Acarbose in the Treatment of Chronic Obstructive Pulmonary Disease

Background: Atherosclerosis may be the main cause of aging and death.

Methods: All patients with sickle cell diseases (SCD) were included.

Results: We studied 222 males and 212 females with mean ages of 30.8 vs 30.3 years, p>0.05, respectively. Smoking (23.8% vs 6.1%, p<0.001), alcohol (4.9% vs 0.4%, p<0.001), transfused red blood cells (RBC) in their lifespans (48.1 vs 28.5 units, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p<0.001), ileus (7.2% vs 1.4%, p<0.001), chronic obstructive pulmonary disease (COPD) (25.2% vs 7.0%, p<0.001), coronary heart disease (CHD) (18.0% vs 13.2%, p<0.05), cirrhosis (8.1% vs 1.8%, p<0.001), leg ulcers (19.8% vs 7.0%, p<0.001), clubbing (14.8% vs 6.6%, p<0.001), chronic renal disease (CRD) (9.9% vs 6.1%, p<0.05), and stroke (12.1% vs 7.5%, p<0.05) were all higher in males.

Conclusion: As an accelerated atherosclerosis, hardened RBC-induced capillary endothelial damage initiating at birth terminates with multiorgan failures in early years of life in SCD. Excess fat tissue may be much more important than smoking and alcohol for atherosclerosis because excess weight-induced diabetes mellitus is the most common cause of CRD, and CHD and stroke are the main causes of deaths even in the COPD. The efficacy of acarbose to lower blood glucose by preventing breakdown of starch into sugar in the small intestine is obvious. Since acarbose is a safe, cheap, oral, and effective drug for excess weight, it should be advised in COPD because there are nearly 20 kg of excess fat even between upper and lower borders of normal weight in adults.

Chronic endothelial damage may be the main cause of aging and death by means of atherosclerotic multiorgan insufficiencies in human being [1]. Much higher blood pressures (BP) of the afferent vasculature may be the chief accelerating factor via recurrent injuries on vascular endothelium. Probably, whole afferent vasculature including capillaries are chiefly involved in the process. Therefore, venosclerosis or phlebosclerosis is not as famous as atherosclerosis in medicine. Due to the chronic endothelial injury, inflammation, edema, and fibrosis, vascular walls thicken, their lumens narrow, and they lose their elastic natures, those eventually reduce blood supply to terminal organs, and increase systolic and decrease diastolic BP further. Some of the well-known accelerating factors of the inflammatory process are sedentary lifestyle, physical inactivity, animal-rich diet, emotional stresses, smoking, alcohol, excess fat tissue, chronic inflammations, prolonged infections, and cancers for the development of terminal consequences including obesity, hypertension (HT), diabetes mellitus (DM), coronary heart disease (CHD), cirrhosis, chronic obstructive pulmonary disease (COPD), chronic renal disease (CRD), stroke, peripheric artery disease (PAD), mesenteric ischemia, osteoporosis, dementia, early aging, and premature death [2,3]. Although early withdrawal of the accelerating factors can delay the above terminal consequences, after development of them, the endothelial changes cannot be reversed, completely due to their fibrotic natures. The accelerating factors and terminal consequences of the vascular endothelial process are researched under the titles of metabolic syndrome, aging syndrome, and accelerated endothelial damage syndrome in medicine [4-6]. Similarly, sickle cell diseases (SCD) are chronic inflammatory and destructive processes on vascular endothelium, initiating at birth and terminating with an accelerated atherosclerosis-induced multiorgan failures in much earlier ages [7,8]. Hemoglobin S causes loss of elastic and biconcave disc shaped structures of red blood cells (RBC). Probably loss of elasticity instead of shape is the main problem since sickling is rare in peripheric blood samples of cases with associated thalassemia minors (TM), and human survival is not affected in hereditary spherocytosis or elliptocytosis. Loss of elasticity is present during whole lifespan, but exaggerated with inflammations, infections, and additional stresses. The hardened RBC-induced chronic endothelial injury, inflammation, edema, and fibrosis terminate with tissue hypoxia in whole body [9]. As a difference from other causes of chronic endothelial damage, SCD keep vascular endothelium particularly at the capillary level since the capillary system is the major distributor of the hardened RBC into the tissues [10,11]. The hardened RBC-induced chronic endothelial injury builds up an accelerated atherosclerosis in much earlier ages. Vascular narrowing’s and occlusions-induced tissue ischemia and multiorgan failures are the terminal consequences, so the mean life expectancy is decreased by 25 to 30 years for both genders in the SCD [8].

