Mark Corson

By Y. Kapotth. Indiana University.

It should be noted that the vital functional products of these cells themselves buy cheap feldene 20 mg line, such as lymphokines generic 20 mg feldene visa, interferons generic feldene 20mg online, and interleukins, are very important immunopharmacological drugs. The immune system has an enormous number of antigens that differentiate between ‘own’ and ‘alien’ molecules. It plays a huge role in autoimmune diseases, hypersensitivity reactions in the body to certain irritants, and in transplant rejections. The immune system is vitally important not only for protecting the body from foreign bodies of organic or inorganic origins, but also from our own cells that transform into for- eign cells. It also serves to remove sick, dead, or foreign cells, and, in all likelihood, serves as the body’s primary protection against cancer, suppressing many tumor centers and fre- quently preventing the formation of metastases. They can both increase the general resistivity of the body or its nonspecific immunity, as well as suppress the body’s immune reactions. Hence controlling diseases with immunological agents means either generation of the necessary immunity in the body, or suppression of undesir- able immune reactions. Commercially accessible α-, β-, and γ - interferons are currently used in medicine. Practically the only purely synthetic immunos- timulant drug that is used is levamisole, which was initially proposed as an anthelminthic agent, and it is currently widely used as such. One of them begins with α-bromoacetophenone, the reaction of which with 2-imino-1,3-thiazolidine gives 3-phenacyl-2-imino-1,3-thiazolidine (31. Reacting this product with acetic anhydride gives 3-phenacyl-2-acetylimino-1,3- thiazolidine (31. The ketone group in the resulting compound is reduced to an alcohol using sodium borohydride, and the resulting hydroxyl group in (31. Heating the product in acetic anhydride, the imidazole cycle closes, forming the product (31. Reacting it with 2-imino-1,3-thiazolidine gives 3-(2-phenyl-2-hydroxyethyl)- 2-imino-1,3-thiazolidine (31. Styrene oxide is reacted with aziridine, forming 2-aziridion-1- phenylethanol-1 (31. Treating this with potassium isothiocyanate or thiourea gives 3- (2-phenyl-2-hydroxyethyl)-2-amino-1,3-thiazolidine (31. It is believed that it regulates cellular mech- anisms of the immune system, and the mechanism of its action may be associated with activation and proliferative growth of T-lymphocytes, increased numbers of monocytes and activation of macrophages, and also with increased activity and hemotaxis of neutrophylic granulocytes. It also increases the body’s over- all resistivity and restores altered T-lymphocyte and phagocyte function. It can also fulfill an immunomodulatory function by strengthening the weak reaction of cellular immunity, weakening strong reaction, and having no effect on normal reaction. Levamisole is used for initial and secondary immunodeficient conditions, autoimmune diseases, chronic and reoccurring infections, large intestine adenocarcinoma, helmintosis, and rheumatoid arthritis. Substances of vari- ous pharmacological groups exhibit immunodepressive activity: glucocorticoids, cytostat- ics, and antibiotics (cyclosporine). Glucocorticoids (cortisone, prednisone, methylprednisolone, betamethasone, dexamethasone, 422 31. Immunopharmacological Drugs triamcinolone, and others) are usually used in combination with other immunodepressants, especially in cases accompanied by inflammation. Immunodepressive action of glucocorticoids is connected with a decreased level of lym- phocytes, eosinophiles, and basophiles in the blood, suppression of antigen recognition, and with suppression of the phase of lymphocyte proliferation. Among these drugs, the most widely used primarily for autoimmune diseases are vincristine, methotrexate, and cytarabine. Only methotrexate is seriously and sufficiently recog- nized as an initial drug for treating rheumatoid arthritis. In addition, one of the sulfur analogs of mercaptopurine, azathioprine, has been pro- posed as a cytotoxic drug, and it turned out to be more effective as an immunosuppressant. This is a possibly reason why it is advantageous over mercaptopurine as an immunosup- pressant. The mechanism of action of azathioprine as a cytotoxic drug is not different from the mechanism of action of other antimetabolites. Azathioprine is the primary drug used for transplants, especially for kidney transplants. However, azathioprine is useful in combination with cyclosporine, and it is even preferred in certain cases. Cyclophosphamide: Synthesis and properties of this drug are described in Chapter 30. Second, it kills proliferating cells, and evidently alkylates a certain region of 31. Finally, its action on T-cells is such that despite its overall suppressive effect, it can, in certain environments, suppress the response of these cells to antigens. Cyclosporine A: Cyclosporine A, [R-[R*,R*-(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-L- leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6- octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine) (31. A new era in the development of immunopharmacology began with the discovery of cyclosporines. Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum, Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground. Cyclosporine A is the first drug to affect a specific line of protecting cells of the body.

