Traditional medicine systems are part of India's culture. Today the whole world has become increasingly interested in Indian ayurveda and other traditional health systems. The demand for medicinal plants is increasing in both developing and more-developed countries as a result of recognition of lack of side effects and easy availability of many herbal drugs.
Ayurveda the traditional Indian system of medicine is as old as the Indian culture and civilization. The term ayurveda means science of life's Ayur means life and veda means knowledge. The ayurveda deals with physical body, herbal medicines, diet, surgery, pshycology, spirituality and religion. Thr therapeutic realm of Ayurveda is based on Tridhosa theory. They are vata, pitta and kapha according to Ayurvedic principles any disturbance in the above constituents may result to diseased state. Ayurveda has well classified Materia medica consisting mainly of drug of plant origin. Various part of plants, roots, rhizomes, stem, leaf, flowers, fruits, bark, extrudates have been employed for therapeutic purpose currently some 1250 plants find uses in Ayurvedic Materia medica. Earliest description of curative properties of medicinal plants was found in Rigveda. Also Charaka samhita and susrutha samhita give extensive description of various medicinal herbs (Kokate et al 2006).
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The ancient healing system from India has steadily increased its popularity in all over the world. This 5000 year old system of medicine recommends a combination of lifestyle management and treatment with specific herbs to cure various diseases. Plants have been the major source of medicine in Ayurveda. Indian folk medicines comprises numerous prescription for therapeutic purposes which may be as varied as healing wounds, treating inflammation due to infections, skin lesions, leprosy, diarrhea, scabies, veneral diseases, snake bites and ulcers etc. A complex disorder like diabetes was little is talked about in aspects of prevention and curation, but rather management. There are so many plants in Ayurveda, which are having hypoglycemic and antihyperglycemic activity. Because of leads provided by traditional medicine to natural products that may be better than currently used allopathic medicine. The ancient physicians also prescribed specific formulation for the treatment of diabetes, some of the drugs with a record of high safety and efficacy which have been validated recently (Bishwas NR et al 1998, Majeed M and Prakash L 2006).
The word siddha comes from siddhi, which means on object to be attained or perfection of heavenly bliss. Siddhars were saintely personalities who attained proficiency in medicine through practice of bhakthi and yoga. Siddha system originated from 18 siddhars Agastiar. this is the system of pre-vedic period and identified with Dravidian culture and it is largely therapeutic in nature. According to siddhantic physicians everything founds in nature have two qualities good and bad; when they are utilized for any purpose they have two actions in medicine. The good action is called "Nalvinai" and the bad action is called "Theevinai". The universe originally consisted of atoms which contributed to five basic eliments, viz. earth, water, fire, and ether which synchronize with the five senses of human body. The identification of causative factors of diaseases is done through pulse reading, colour of body, study of voice, urine examination, status of digestive system and examination of tongue. Siddha is essencially a psychometric system where in alteration as given to minerals and metals rather than plant constituents. Herbs are used only to triturate and calcinate metals into their bhasmam and sindooram. The deep rooted difficulties in the siddha system are the lack of scientific validation of the therapeutic claims based drugs using standardize clinical models (Kokate et al 2006).
The roots of unani system go deep to the time of well known Greek philosophers Hippocrates and Aristotle Golen. It is known as Greco-Arabic systems of Islamic medicine. This system of medicine is originated in the fourth and fifth centuries B.C. the system is based on the two theories viz. the Hippocratic theory of four humours and the pythagorian theory of four proximate qualities. The humoural theory of medicine forms the basic principles of unani system are blood, phlegm, yellow bile and black bile, which represents the states of human body like hot, cold, moist and dry. Many dietary ingredients, vegetables, fruits etc. are also classified to Hot and cold.
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The maintenance of the humoural is based on the above hypothesis and medicaments are given to correct the humoural balance. The unani system of medicine aims treating the cause of disease and not its symptoms. For this purpose, through history the patient is recorded in addition to his pulse, urine, and stool examinations. The diseased condition is considered to be due to the imbalance between humours and accordingly treatment is given. The unani medicinal system advocates the usage of naturally occurring herbal medicines (Kokate et al 2006).
Homeopathy system is newer when compared with other alternative systems and was introduced by the German physician Dr. Christian Frederick Samule Hehniman in the 18th century. This system is based on his principle of like cures like. It aims to stimulates body's vital force to such a point that the body can overcome the diseases and gets back to the normal health without causing any adverse side effects. The drug treatment in this system is not specified, but the choice of drug depends on symptoms and clinical condition of patient. The symptoms are compared with similar symptoms and accordingly the same extract is given for treatment. During treatment the drug extracts are extremely diluted, which is believed to cause potentiation and enhancement of curative effect. Homeopathic system in general is considerate as a slow process of cure in homeopathy; however it's the patient who is treated, not the disease (kokate et al 2006).