The study was done in the Medical Faculty of the Mustafa Kemal University between March 2007 and June 2016. All cases with the SCD were studied. The SCD were diagnosed with the hemoglobin electrophoresis performed by means of high-performance liquid chromatography (HPLC). Health histories including smoking, alcohol, acute painful crises per year, transfused units of RBC in their lifespans, leg ulcers, stroke, surgical procedures, deep venous thrombosis (DVT), epilepsy, and priapism were learnt. Cases with a history of one pack-year were accepted as smokers, and one drink-year were accepted as drinkers. A full physical examination was performed by the Same Internist, and cases with disseminated teeth losses (<20>

The study included 222 males and 212 females with similar ages (30.8 vs 30.3 years, p>0.05, respectively), and there was no patient above the age of 59 years neither in males nor in females. Prevalence’s of associated TM were similar in males and females (72.5% vs 67.9%, p>0.05, respectively). Smoking (23.8% vs 6.1%) and alcohol (4.9% vs 0.4%) were both higher in males (p less than 0.001 for both) (Table 1). Transfused units of RBC in their lifespans (48.1 vs 28.5, p=0.000), disseminated teeth losses (5.4% vs 1.4%, p less than 0.001), ileus (7.2% vs 1.4%, p less than 0.001), COPD (25.2% vs 7.0%, p less than 0.001), CHD (18.0% vs 13.2%, p less than 0.05), cirrhosis (8.1% vs 1.8%, p less than 0.001), leg ulcers (19.8% vs 7.0%, p less than 0.001), digital clubbing (14.8% vs 6.6%, p less than 0.001), CRD (9.9% vs 6.1%, p less than 0.05), and stroke (12.1% vs 7.5%, p less than 0.05) were all higher in males, significantly. Although the mean age of mortality (30.2 vs 33.3 years) was lower in males, the difference was nonsignificant, probably due to the small sample size (Table 2). On the other hand, mean ages of the atherosclerotic consequences were shown in Table 3.

Table 1: Characteristic features of the study patients.

*Sickle cell diseases; †Nonsignificant (p>0.05); ‡Thalassemia minors

Table 2: Associated pathologies of the study patients.

*Sickle cell diseases; †Nonsignificant (p>0.05); ‡Red Blood Cells; §coronary heart disease; Chronic Obstructive Pulmonary Disease; **Chronic Renal Disease; ***Pulmonary Hypertension; ****Deep Venous Thrombosis; *****Acute Chest Syndrome

Table 3: Mean ages of consequences of the sickle cell diseases.

*Acute chest syndrome; †Chronic obstructive pulmonary disease; ‡Pulmonary hypertension; §coronary heart disease; ¶Deep venous thrombosis; **Chronic renal disease

Excess weight may be the most common cause of vasculitis, and actually the term should be replaced with excess fat tissue in medicine. Probably, obesity is one of the endpoints of the metabolic syndrome, since after development of obesity, nonpharmaceutical approaches provide little benefit either to reverse obesity or to prevent its consequences. Excess fat leads to a chronic and low-grade inflammatory process on vascular endothelium, and risk of death from all causes including cardiovascular diseases and cancers increases parallel to the range of excess fat [19]. The low-grade chronic inflammation may also cause genetic changes on the endothelial cells, and the systemic atherosclerosis may even decrease the clearance of malignant cells by natural killers [20]. The chronic inflammatory process is characterized by lipid-induced injury, invasion of macrophages, proliferation of smooth muscle cells, endothelial dysfunction, and increased atherogenicity [21,22]. Excess fat is considered as a strong factor for controlling of C-reactive protein (CRP) concentration in serum, since excess fat tissue produces biologically active leptin, tumor necrosis factor-alpha, plasminogen activator inhibitor-1, and adiponectin-like cytokines [23,24]. On the other hand, individuals with excess fat will also have an increased cardiac output. The prolonged increase in blood volume may aggravate myocardial hypertrophy and decrease cardiac compliance further. Beside the systemic atherosclerosis and HT, fasting plasma glucose (FPG) and serum cholesterol increased and high-density lipoproteins (HDL) decreased parallel to the increased body mass index (BMI) [25]. Similarly, CHD and stroke increased parallel to the increased BMI [26]. Eventually, the risk of death from all causes including atherosclerotic end-organ failures and cancers increased parallel to the severity of excess fat in all age groups, and the cases with underweight may even have lower biological ages and longer survival [27]. Similarly, calorie restriction prolongs survival and retards age-related chronic diseases [28].

