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The development of drug utilization research was sparked by initiatives taken in Northern Europe and the United Kingdom in the mid-1960s (1, 2). The pioneers of this research understood that a correct interpretation of data on drug utilization requires investigations at the patient level. The ultimate goal of drug utilization research must be to assess whether drug therapy is rational or not. The early work did not permit detailed comparisons of the drug utilization data obtained from different countries because the source and form of the information varied between them.
Figure 1a Utilization of insulin and oral antidiabetic drugs in seven European countries from 1971-1980 expressed in defined daily doses (DDDs) per 1000 inhabitants per day. Figure 1b Utilization of insulin and oral antidiabetic drugs in seven European countries from 1971-1980 expressed in defined daily doses (DDDs) per 1000 inhabitants per day. Drug utilization research developed quickly during the following 30 years and soon became a respectable subject for consideration at international congresses in pharmacology, pharmacy and epidemiology. History has taught us that successful research in drug utilization requires multidisciplinary collaboration between clinicians, clinical pharmacologists, pharmacists and epidemiologists.
Without the support of the prescribers, this research effort will fail to reach its goal of facilitating the rational use of drugs. The WHO Essential Medicines and Health Products Information Portal was designed and is maintained by Human Info NGO. Anti-diabetic medicationAnti-diabetic medications treat diabetes mellitusby lowering glucose levels in the blood. Diabetes mellitus type 2• Diabetes mellitus type 2 (formerly noninsulin-dependentdiabetes mellitus (NIDDM) or adult-onset diabetes) is ametabolic disorder that is characterized by high bloodglucose in the context of insulin resistance and relativeinsulin deficiency. Diabetes mellitus type 2• Type 2 diabetes is initially managed byincreasing exercise and dietary modification.
Insulin• Insulin is usually given subcutaneously, eitherby injections or by an insulin pump. Biguanides• Biguanides reduce hepatic glucose output andincrease uptake of glucose by theperiphery, including skeletal muscle.
Other Biguanides• Phenformin (DBI) was used from 1960sthrough 1980s, but was withdrawn due tolactic acidosis risk.• Buformin also was withdrawn due to lacticacidosis risk.
Sulfonylureas• Sulfonylureas were the first widely used oral anti-hyperglycaemicmedications.
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Lipid Profile, Antidiabetic and Antioxidant Activity of Acacia ataxacantha Bark Extract in Streptozotocin-Induced Diabetic RatsRotimi O. The pioneering work of Arthur Engel in Sweden and Pieter Siderius in Holland (3) alerted many investigators to the importance of comparing drug use between different countries and regions.
To overcome this difficulty, researchers in Northern Ireland (United Kingdom), Norway and Sweden developed a new unit of measurement, initially called the agreed daily dose (5) and later the defined daily dose (DDD) (6). For comparison the prescribed daily doses (PDD) per 1000 inhabitants per day of oral antidiabetic drugs are given for Northern Ireland (UK) and Sweden for 1980 (indicated with an asterisk).
With theexceptions of insulin, exenatide, liraglutide andpramlintide, all are administered orally and arethus also called oral hypoglycemic agents or oralanti hyperglycemic agents.
Theclassical symptoms are polyuria (frequenturination), polydipsia (increased thirst),polyphagia (increased hunger), and weight loss. This is in contrast to diabetes mellitustype 1, in which there is an absolute insulin deficiency dueto destruction of islet cells in the pancreas.
Ifblood glucose levels are not adequatelylowered by these measures, medications suchas metformin or insulin may be needed. Thetherapeutic combination in Type II may includeinsulin, not necessarily because oral agents havefailed completely, but in search of a desiredcombination of effects. Researchof other routes of administration is underway.In acute-care settings, insulin may also begiven intravenously. Although itmust be used with caution in patients withimpaired liver or kidney function, metformin, abiguanide, has become the most commonly usedagent for type 2 diabetes in children andteenagers.
In general,it is prescribed at initial diagnosis in conjunctionwith exercise and weight loss, as opposed to inthe past, where it was prescribed after diet andexercise had failed. They are insulin secretagogues, triggering insulinrelease by inhibiting the KATP channel of the pancreatic beta cells.Eight types of these pills have been marketed in North America, butnot all remain available. Effects of ethanolic extract of Acacia ataxacantha bark on the hepatic glycogen concentration of STZ-induced diabetic ratsTable 1. Effect of administration of ethanolic extract of Acacia ataxacantha bark on serum parameters of streptozotocin-induced diabetic rats3.5. Effects of ethanolic extract of Acacia ataxacantha bark on the serum lipid profile of STZ-induced diabetic ratsTable 2. Effect of the administration of ethanolic extract of Acacia ataxacantha bark on aspartate and alanine aminotransferase activities in streptozotocin induced diabetic rats 3.7.