NATUROPATHY AND YOGA
Naturopathy is not merely a system of treatment, but also the way of life, which is based on the laws of nature. The attention is particularly on eating and living habits, hydrotherapy, mud pack, baths, massage, etc. The system of yoga is as old as Ayurveda. The eight components of yoga are restraint, observance of austerity, physical postures, restraining of sense organs, breathing exercises, contemplation, mediation and Samadhi. Yoga practice have potential in improvement in better circulation of oxygenated blood in the body, restraining the sense organs, improvement of social and personal behavior and induction of tranquility and serenity in the mind (kokate at al 2006).
POLY HERBAL FORMULATIONS
There are many drugs used in treatment of various disorders, most of the drugs are having adverse reactions. Thus there is a need of more effective and less toxic agents for the treatment of various ailments. Plants are some of most attractive sources and have been shown to produce promising result for the treatment of various disorders (Joshi CS et al 2007).
Poly herbal formulations are the formulation which contains multiple ingredients of different herbal origin. The plant ingredients may have wide spectrum of biological activities. In Ayurvedic system of medicine, poly herbal formulations were frequently used to enhance the activity or to counteract the toxic effects of compounds from the other plants, but may also act synergistically with other constituents from the same or other plants. Poly herbal therapies have synergistic, potentiative, agonistic/antagonistic pharmacological agents within themselves that work together in dynamic way to produce therapeutic efficacy with minimum side effects. The therapeutic output may be due to the various active constituents with different mechanism, which can produce a combined action against various ailments including metabolic disorders (Ebong PE et al 2008, Chandrashekar CN et al 2008).
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glycosuria, and negative nitrogen balance sometime ketonemia. Resulting either inadequate secretion of insulin, an inadequate response of target cells to insulin, or combination of these factors. Insulin deficiency is due to functional disorder of the pancrease1.
ANATOMY AND PHYSIOLOGY OF THE PANCREAS
pan-all kreas-flesh is retro peritoneal exocrine and endocrine gland about 12 to 15 c.m. long and 2.5 c.m. in thickness and is connected usually by two ducts, to the duodenum, pancreas divided into Head, Body and Tail. Head is 'C' shape curve of duodenum, central body and tapering tail. As shown in Plate 1. Small ducts of pancreas unite and form two ducts that convey the secretion in to small intestine. In most people pancreas ducts join the common bile ducts from liver and gall bladder and enters the duodenum as a common duct called hepatopancretic ampulla.
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Pancreas is made-up of small clusters of glandular epithelial cells, about 99% of the cells are arranged in clusters called acini, and constitute exocrine portion of the organ. The cells with in the acini secrets the mixture of fluid and digestive enzymes, called pancreatic juice. And remaining 1% of the cells are organized into clusters called islets (islets of langerhans). They form endocrine portion of the pancreas. And consists of the cells that secret the hormones Glucagon, Insulin, Somtostatin and Pancreatic Polypeptide.
Fig 1 : LOCATION AND STRUCTURE OF PANCREAS
1.1 Cells types in the pancreatic islets
Each pancreatic islets includes four types of hormones, secreting cells.
1. Alpha- a cells constitutes about 20% of pancreatic islets secretes glucagon,
2. Beta cells (70%) of pancreatic islets cells and secrets insulin.
3. Delta constitute about 5% of pancreatic islets cells and secretes somastostatin.
4. F cells constitute the remainder of pancreatic islets cells and secretes pancreatic polypeptides. Glucagon raises blood glucose level, insulin lower blood glucose
level, somastotatin inhibits the insulin release and pancreatic polypeptide inhibits the secretion of somastotatin.
1.2 Regulation of glucagon and insulin secretion
1. Hypoglycemia stimulate the release of glucagon and helps in conversion of glycogen into
glucose in liver. (glycogenolysis)
2. Hyperglycemia stimulate the release of insulin from beta cells of pancreatic islets.
Insulin facilitated diffusion of glucose into cells, especially skeleton muscle fibers.
Conversion of glucose into glycogen.
Increase the amino acids uptake by cells and increase protein synthesis.
Synthesis of fatty acids as a result of the blood glucose level falls and low blood glucose level inhibits the insulin release2.
1.3 Biosynthesis, storage, and catabolism of insulin
It is already stated that insulin is synthesized by the Î²-cells of Islets of Langerhans but details of the synthesis are unknown. After synthesis, insulin is stored in the Î²-cells of the pancreas and the hormone is released in a controlled and graded manner. The insulin in Î² cells appears to be associated with granules of the cells. Insulin is released from the Î² cells into the plasma by the action of glucose and certain other sugars. Growth hormone appears to stimulate insulin secretion. Tolbutamide and other sulfonylureas enhance insulin secretion but C7 sugar, mannoheptulose, may depress its secretion. A number of studies suggests that glucose utilization in the Î² cells is more or less related to insulin release. Insulin is inactivated in tissues by both enzymic and non-enzymic reductive cleavage of disulfide bonds and by proteolysis. The glutathione reductase enzyme system may be particularly involved in the reductive inactivation.