Smoking may be the second most common cause of vasculitis in human being. Probably, it causes a systemic inflammation on vascular endothelial cells terminating with an accelerated atherosclerosis-induced multiorgan failures in early years of life [29]. Its atherosclerotic effect is obvious in the COPD and Buerger’s disease [30]. Buerger’s disease is an obliterative vasculitis characterized by inflammatory changes in the small and medium-sized arteries and veins, and it has never been reported in the absence of smoking. Its characteristic findings are acute inflammation, fibrosis, and narrowing and occlusions of arteries and veins, particularly in the hands and feet. Probably, claudication is the most common symptom in Buerger's disease. It is an intense pain caused by insufficient blood supply during exercise in feet and hands but it may even develop at rest in severe cases. It typically begins in extremities but it may also radiate to more central areas in advanced cases. Numbness or tingling of the limbs is also common. Raynaud's phenomenon may also be seen in which fingers or toes turn a white color upon exposure to cold. Skin ulcerations and gangrene of fingers or toes are the final consequences. Gangrene of fingertips may even need amputation. Similar to the venous ulcers, diabetic ulcers, leg ulcers of the SCD, digital clubbing, onychomycosis, and delayed wound and fracture healings of the lower extremities, pooling of blood due to the gravity may be important in the development of Buerger's disease, particularly in the lower extremities. Angiograms of upper and lower extremities are diagnostic. In angiogram, multiple narrowings and occlusions in the arms and legs are seen. In order to rule out some other forms of vasculitis, it is sometimes necessary to perform angiograms of other body areas. Skin biopsies are rarely required since a biopsy site near a poorly perfused area will not heal, completely. Association of Buerger's disease with tobacco use, particularly cigarette smoking is clear. Although most patients are heavy smokers, some cases with limited smoking history have also been reported. The disease can also be seen in users of smokeless tobacco. The limited smoking history of some patients may support the hypothesis that Buerger's disease may be an autoimmune reaction triggered by some constituent of tobacco. Although the only treatment way is complete cessation of smoking, the already developed narrowings and occlusions are irreversible. Due to the obvious role of inflammation, anti-inflammatory dose of aspirin plus low-dose warfarin may be effective to prevent microvascular infarctions in fingers and toes. On the other hand, FPG and HDL may be negative whereas triglycerides, low density lipoproteins (LDL), erythrocyte sedimentation rate, and CRP may be positive acute phase reactants indicating such inflammatory effects of smoking on vascular endothelial cells [31]. Similarly, smoking was associated with the lower BMI values due to the systemic inflammatory effects [32]. In another definition, smoking causes a chronic inflammation in human body [33]. Additionally, an increased heart rate was detected just after smoking even at rest [34]. On the other hand, nicotine supplied by patch after smoking cessation decreased caloric intake in a dose-related manner [35]. According to an animal study, nicotine may lengthen intermeal time, and decrease amount of meal eaten [36]. Smoking may be associated with a postcessation weight gain, but the risk is the highest during the first year, and decreases with the following years [37]. Although the CHD was detected with similar prevalences in both genders, prevalences of smoking and COPD were higher in males against the higher prevalences of white coat hypertension, BMI, LDL, triglycerides, HT, and DM in females [38]. Beside that the prevalence of myocardial infarction is increased three-fold in men and six-fold in women who smoked at least 20 cigarettes per day [39]. In another definition, smoking may be more dangerous for women about the atherosclerotic consequences probably due to the higher BMI. Several toxic substances found in the cigarette smoke-induced vascular endothelial inflammation can affect various organ systems. For example, smoking is usually associated with depression, irritable bowel syndrome (IBS), chronic gastritis, hemorrhoids, and urolithiasis [40]. There may be several underlying mechanisms to explain these associations [41]. First of all, smoking may have some antidepressant properties with several side effects. Secondly, smoking-induced vascular endothelial inflammation may disturb epithelial functions for absorption and excretion in the gastrointestinal and genitourinary tracts which may terminate with urolithiasis, loose stool, diarrhea, and constipation. Thirdly, diarrheal losses-induced urinary changes may cause urolithiasis [42]. Fourthly, smoking-induced sympathetic nervous system activation may cause motility problems in the gastrointestinal and genitourinary tracts terminating with the IBS and urolithiasis. Eventually, immunosuppression secondary to smoking-induced vascular endothelial inflammation may terminate with the gastrointestinal and genitourinary tract infections causing loose stool, diarrhea, and urolithiasis, because some types of bacteria can provoke urinary supersaturation, and modify the environment to form crystal deposits in the urine. Actually, 10% of urinary stones are struvite stones which are built by magnesium ammonium phosphate produced by the bacteria producing urease. Parallel to the results above, urolithiasis was detected in 17.9% of cases with the IBS and 11.6% of cases without the IBS (p<0>