Effects of ethanolic extract of Acacia ataxacantha bark on the lipid peroxidation in STZ-induced diabetic ratsTable 3. Effects of ethanolic extract of Acacia ataxacantha bark on the superoxide dismutase activity of STZ-induced diabetic rats4.
Effect of administration of ethanolic extract of Acacia ataxacantha bark on serum parameters of streptozotocin-induced diabetic ratsThe influence of administration of ethanolic extract of Acacia ataxacantha bark on serum parameters is shown in Table 2.
Effects of ethanolic extract of Acacia ataxacantha bark on pancreatic superoxide dismutase activities of streptozotocin-induced diabetic ratsFigure 9 shows the effects of ethanolic extract of Acacia ataxacantha bark on the activity of pancreatic superoxide dismutase. The Relationship of Sugar to Population- Level Diabetes Prevalence: An Econometric Analysis of Repeated Cross-Sectional Data. Their demonstration of the remarkable differences in the sales of antibiotics in six European countries between 1966 and 1967 inspired WHO to organize its first meeting on A«Drug consumptionA» in Oslo in 1969 (4). This unit was defined as the average maintenance dose of the drug when used on its major indication in adults.
The number of English-language papers on the subject listed in the Cumulative index medicus rose from 20 in 1973 (when the term A«drug utilizationA«first appeared) to 87 in 1980, 167 in 1990, and 486 in 2000. Multicenter study on self-medication and self-prescription in six Latin American countries. There are differentclasses of anti-diabetic drugs, and their selectiondepends on the nature of the diabetes, age andsituation of the person, as well as other factors. The great advantage ofinjected insulin in Type II is that a well-educatedpatient can adjust the dose, or even takeadditional doses, when blood glucose levelsmeasured by the patient, usually with a simplemeter, as needed by the measured amount ofsugar in the blood.
In general, there are threetypes of insulin, characterized by the ratewhich they are metabolized by the body. There is an immediate releaseas well as an extended-release formulation,typically reserved for patients experiencing GIside-effects.
Effect of the administration of ethanolic extract of Acacia ataxacantha bark on aspartate and alanine aminotransferase activities in streptozotocin induced diabetic rats Tables 3 and 4 show the effect of administration of ethanolic extract of Acacia ataxacantha bark on alanine and aspartate aminotransferase activities in the liver and serum respectively.

Effect of an aqueous extract of Phaseolus vulgaris on the properties of tail tendon collagen of rats with streptozotocin-induced diabetes.
The first study used antidiabetic drugs as an example: it was found that the sum of the DDDs of insulin and oral antidiabetic drugs (about 20 DDDs per1000 inhabitants per day) roughly corresponded to the morbidity due to diabetes after correction for the number of patients treated with dietary regimens alone. Type 2 diabetes makes up about 90% ofcases of diabetes with the other 10% due primarily todiabetes mellitus type 1 and gestational diabetes. Oguntibeju2[1] Department of Biochemistry, Faculty of Science, University of Ilorin, Ilorin, Nigeria[2] Department of Biomedical Sciences, Faculty of Health & Wellness Sciences, Cape Peninsula University of Technology, South Africa1.
DiscussionDiabetes mellitus is a metabolic disorder that has arguably achieved epidemic proportions. Among the first countries to adopt the DDD methodology was the former Czechoslovakia (7) and the first comprehensive national list of DDDs was published in Norway in 1975 (8).
Copenhagen, WHO Regional Office for Europe, 1979 (WHO Regional Publications, European Series No. Obesityis thought to be the primary cause of type 2 diabetes inpeople who are genetically predisposed to the disease. Introduction Diabetes mellitus is a heterogeneous primary disorder of carbohydrate metabolism which exists everywhere in the world and interests approximately 371 million people worldwide. It is known to affect more than 371 million persons globally, and is projected to affect 522 million people by the year 2030 [1, 2 and 11].
Diagnosis, epidemiology and pathogenesis of diabetes mellitus: an update for psychiatrists.
