) that catalyze the direct oxidation of cellular proteins by smoke oxidants. The oxidation of cellular proteins causes a loss of microtubule stability, culminating in microtubule depolymeratization. In consequence cytoskeletal structures break down, leading finally to a contraction of vascular endothelial cells. The oxidative stress and the endothelial dysfunction were already mentioned above, as the manifestation of the smoke-induced damage. Such data may be used to explain numerous epidemiological results, according to which in the elderly smokers there is an increased risk of ischemic cardiopathies (Benfante et al., 1991), ictus (Shinton and Beevers, 1989) and silent strokes (Howard et al., 1998), aneurysma of the abdominal aorta (Auerbach and Garfinkel, 1980), obliterating arteriopathies of the lower limbs and erectile dysfunctions (Tengs and Osgood, 2001). After a cardiac event requiring hospitalization as many as 50% of patients continue their smoking habit and so there is further potential to reduce the risk of recurrent coronary disease. Advise to stop smoking motivates patients to seek help and to attempt to stop smoking (Van Berkel et al., 1999). More than 1 in every 10 cardiovascular deaths in the world in the year 2000 were attributable to smoking, demonstrating that it is an important preventable cause of cardiovascular mortality (Ezzati et al., 2005). Lung cancer is the most frequent tumor observed in smokers, and represents actually the first cause of death for neoplastic diseases worldwide. The risk of lung cancer is strongly associated to the elderly people who started smoking at young ages, because the effects of smoke become clinically evident usually after about 40 years of smoking habit. On the whole, about 85% of lung cancer cases can be attributed to smoking, which means in Italy about 25,000 death cases every year. The carcinogenic effects of smoking are manifested also to a more or less pronounced extent in numerous organs, too. A significantly increased risk of tumors in smokers has widely been documented in the oral cavity, pharynx, larynx, esophagus, kidney, bladder, pancreas, and also for leukemias and lymphomas. Cigarette smoking induces senescence in alveolar epithelial cells and this induction may contribute to impaired re-epithelialization, leading to cigarette smoking-related chronic lung disease (Tsuji et al., 2004). As regards the pulmonary emphysema, in a large part of smokers an acquired deficit of a1-antitrypsin can be observed. Smoking plays an important role also in the development of other pathological conditions being particularly frequent in geriatric ages. For example, the bone mass decreases in the elderly smokers, both in men and women, and increases the risk of fractures (Hollenbach et al., 1993; Law and Hackshaw, 1997). Also the endocrine system displays numerous modifications, in particular, increased insulin secretion and insulin-resistance, increased risk of Type 2 diabetes, (Meisinger et al. 2006), increased levels of circulating b-endorphines, cortisol, ACTH, vasopressine and decrease of prolactin (Black, 1990). A number of modifications are also observed in the digestive system, in particular, increased secretion of gastric acid, decrease of the pancreatic secretion, decrease of the tone of the lower esophageal sphincter, increase of the gastro-esophageal and duodeno- gastric refluxes. These data explain the higher incidence of peptic ulcer in smokers (Myren, 1988), both of gastric and duodenal types, and also a delay in their healing. The role of smoking may take also some controversary character in the light of several epidemiological data regarding the Alzheimer and Parkinson diseases. Indeed, several authors hypothesized the existence of a protective role of smoking against these pathologies, considering the stimulatory actions of nicotine on the cholinergic and dopaminergic systems (Perez-Stable et al., 1998). Nevertheless, a wide population study (Ott et al., 1998) has shown that the risk of dementia in general, and the risk of Alzheimer disease in particular, is significantly higher in smokers than in non-smokers. Most recently a study showed that current smokers aged >75 years perform more poorly on cognitive tests and appear to decline in memory more rapidly than their peers who do not smoke, especially if they lack the APOE-epsilon4 allele. In this study smoking does not affect cognitive performances in those persons aged