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Diabetes mellitus is one of the diseases that affect many Americans. It has existed it has existed since the B.C era, with the cases expected to rise in future. This led the scientists to concentrate on finding its cure from as early as the disease was discovered. This is an essay about the development of the drug used in cuing the disease, sulfonylurea.
Drug development: sulfonylurea
History of diabetes
The history of the earliest recognition of diabetes and the path to the discovery of insulin was filled with many insights, errors, futile labors, triumphs, and defeats. The best early evidence of a description of the symptoms of diabetes in the world’s literature was recorded in the Ebers papyrus that appears to date from 1550 B.C. This links the description of polyuria to Imhotep, a man of medicine, architecture and magic, who was a high priest and minister to the Pharaoh Zosser in 3,000 B.C. Two Greek physicians in the Roman era, Galen (A.D 130-201) and Arateus, who were from Cappadocia, delineated the disease further. Arateus is credited despite the survival of only fragments of his document, with some of the best descriptions of medicine in the ancient literature. In his work Acute and Chronic Diseases, he coined the term diabetes, meaning “siphon” to explain the “liquefaction of the flesh and bones into urine”. Arateus’ description of diabetes from 150 A.D. was held until the second half of the 17th century.
Early attempts to find the cure for diabetes mellitus
In 1674, Thomas Willis, a physician, an anatomist and a professor of natural philosophy at oxford, discovered (by tasting) that the urine of individuals with diabetes was sweet. He could not however pinpoint the chemical nature of the “sweet” substance because a variety of different chemical substances could be actually sweet if tasted. Matthew Dobson, a doctor fromManchester,England, demonstrated in 1776, that people with diabetes actually excrete sugar in the urine. After boiling urine to dryness, he noted that the residue, a crystalline material, had the appearance of “brown sugar.” John Rollo, A surgeon and General of The Royal Artillery, in 1797, applied the discovery of glycosuria in to the quantitative metabolic study of diabetes. Rollo advised the first rational approach to the dietary treatment of the disease, shifting the current viw that the primary start of the disorder was in the kidneys to a view of its being the gastrointestinal tract. After several researches, he indicated that the treatment of the disease was a diet low in carbohydrates and high in fat and protein.
The development in the discovery of diabetes was advanced by Apollinaire Bouchardat, who followed the essentials of Rollo’s dietary regimen in treating diabetes but added a very important therapeutic arm by encouraging hard physical labor, having observed ameliorative effects of muscular work on glycosuria and hyperglycemia. Yet above all, his clinical experience taught him to distinguish at least two different types of diabetes: the severe type in younger persons who responded poorly to his regimen and the type in older, obese persons for whom the prescribed therapy of diet and physical exertion worked admirably. Between 1921 ad 1922, Fredrick Banting, a young surgeon, John Macleod, a professor of psychology, Charles Best, a graduate student and J.B Collip, a skilled chemist, succeeded in fulfilling all of the criteria for a therapeutically active insulin and produced the first useful and consistently successful insulin preparation for the treatment of human diabetes.( Joslin etal, pg 3-9)
The study of clinical diabetes in the early years of insulin use convinced a young doctor- Dr. Joslin- of the need for different strategies for delivery of care. Half dozen initiatives were incorporated in to his clinic programs, some of which have gained broad acceptance in the decades since their initiation. His main goal was to create team of sub-specialists to maximize the benefit to the patient. The team approach of care was originally an approach to treating diabetic coma. The use special duty nurses with expertise regarding fluid replacement, constant observation of signs and symptoms, and the monitoring of laboratory results was championed by Joslin before the replacement of intravenous fluids to act as phlebotomists for the critically ill and often dehydrated patient was a pioneering step.
In 1928, the team published the first monograph entitled the Diabetic Surgery. This group acknowledged the need for a special foot-dressing nurse to apply frequent bandages to prevent progression of foot lesions. In addition to the surgeon and internists, importance was placed on the team’s schedule of daily and weekly conference rounds, with the inclusion of a chiropodist to preventive foot care with proper booting of the patient. During the 1930s, there was an eruption of information about hormonal regulation of intermediary metabolism. Developments in the field of pharmacology spearhead advances in the clinical isolation of hormones.
In 1938, an American pioneer in the field, J. J. Abel, isolated epinephrine and later produced crystalline insulin, an advance that facilitated production of insulin for therapy. The adrenal gland became a continued focus of investigation, aided by Cushing’s work on human adrenal pathology earlier in the decade. Long’s work on the effect of adrenal hormones on carbohydrate metabolism was a significant step in understanding the regulation of blood sugar in health and disease stakes like diabetes. A study was conducted in late 1930s by two scientists, Atchley and Loeb inNew Yorkon the electrolyte changes in diabetic acidosis. Atchley suggested that they bring well-regulated diabetic patients into the hospital and follow the sequential metabolic changes after discontinuing their insulin.