Another important methodological advance was the adoption of the uniform anatomical therapeutic chemical (ATC) classification of drugs (see chapter 5.2).
A2012 study found sulfonylureas raise the risk of death comparedwith metformin.[4]• Sulfonylureas bind strongly to plasma proteins.
The prevalence of diabetes mellitus is increasing with ageing of the population and lifestyle changes associated with rapid urbanization and westernization. Effect of administration of ethanolic extract of Acacia ataxacantha bark on the lipids profile of streptozotocin-induced diabetic ratsFigure 6 shows the effect of ethanolic extract of Acacia ataxacantha bark on serum total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and triglyceride. Phytotherapy for some decades has played an important role in the management of the disease especially in resource-poor countries. Diabetes mellitus and multiple therapeutic approaches of phytochemicals: Present status and future prospects. The use of standardized methodology allowed meaningful comparisons of drug use in different countries to be made (Fig. WHO Regional Office for Europe, Copenhagen, 1979 (WHO Regional Publications European Series No.
The disease is found in all parts of the world and is rapidly increasing in its coverage [1, 2]. Clearly, the identification of plant materials that can manage diabetes and its complications would save millions of people, especially in developing countries, from untimely death. Effects of ethanolic extract of Acacia ataxacantha bark on pancreatic lipid peroxidation of streptozotocin-induced diabetic ratsFigure 8 depicts the effects of ethanolic extract of Acacia ataxacantha bark on the pancreatic lipid peroxidation in STZ - induced diabetic rats. The presence of secondary metabolites such as alkaloids, polyphenols, flavonoid, saponins, tannins, and terpenoid in the ethanolic extract of Acacia ataxacantha bark may contribute to its hypoglyceamic activity and medicinal value.
It is a metabolic disorder initially characterized by a loss of glucose homeostasis with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both [4].
These compounds have been shown to be responsible for hypoglyceamic activity in Momordica charantia [37]. Without enough insulin, the cells of the body cannot absorb sufficient glucose from the blood; hence blood glucose levels increase, which is termed as hyperglycemia. The activities of flavonoids and polyphenol have been ascribed to the structural relationship between different parts of their chemical structures [38].
If the glucose level in the blood remains high over a long period of time, this can result in long-term damage to organs, such as the kidneys, liver, eyes, nerves, heart and blood vessels. Complications in some of these organs can lead to death [5]The roles of certain organs such as the pancreas, liver and kidney in diabetes mellitus are very important.The pancreas plays a primary role in the metabolism of glucose by secreting the hormones insulin and glucagon (Figure 1).
The STZ-induced diabetes causes the destruction of pancreatic ? cells of islets, which leads to a reduction of insulin release and increase in blood glucose.
STZ – induced diabetes has been described as a useful experimental model to study the antidiabetic activity of several agents [39]. Insulin is a protein that is essential for proper regulation of glucose and for maintenance of proper blood glucose levels [6].
STZ is well known for its selective pancreatic islet ?-cell cytotoxicity used to induce diabetes mellitus in animals.
Glycemic effects of ethanolic extract of Acacia ataxacantha bark in streptozotocin-induced diabetic rats3.3. It increases blood glucose concentration partly by breaking down stored glycogen in the liver by a pathway known as glycogenolysis. This observed hyperglycemia may be due to induced gluconeogenesis in the absence of insulin [40]. Gluconeogenesis is the production of glucose in the liver from non-carbohydrate precursors such as glycogenic amino acids [7].WHO classification of diabetes introduced in 1980 and revised in 1985 was based on clinical characteristics.
The two most common types of diabetes were insulin-dependent diabetes mellitus (IDDM) or (type I) and non-insulin-dependent diabetes mellitus (NIDDM) or (type II). These decreases could be due to the direct stimulation of the secretion of insulin thus promoting glucose uptake metabolism by inhibiting hepatic gluconeogenesis through the stimulation of a regeneration process and revitalization of the remaining beta cells [41]. WHO classification also recognized malnutrition-related diabetes mellitus and gestational diabetes.
The increased levels of hepatic glucose in streptozotocin - induced diabetic rats were reduced following the administration of ethanolic extract of Acacia ataxacantha bark.