Beside the stroke, CHD is the other terminal cause of death in human being. The most common triggering event is the disruption of an atherosclerotic plaque in an epicardial coronary artery, which leads to a clotting cascade. The plaque is a gradual and unstable collection of lipids, fibrous tissue, and white blood cells (WBC), particularly the macrophages in arterial walls in decades. Stretching and relaxation of arteries with each heart beat increases mechanical shear stress on atheromas to rupture. After the myocardial infarction, a collagen scar tissue takes its place which may also cause life threatening arrhythmias since the scar tissue conducts electrical impulses more slowly. The difference in conduction velocity between the injured and uninjured tissue can trigger re-entry or a feedback loop that is believed to be the cause of lethal arrhythmias. Ventricular fibrillation is the most serious arrhythmia that is the leading cause of sudden cardiac death. It is an extremely fast and chaotic heart rhythm. Ventricular tachycardia may also cause sudden cardiac death that usually results in rapid heart rates preventing effective cardiac pumping. Cardiac output and BP may fall to dangerous levels which can lead to further coronary ischemia and extension of the infarct. This scar tissue may even cause ventricular aneurysm, rupture, and sudden cardiac death. Aging, physical inactivity, sedentary lifestyle, animal-rich diet, excess fat tissue, emotional stresses, smoking, alcohol, prolonged infections, chronic inflammations, and cancers are important in atherosclerotic plaque formation. Moderate physical exercise is associated with a 50% reduced incidence of CHD [43]. Probably, excess fat tissue may be the most important cause of CHD since there are nearly 20 kg of excess fat tissue between the lower and upper borders of normal weight, 35 kg between the obesity, 66 kg between the morbid obesity (BMI ≥ 40 kg/m2), and 81 kg between the super obesity (BMI ≥ 45 kg/m2) in adults. In fact, there is a significant percentage of adults with a heavier fat mass than their organ plus muscle masses in their bodies that brings a heavy stress both on the heart and brain.

Cirrhosis was the 10th leading cause of death for men and the 12th for women in the United States in 2001 [6]. Although the improvements of health services worldwide, the increased morbidity and mortality of cirrhosis may be explained by prolonged survival of the human being, and increased prevalence of excess fat tissue all over the world. For example, nonalcoholic fatty liver disease (NAFLD) affects up to one third of the world population, and it became the most common cause of chronic liver disease even at childhood, nowadays [44]. NAFLD is a marker of pathological fat deposition combined with a low-grade inflammation which results with hypercoagulability, endothelial dysfunction, and an accelerated atherosclerosis [44]. Beside terminating with cirrhosis, NAFLD is associated with higher overall mortality rates as well as increased prevalence’s of cardiovascular diseases [45]. Authors reported independent associations between NAFLD and impaired flow-mediated vasodilation and increased mean carotid artery intima-media thickness (CIMT) [46]. NAFLD may be considered as one of the hepatic consequences of the metabolic syndrome and SCD [47]. Probably smoking also takes role in the inflammatory process of the capillary endothelium in liver, since the systemic inflammatory effects of smoking on endothelial cells is well-known with Buerger’s disease and COPD [36]. Increased oxidative stress, inactivation of antiproteases, and release of proinflammatory mediators may terminate with the systemic atherosclerosis in smokers. The atherosclerotic effects of alcohol are much more prominent in hepatic endothelium probably due to the highest concentrations of its metabolites there. Chronic infectious or inflammatory processes and cancers may also terminate with an accelerated atherosclerosis in whole body [48]. For instance, chronic hepatitis C virus (HCV) infection raised CIMT, and normalization of hepatic function with HCV clearance may be secondary to reversal of favourable lipids observed with the chronic infection [48,49]. As a result, cirrhosis may also be another atherosclerotic consequence of the SCD.