They selected three patients: in the first, when insulin was taken away, the diabetes was so mild that little changes occurred. The second had more severe diabetes, and the third had very severe diabetes and became seriously ill within a few hours after his insulin was discontinued. Their quantitative observations demonstrated the progressive loss of body water, sodium and potassium. These elegant balance studies represent one of the classic contributions in the evolution of our understanding of the electrolyte changes that occur in diabetes mellitus.
The discovery of sulfonylureas (first generation sulfonylureas)
The search for oral agents to treat hyperglycemia and glycosuria and other signs and symptoms of diabetes mellitus started before the Second World War. In the desperate times of the peninsular era, every available drug was tried, without success. Even following the introduction of insulin treatment, research and trials on orally administered pharmaceuticals (including insulin) continued. The discovery that sulfonylureas were effective oral hypoglycemic agents was accidental. In 1941, Janbon and colleagues in the Infectious Disease Clinic of the Medical School in Montpellier, France, studying the efficacy of a sulfonamide [p-amino-benzene-sulfamido-isopropyl-thiodiazole, (2254 RP)], in the treatment or typhoid fever and pneumonia observed hypoglycemia and seizures, particularly in undernourished patients. Janbon commented on this to Auguste Loubatieres who was studying insulin-induced seizures. Dr. Loubatieres and colleagues between 1942 and 1946 described the hypoglycemic action of a 2254 RP in a series of sophisticated animal experiments. Loubatieres hypothesized a common cause and was able to show that 2254 RP caused hypoglycemia in dogs, an effect that was then abolished by pancratectomy. Subsequent work showed that blood from 2254 RP also reduced glucose in the oldest patient, but was ineffective in the two youngest women.
These studies showed that β-cells were the major target for sulfonylureas and led Loubatieres to propose that “the concentration of the sulfonamide in contact with the inslet cells was the factor responsible for the liberation of insulin” and that 2254 RP was the “agent exciting insulin secretion.” Loubatieres also suggested the sulfonylureas might be used to treat a type of diabetes (type 2) that arose as a result of a “deficiency of insulin secretory mechanisms. (Joslin etal, pg 3-9)
It was not until the mid-1950s that a number of German investigators described the use of another sulfonamide derivative, 1-butyl-3-sulfonamide (carbutamide), for the treatment of certain diabetic patients. In these early publications, it was noted that carbutamide was effective only in non-diabetic and in moderately severe maturity-onset diabetic patients, but it was not effective in patients who had type 1 or insulin-dependent diabetes mellitus. In 1956 the first report of experimental and clinical data on the sulfonamide derivative N-4-methyl-benzoyl-sulphonyl)-N-butyl-carbamide (tolbutamide), a substance virtually free of bacteripstatic, but possessing unequivocal hypoglycemic properties was published. Since then, uncounted reports on an ever-increasing number of sulfonylurea drugs have appeared in the literature.
Second generation sulfonylureas
Sulfonylureas were developed in the U.S from 1975 to1983. These were the second generation sulfonylureas. Developments in sulfonylureas started in the mid 1970s, when John Levitt of noted that the first generation of sulfonylureas exhibited weaknesses. In June 1975, Levitt prepared the second generation of sulfonylurea, to which he strengthened with other properties. By the year 1975, many other developments of the drugs had come up. Through the continued support from other scientists, the second generation of sulfonylurea was soon produced, with an effectiveness of up to 100 times more than the first generation sulfonylureas.
Although they are similar to first generation agents, second generation sulfonylureas are more potent and lack some of the side effects seen with older agents. As a result, they have largely replaced first-generation agents in the clinical setting. Of the second-generation sulfonylureas available, the glipizide extended release and glimepiride formulations have the convenience of maximum effectiveness with once-a-day dosing and the potential for greater long-term compliance. Glipizide extended release (Glucontrol XL®) provides controlled release of the short-acting sulfonylurea.