Malnutrition-related diabetes was omitted from the new classification because its etiology is uncertain, and it is unclear whether it is a separate type of diabetes [8, 9, and 10].International Diabetes Federation [11] reported that one in 10 adults will have diabetes by 2030, posing a huge challenge to health care systems around the world. The reduced glucose levels suggests that ethanolic extract of Acacia ataxacantha bark may have exerted insulin-like effect on peripheral tissues by either promoting glucose uptake metabolism by inhibiting hepatic gluconeogenesis [42] or by absorption of glucose into the muscle and adipose tissues [43] through the stimulation of a regeneration process and revitalization of the remaining beta cells [42,43].Glycogen is the primary intracellular storable form of glucose in various tissues and its level in such tissues especially the liver is a direct reflection of insulin activity [44]. According to the report, the number of people living with diabetes worldwide will increase to 552 million by 2030 from 366 million in 2011 unless action is taken. But upon oral administration of ethanolic extract of Acacia ataxacantha bark, glycogen content were increased significantly which is comparable to that of metformin, thus confirming its insulin potentiating action to a marked extent. This may be due to the activation of glycogen synthase system and inhibition of glycogen phosphorylase [45] by the extract. However these have been shown to have prominent side effects and they do not modify the course of diabetic complications [13, 14]. It may also be due to decreased enzymatic activities of hexokinase and phosphofructokinase resulting in depletion of liver and muscle glycogen [46]. The need to develop new antidiabetic drugs has led to studies that have attempted to screen some indigenous plants for antidiabetic activity [15, 16].
The concentrations of total protein, bilirubin and albumin may indicate state of the liver and type of damage [47].

Traditional preparations of plant sources are widely used almost everywhere in the world to treat this disease.
Bilirubin is formed by the breakdown of hemoglobin in the liver, spleen and bone marrow [48]. Therefore plant materials are considered to be the alternative sources for finding out new leads for antihyperglycemic agents. The plant drugs are frequently considered to be less toxic when compared to synthetic drugs [17]. More than 1,123 plant species have been used to treat diabetes and more than 200 pure compounds have been shown to possess characteristics of lowering blood glucose activity [18]. The significant increase in the total bilirubin, conjugated bilirubin and albumin levels in the diabetic control rats and reduction following oral administration of ethanolic extract of Acacia ataxacantha bark are indicative of amelioration of the adverse effects caused by diabetes. Acacia ataxacantha or Flame Thorn is an African tree species with conspicuous red pods and numerous hooked prickles.
The kidneys remove metabolic wastes such as urea, uric acid, creatinine and ions and thus optimum chemical composition of body fluids is maintained. It is widespread in sub-Saharan Africa from Senegal in the west to Sudan in the east, Namibia, Botswana, Zimbabwe, and in the Transvaal and KwaZulu-Natal. The concentrations of these metabolites increase in blood during renal diseases or renal damage associated with uncontrolled diabetes mellitus.
In arid regions it prefers low-lying sites near streams, water courses and in valleys, but in higher rainfall areas it is a common member of the vegetation, often favouring forest margins.
The flaking bark is light grey, splitting longitudinally and transversely, and revealing a buff under-colour.
Observed increase in urea and creatinine level in the diabetic control were reduced following the administration of ethanolic extract of Acacia ataxacantha bark to a level close to the value obtained for the normal control. Due to continuous catabolism of amino acid during diabetic state, high quantity of urea will be formed from urea cycle. On the other hand, it may be as a result of repression of glycolytic enzymes, thus glucose is channeled into pentose phosphate pathway resulting in the increased availability of ribose-5-phosphate which may lead to increased formation of phosphoribosyl pyrophosphate (PRPP) and ultimately resulting in high concentration of uric acid in the blood [51].Lipids play a vital role in the pathogenesis of diabetic mellitus. Diabetic is associated with profound alterations in the plasma lipid, triglycerides and lipoprotein profile and with an increased risk of coronary heart disease [52]. The most common lipid abnormalities in diabetes are hypertriglyceridemia and hypercholesterolemia. The increase in the levels of serum lipids such as cholesterol and triglycerides in the diabetic rats may be due to the fact that under normal circumstances, insulin activates lipoprotein lipase and hydrolyses triglycerides.
Experimental animals and reagents36 Albino rats (Rattus norvegicus) with an average weight of 132.5 g were obtained from the Animal Holding Unit of the Department of Biochemistry, University of Ilorin, Ilorin, Kwara State, Nigeria.
Insulin increases uptake of fatty acids into adipose tissue and increases triglyceride synthesis. Animal husbandry and experimentation were consistent with Guiding Principles in the use of Animals in Toxicology [20].