Acute painful crises are the most disabling symptoms of the SCD. Although some authors reported that pain itself may not be life threatening directly, infections, medical or surgical emergencies, or emotional stress are the most common precipitating factors of the crises [50]. The increased basal metabolic rate during such stresses aggravates the sickling, capillary endothelial damage, inflammation, edema, tissue hypoxia, and multiorgan insufficiencies. So, the risk of mortality is much higher during the crises. Actually, each crisis may complicate with the following crises by leaving significant sequelaes on the capillary endothelial system all over the body. After a period of time, the sequelaes may terminate with sudden multiorgan failures and death during a final acute painful crisis that may even be silent, clinically. Similarly, after a 20-year experience on such patients, the deaths seem sudden and unexpected events in the SCD. Unfortunately, most of the deaths develop just after the hospital admission, and majority of them are patients without hydroxyurea therapy [51,52]. Rapid RBC supports are usually life-saving for such patients, although preparation of RBC units for transfusion usually takes time. Beside that RBC supports in emergencies become much more difficult in terminal cases due to the repeated transfusions-induced blood group mismatch. Actually, transfusion of each unit of RBC complicates the following transfusions by means of the blood subgroup mismatch. Due to the significant efficacy of hydroxyurea therapy, RBC transfusions should be kept just for acute events and emergencies in the SCD [51,52]. According to our experiences, simple and repeated transfusions are superior to RBC exchange in the SCD [53,54]. First of all, preparation of one or two units of RBC suspensions in each time rather than preparation of six units or higher provides time to clinicians to prepare more units by preventing sudden death of such high-risk patients. Secondly, transfusions of one or two units of RBC suspensions in each time decrease the severity of pain, and relax anxiety of the patients and their relatives since RBC transfusions probably have the strongest analgesic effects during the crises [55]. Actually, the decreased severity of pain by transfusions also indicates the decreased severity of inflammation all over the body. Thirdly, transfusions of lesser units of RBC suspensions in each time by means of the simple transfusions will decrease transfusion-related complications including infections, iron overload, and blood group mismatch in the future. Fourthly, transfusion of RBC suspensions in the secondary health centers may prevent some deaths developed during the transport to the tertiary centers for the exchange. Finally, cost of the simple and repeated transfusions on insurance system is much lower than the exchange that needs trained staff and additional devices. On the other hand, pain is the result of complex and poorly understood interactions between RBC, WBC, platelets (PLT), and endothelial cells, yet. Whether leukocytosis contributes to the pathogenesis by releasing cytotoxic enzymes is unknown. The adverse actions of WBC on endothelium are of particular interest with regard to the cerebrovascular diseases in the SCD. For example, leukocytosis even in the absence of any infection was an independent predictor of the severity of the SCD [56], and it was associated with the risk of stroke in a cohort of Jamaican patients [57]. Disseminated tissue hypoxia, releasing of inflammatory mediators, bone infarctions, and activation of afferent nerves may take role in the pathophysiology of the intolerable pain. Because of the severity of pain, narcotic analgesics are usually required to control them [58], but according to our practice, simple and repeated RBC transfusions may be highly effective both to relieve pain and to prevent sudden death that may develop secondary to multiorgan failures on the chronic inflammatory background of the SCD.

Hydroxyurea may be the only life-saving drug for the treatment of the SCD. It interferes with the cell division by blocking the formation of deoxyribonucleotides by means of inhibition of ribonucleotide reductase. The deoxyribonucleotides are the building blocks of DNA. Hydroxyurea mainly affects hyperproliferating cells. Although the action way of hydroxyurea is thought to be the increase in gamma-globin synthesis for fetal hemoglobin (Hb F), its main action may be the suppression of leukocytosis and thrombocytosis by blocking the DNA synthesis in the SCD [59,60]. By this way, the chronic inflammatory and destructive process of the SCD is suppressed with some extent. Due to the same action way, hydroxyurea is also used in moderate and severe psoriasis to suppress hyperproliferating skin cells. As in the viral hepatitis cases, although presence of a continuous damage of sickle cells on the capillary endothelium, the severity of destructive process is probably exaggerated by the patients’ own WBC and PLT. So, suppression of proliferation of them may limit the endothelial damage-induced edema, ischemia, and infarctions in whole body [61]. Similarly, final Hb F levels in hydroxyurea users did not differ from their pretreatment levels [62]. The Multicenter Study of Hydroxyurea (MSH) studied 299 severely affected adults with the SCA, and compared the results of patients treated with hydroxyurea or placebo [63]. The study particularly researched effects of hydroxyurea on painful crises, ACS, and requirement of blood transfusion. The outcomes were so overwhelming in the favour of hydroxyurea that the study was terminated after 22 months, and hydroxyurea was initiated for all patients. The MSH also demonstrated that patients treated with hydroxyurea had a 44

As a conclusion, hardened RBC-induced capillary endothelial damage initiating at birth terminates with multiorgan failures in early years of life in the SCD. Excess fat tissue may be much more important than smoking and alcohol for atherosclerosis because excess weight-induced DM is the most common cause of CRD, and CHD and stroke are the main causes of deaths even in the COPD. The efficacy of acarbose to lower blood glucose by preventing breakdown of starch into sugar in the small intestine is obvious. Since acarbose is a safe, cheap, oral, and effective drug for excess weight, it should be advised in COPD because there are nearly 20 kg of excess fat tissue even between the upper and lower borders of normal weight in adults.