Once-daily administration provides effective control of plasma glucose concentrations throughout the 24-hour dosing interval, with less peak-to-through fluctuation than conventional glipizide. A multi-center, open-label, randomized, two-way crossover study demonstrated that extended release glipizide is as effective as conventional glipizide in lowering postprandial plasma glucose levels but it is significantly more effective in reducing FPG levels than conventional glipizide at week of treatment. (Porte D, 2002, pg 533-535)
Comparison between the first generation and the second generation sulfonylureas
The second generation sulfonylureas have several advantages over the first generation sulfonylureas. The first advantage is that second-generation drugs, although having an acute effect on pancreatic insulin secretion, have their primary, long-term effect on stimulating insulin receptors and have some post receptor effect. Since the pathology of Type 2 diabetes may be the receptor and post receptor abnormalities, it makes sense to use the drugs that work at that level. The second reason for using second-generation drugs is drug-drug interaction. The first generation drugs are carried in the plasma bound to albumin. Many other drugs are carried in the same way and may displace these drugs or be displaced by them, crating drug-drug interaction, which can create serious toxic effects or eve death.
Second-generation drugs are transported in the plasma nonionically, bound to albumin and do not compete for binding sites with other drugs. They are therefore safer to use particularly in older patients who are taking multiple drugs for other conditions such as heart disease, hypertension, neuropathy, arthritis, and so forth. Modern diabetologists almost universally recommend the nearly exclusive use of second-generation oral agents. If people who have Type 2 diabetes are doing well on a first-generation oral hypoglycemic agent, they probably should not be changed. If they are not doing well on a first-generation agent or they are an older generation individual with any kidney dysfunction, they should not be changed to a second generation agent. (Guthrie R.A. pg 154-155)
Third generation sulfonylureas
Third generation sulfonylureas were introduced in the 1990s in theU.S.They were just an improvement of the second generation. Glimepiride is the major third generation Sulfonamide, before then, it had been used as a second generation drug. The major reason for the development of the third generation sulfonylurea was because it has a set quick of action and a long duration, may bind to a different protein in the putative sulfonylurea receptor than earlier drugs, and may exert its hypoglycemic effect with less secretion of insulin.
In the development of the third generation sulfonylurea, several experiments were done on mice. Glimepiride reduced serum glucose by 40%, plasma insulin by 50%, and HbA by 33%, whereas glyburide had no effect on these parameters. In the dog, glimepiride exhibits a lower ratio of insulin-increasing ratio of insulin-increasing to glucose-lowering activity, which is thought to represent the most unusual of the earlier sulfonamides. The tests were then done on diabetes mellitus patients. Results showed that these were much more effective than the first generation and second generation sulfonylurea. They could be taken in much less amounts, and for a shorter time. It also has the benefits of reduced risks of hypoglycemia, potentially lower risk of adverse cardiovascular effects, and perhaps reduced potential for secondary failure.
Classification of sulfonylureas
In summary, sulfonylurea drugs have been marked as generations, with tolbutamide, chlorpropamide, tolazamide, and acetohexamide being coined as first-generation sulfonylureas. Today, these drugs have been almost completely replaced by the second-generation sulfonylureas, namely glibenclamide, gliclazide, glimepiride, and gliquidone, which are much more potent on an effect-to-weight basis. Most recently, a third-generation sulfonylurea, glimepiride, and the benzoic acid derivative repaglinide have been introduced into various international markets, in an attempt to decrease the risks of iatrogenic hypoglycemia. (Davidson, 2000, 416-417)
Characteristics of first, second and third generation sulfonylureas
The mentioned classifications are based on several distinguishing characteristics. First, sulfonylureas are categorized based on their potency. The second generation sulfonylureas are approximately 200 times more potent than the first generation drugs. Second, these drugs are distinguished based on their potential for adverse effects, with the first generation sulfonylureas having much greater potential for adverse effects. Third, the first-and-second-generation drugs differ in their binding to serum proteins; this also affects their risk of drug interactions.
The discovery of the cure for diabetes mellitus has definitely had numerous effects on the American economy. A lot of investment in terms of cash has been directed towards improving treatment of the disease. However, the government should also allocate more money to the research and development for finding better the cure for the disease, and for campaigning against the disease. Research has also shown that many American are spending their money in hospitals for treatment of the disease. This could be avoided, if only Americans could eat healthy to avoid being diabetic. It has also been said that the money spent in trying to prevent the disease would be less than that used in its treatment. (Porte, 2002) Doctors recommend exercise and healthy eating to prevent diabetic conditions. The impact the disease has on the economy may not be seen to day, but if we do not reduce the rates at which diabetics are increasing, the effects of the disease in the economy will be seen. Moreover, due to the increasing cases of diabetics, there has been a reduction of labor output in the industries. The sickness reduces the work output of labors, with the rate increasing in the past few years. It would best be advisable for Americans to keep healthy to avoid becoming a diabetic.