This may reflect an overgrowth of this organism that might increase initiation and progression of periodontitis order feldene 20 mg otc. This study demonstrates the 47 impact of obesity on systemic inflammation and need for not only periodontal intervention but also obesity counseling to reduce cardiovascular risk buy cheap feldene 20 mg on line. The potential observational evidence for obesity to increase the risk for periodontitis order feldene 20 mg with mastercard, another chronic inflammatory disease has been discussed above. The proposed mechanisms underlying this association are not fully elucidated at present but some lines of evidence exist relating the pathogenesis of these diseases. From early animal experiments it was shown that obese rats were more likely to develop periodontitis than normal rats (Perlstein et al. Obesity is commonly associated high circulating free fatty acids levels which have been shown to directly cause proliferation of the junctional epithelium and bone loss in rat periodontitis lesions (Tomofuji et al. As mentioned earlier, adipose tissue, especially visceral adipose tissue, is an important organ that produces several systemically active substances known as adipocytokines. One study analyzed 49 gingival crevicular fluid levels of tumor necrosis factor-α in young subjects (Lundin et al. Some studies have hypothesized that the association of obesity with periodontitis is inextricably linked with insulin resistance and diabetes. It is hypothesized that this priming of the inflammatory response that causes the immune system to exhibit an exaggerated immune reaction to periodontal pathogens. As already mentioned there is evidence for the independent association of obesity with periodontitis (Saito et al. Proinflammatory cytokines play essential roles in the inflammatory reaction in periodontal disease. The adiopkine leptin stimulates the immune system by increasing cytokine production and phagocytosis by macrophages and increasing oxidative stress (Fantuzzi et 50 al. In obesity leptin upregulates adhesion molecules on endothelial cells, leading to transmigration of monocytes and therefore increased numbers of macrophages. Although reports consistently point to an association between obesity and periodontitis, more longitudinal randomized controlled studies are necessary to further elucidate the complex role of obesity in periodontitis. However, due to increased risks for diseases associated with obesity and the potential impact on periodontal tissues, counseling on obesity is recommended as an important component of patient management in the periodontal office. Management and education of obese patients may necessitate provision of nutritional information which may also impact periodontal health (Chapple, 2009). As already discussed research has shown that obesity can be significantly associated with increased risk of systemic (Kopelman et al. However, until recently interest on the effects of nutrition in the periodontal literature has been minimal. Revival of interest in the association between periodontitis and malnutrition has been largely mitigated through the early hypothesis that deficiencies in certain micronutrients may lead to increased oxidative stress and a decrease in the body’s ability to combat infection. A significant association between poor overall diet quality and higher periodontitis prevalence has been recently reported (Al-Zahrani et al. Due to the multifactorial etiology of the disease, it can be difficult to find direct associations between risk factors and periodontitis. Problems are further increased with a potential risk factor like nutrition due to conflicting opinions on what constitutes an appropriate balanced diet, the use of self-reported diet analysis in epidemiological studies and complications in assessing micronutrient deficiencies among individuals. These issues were present in earlier studies, which reported conflicting results regarding 52 associations between several individual micronutrients and prevalence of periodontitis (Slade et al. Dietary questionnaires have been found to have weak associations with serum biochemistry levels of micronutrients and with a lack of intervention studies, our ability to draw any solid conclusions on causality have been limited (Knutsen et al. Although the nutritional value of these recommendations are adequate for most individuals, small variations