In case of insulin deficiency, lipolysis is not inhibited but an increased lipolysis which finally leads to hyperlipidemia. Plant extract preparationThe bark of Acacia ataxacantha was obtained from Akure, Ondo State, Nigeria.
In diabetic condition, the concentration of serum free acids is elevated as a result of free fatty acid outflow from fat deposited, where the balance of the free fatty acid esterification-triglyceride lipolysis cycle is displaced in favour of lipolysis [53].HDL is an anti-atherogenic lipoprotein.
Identification was carried out at the University Ilorin Herbarium, Department of Plant Biology, Ilorin, Nigeria where voucher number 872 was deposited.
It transports cholesterol from peripheral tissues into the liver and thereby acts as a protective factor against coronary heart disease.
This might be due to increase in the activity of lecithin cholesterol acyl transferase (LCAT), which may contribute to the regulation of blood lipids [54]. The percolated mixture was filtered and evaporated at room temperature according to the method of Majekodunmi et al. Significant lowering of total cholesterol, triglycerides, LDL-cholesterol and rise in HDL-cholesterol is a very desirable biochemical state for prevention of atherosclerosis and ischaemic conditions [55].Liver is the vital organ of metabolism, detoxification, storage and excretion of xenobiotic and their metabolites [56]. Aspartate aminotransferase, alanine aminotransferase, albumin and bilirubin are considered as part of liver toxicity markers [57]. In streptozotocin-induced diabetic animals, change in the serum enzymes is directly related to change in the metabolic functions of aspartate aminotransferase, alanine aminotransferase, albumin and bilirubin [58, 59].
The animals were allowed to drink 5% glucose solution overnight to overcome the drug-induced hypoglycaemia.
It has been reported that the increased aminotransferase activities under insulin deficiency [60] were responsible for the increased gluconeogenesis and ketogenesis during diabetic. Aspartate aminotransferase is an enzyme found mainly in the cell of the liver, heart, skeletal muscles, kidney, and pancreas and to a lesser amount in red blood cells. Its serum concentration is proportional to the amount of cellular leakage or damage and it is released into the serum in larger quantities when any one of these tissues is damaged and its increase is usually associated with heart attack or liver disease. The treatment was started on the fourth day after the STZ injection and this was considered the first day of treatment. While on the other hand, alanine aminotransferase is an enzyme found mainly in the liver and elevated levels in serum usually indicates liver damage [61].
The mechanism by which the serum aspartate and alanine aminotransferases are raised in diabetic untreated may involve increased liberation of these enzymes from tissues (mainly liver), owing to oxidative stress or the formation of advanced glycosylation end product [57]. The increase in the activities of these enzymes in serum of diabetic control might be induced due to liver dysfunction.
Therefore an increase in the activities of ALT and AST in the serum might be mainly due to the leakage of these enzymes from the liver cytosol into the blood stream [63] which gives an indication of hepatotoxic effect of STZ.
Sample preparationAt the end of the experimental period, venous blood was collected from the experimental animals and serum was prepared by centrifuging the blood samples at 3000 rpm for 5 minutes [23] and serum collected by pippeting. Malondialdehyde participate in a variety of chemical and biological reactions including covalent binding to protein, RNA, and DNA.
These may be due to the presence of antioxidant phytochemicals in the extract which reduced the oxidative stress that caused lipid peroxidation thereby reducing the generation of free radicals and thus may have prevented the damage of cellular organelles either by decreasing localized oxygen concentration, presenting first chain initiation by scavenging initial radicals and binding metals or by decomposing peroxide. Antioxidant enzymes have been shown to play important role in maintaining physiological levels of oxygen and hydrogen peroxide by hastening the dismutation of oxygen radicals and eliminating organic peroxide and hydro-peroxides generated from inadvertent exposure to STZ [66]. In the enzymatic antioxidant defense system, SOD is one of the important enzymes that scavenge the superoxide radicals by converting them to hydrogen peroxides and molecular oxygen [67]. The observed decrease in the pancreatic SOD activity in diabetic control rats could result from inactivation by H2O2 or by glycosylation of the enzymes, which has been reported to occur in diabetes [68, 69]. Lipids profile analysis Total cholesterol, triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol were assayed using the method of Zlakis et al. However, the increased SOD activity following oral administration of ethanolic extract of Acacia ataxacantha bark might be due to presence of antioxidant phytochemicals which scavenge the superoxide radical by converting them to hydrogen peroxides and molecular oxygen [67].5.

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