in micronutrients such as vitamins and minerals may have an effect on periodontal tissues (Chapple, 2009). Much of the basic research thus far has tested nutrient mechanisms in chronic disease processes other than in periodontal disease; hence, there is a need to consider the influence of nutrient mechanisms and inflammation associated with periodontal disease. Dietary choices are usually based on price, ease of preparation and taste with frank disregard to supplying nutrients to the body (Howarth et al. Although malnutrition will most likely result in macro- and micro-nutrient deficiency, it is also important to note that obese individuals are more likely to consume a diet high in fatty acids and refined carbohydrates and lacking essential vitamins and antioxidants (Mann, 2002). Using data from the National Health Interview Survey it was estimated that on any given day, nearly 50% of the population did not eat any fruit, 80% consumed no vegetables, and most diets were low in vitamin A and C rich foods as well as dietary fiber 53 (Patterson et al. Based on these findings it is likely that periodontal patients are likely to be making poor dietary choices. The type of food consumed has been linked to the development and survival of plaque biofilm, by providing a direct nutrient source or by altering its surrounding environment (Bowden et al. Nutrition is acknowledged to have a significant impact on optimal functioning of the immune response (Boyd et al. Malnutrition is characterized by depletion of antioxidants, immune dysfunction, reduction of T lymphocytes and hormonal disturbances with increased cortisol levels in blood and saliva (Hughes et al. Periodontal infections may be adversely affected by malnutrition with alterations in the oral microbial flora as well as reductions in saliva production and its antibacterial components (Enwonwu, 1995). Studies linking nutritional status and periodontitis have largely focused on a number of micronutrients including the Ascorbic acid (vitamin C), vitamin B-complex, and calcium levels. Of the vitamins, ascorbic acid has received the majority of attention largely due to its historical association with scurvy, which has pronounced effects on the oral cavity (Fain et al 1998). Other forms of periodontal destruction have been noted with the 55 reduction of vitamin C intake.

Fenfluramine is a drug of many effects buy generic feldene 20mg, but medically its primary use has been for weight loss cheap feldene 20mg with mastercard. Studies consistently indicate the drug’s effectiveness for Fenfluramine 161 that purpose cheap feldene 20 mg with amex. Other unwanted actions can include headache, peevish feel- ings, dizziness, tiredness, nausea, vomiting, diarrhea, and frequent urination. Experience indicates that persons need to be weaned off the drug; cold turkey cessation can cause depression or even a medical emergency called “serotonin syndrome. Experimental animals have shown little interest in receiving fenfluramine doses, a classic sign of small addiction potential. Researchers discovered that fenfluramine could be administered in combi- nation with phentermine, an anorectic that works in a different way. Rat experiments showed that fen-phen reduces food intake far more than either drug can do alone, and experience confirmed the same kind of multiplier effect in humans. Such impact allows persons to take lower doses than would be necessary with either drug alone, thereby minimizing any undesired actions of the drugs. Phentermine counteracts fenfluramine’s common sedative quality, allowing users to function more normally. Weight control is one of the most challenging conditions encountered by medical practitioners, and fen-phen became tremendously popular. One study found that almost 90% of 88 obesity patients taking fenfluramine or the closely related drug dexfenfluramine were also taking phentermine and that almost 33% of the 88 patients lacked obesity levels for which these or other anti- obesity drugs were an appropriate treatment. Suddenly, after many years of wide use without much report of alarming adverse effects, in 1997 accounts began associating fenfluramine with rapidly developing fatal heart valve disorders. Food and Drug Administra- tion asked the manufacturer to withdraw fenfluramine and dexfenfluramine from the market. Hot debate then erupted in medical circles about whether heart disease was caused by fenfluramine, phentermine, or the two drugs in combination. Studies purported to confirm that the drugs alone or in combi- nation really did create heart valve affliction. Highly knowledgeable and distin- guished medical authorities took differing stances on the question and raged at one another in scientific journals. An issue also arose of whether fen-phen caused fatal pulmonary hypertension (high pressure in blood circulation to lungs), with researchers reminding fellow scientists that fenfluramine works in ways similar to the anorectic drug aminorex, which had been linked to pulmonary hypertension in the 1960s and was thereafter withdrawn from the market. Particular concern was expressed about fenfluramine’s impact on pul- 162 Fenfluramine monary hypertension and edema among users living or traveling in high al- titudes. Phentermine is a monoamine oxidase inhibitor, and despite a lack of reports about acute adverse interaction with fenfluramine, some researchers noted that a more chronic interaction could cause the kind of heart and pul- monary damage that was appearing. Researchers began reporting organic brain damage from fenfluramine and dexfenfluramine in animal experiments. Investigators now noticed many instances of psychiatric disturbance among persons taking fenfluramine and noted that the disorders implied organic brain damage. The drug was also linked to human angina pectoris (a fright- ening sensation of pain and suffocation typically caused by insufficient oxygen supply to the heart) and to a case of a gangrenous condition resulting in amputation of fingers. As time passed, evidence appeared that the heart valve and pulmonary hypertension disorders could stabilize and even improve after patients stopped taking fen-phen. Scientific debate continues about fenflura- mine’s role in heart ailments and pulmonary hypertension. Despite the beating that fen-phen took from the news media and from many scientists, researchers remain curious about whether the drug combination still has a role in medicine. Even though fenfluramine can cause depression, in- terest arose in possible psychotherapeutic uses. As the twenty-first century began, experimenters reported that fen-phen can ease withdrawal from co- caine. Rat experiments find that fen-phen reduces alcohol intake and elimi- nates alcohol withdrawal symptoms, findings that may be relevant to treatment of alcoholism. Indeed in 1995 one medical practitioner reported suc- cess in treating alcohol and cocaine addicts with fen-phen, sometimes substi- tuting pemoline for phentermine. Experimenters who gave fenfluramine to pregnant mice found no measurable effect on fetal development and no effect on offspring’s ability to perform in learning tests. For primates evidence exists that the drug passes into the fetus and reaches high levels there. Studies comparing the two drugs find little or no difference in effect, although dexfenfluramine was introduced with the hope that it had fewer unwanted actions than fenfluramine when used for weight loss. A re- port praising dexfenfluramine characterized its weight loss capability as equal- ing that produced by the antidepressant fluoxetine (Prozac) or by a combination of ephedrine and caffeine. Diarrhea is noted as a dexfenflura- mine effect, and concern arose that the drug can aggravate glaucoma. De- pending on laboratory manipulations of circumstances, it can promote or diminish panic attacks. Developed in Europe during the 1950s, this drug became available for medical use in the United States during the 1960s. Depending on means of administration (injec- tion, oral) fentanyl can be 10 times stronger than morphine, and fentanyl citrate can be 8 to 100 times stronger. With cancer, the drug is normally given only when a patient is dying and unable to experience enough pain control from other opioids. Fentanyl does not necessarily reduce the amount of pain per se but can make people less aware of discomfort. Fentanyl can alter a person’s spirits, making some- one euphoric or provoking an opposite feeling of sadness and discontent. One dosage format is the fentanyl patch, allowing the drug to be absorbed through the skin. Patches are potent enough in themselves, but a case report tells of one drug abuser who decided to heat a patch and inhale the vapor; he instantly lost consciousness, but prompt attention by skilled medical personnel saved his life.