1.4 The role of insulin carbohydrate metabolism
By depancreatizing an animal or in diabetes that occurs in human beings, the insulin insufficiency manifests itself in the following manner:
1. Hyperglycemia and glycosuria
2. Depletion of glycogen stores in the liver tissues
3. Lowered respiratory quotient indicating the lack of carbohydrate oxidation.
4. Increase in urinary nitrogen excretion indicative of the conversion of protein into
5. The occurrence of acetone and Î²-hydroxybutyric acid in the blood and urine owing to
faulty fat metabolism.
The injection of insulin will relieve these symptoms and restore to normal the distorted metabolic pattern.
The main effect of insulin is to increase the utilization of glucose by most body tissues. In the whole animal the most important overall effect of insulin quantitatively is to increase the rate of glycogen formation and oxidation of carbohydrate in muscles. The primary effect of insulin in increasing glucose utilization is to transport glucose across the cell membrane into the cell. Insulin has been shown to increase the penetration into the cell. Insulin has been shown to increase the penetration into cells of many monosaccharides. Insulin appeared to promote the entry into cells of such sugars which possess the same chemical configuration at carbon atoms 1, 2 and 3 as does Î²-glucose. The insulin effect has been demonstrated in cats, dogs, rats, rabbits and man and on diaphragm, erythrocytes, heart and skeletal muscles, but not in brain. It is of interest that insulin is not necessary in the metabolism of brain tissue.
In relation to the action of insulin in increasing the passage of sugar into the the concept of a membrane carrier system as the functional mechanism governing the transport of glucose and other sugars is considered the most valid. According to the theory, the sugar on the outside of the cell membrane is postulated to form a complex with a "Carrier" substance in the membrane. The complex then moves across the membrane. Within the cell the "sugar-carrier" complex dissociates and releases free sugar. The free carrier may either combine with free sugar in the cell and transport it to the extracellular fluid, or may move back to the outside membrane to complex with free sugar and transport it into the cell.
Nothing is known about the chemical nature of the carrier. Presumably it may be a lipid character which combines reversibly with sugar molecules; the complex formed possessing membrane solubility.
As primary action of insulin on Carbohydrate metabolism appears to reduce blood concentration by greatly enhancing the rate of entrance of sugar to the intracellular compartment, and considering the carrier theory of sugar transport to be valid, the action of insulin may be implied to occur upon some component of the carrier system.
Insulin particularly facilitates the transport of glucose into the skeletal and cardiac muscles and possibly into the adipose tissues. In the transport of glucose into the tissues such as liver, brain, kidney, intestinal mucosa etc. Insulin does not appear to be involved. These tissues offer much less resistance to glucose penetration. Within the cell, glucose enters the metabolic stream. At the initial stage the metabolism of glucose generally involves phosphorylation by ATP to the glucose-6-phosphate in a reaction catalyzed by the glucokinase enzyme in the hexokinase reaction.
On addition of unabsorbable gel-forming, hydrocolloidal polysaccharide fibers (such as guar gum from the seeds of 'cluster beam') to the diet of diabetics, reduces carbohydrate absorption and flattens the post prandial blood glucose curve, and requirements of insulin and oral hypoglycemic agents are reduced, which has been reported. But large amount causes discomfort due to flatulence6.
2.3.4 NATURAL ANTIDIABETIC DRUGS
Man's existence on this earth has been made possible only because of the vital role played by the plant kingdom in sustaining his life.
The nature has provided a complete store-house of remedies to cure all ailments of mankind. Since the dawn of civilization, in addition to food, crops, man cultivated herbs for his medicinal needs. The knowledge of drugs has accumulated over thousands of years as a result of man's inquisitive nature7,8.
The development pipeline for new oral therapeutic agents for Type 2 Diabetes is encouraging and continues to expand. These intensive research and development efforts are in response to the increasing prevalence of the disease and related co-morbidities, realization by care givers that successful glycemic control will likely require combination therapy, a growing understanding of the pathophysiology of the disease, and the identification and validation of new pharmacological targets. These targets include receptors and enzymes that: enhance glucose-stimulated insulin secretion, suppress hepatic glucose production, increase skeletal muscle glucose transport and utilization, increase insulin sensitivity and intracellular insulin signaling, and reduce circulating and intracellular lipids. Due to their promise for future clinical success and because they exhibit mechanisms of action distinct from current therapies, some of the emerging approaches will be highlighted here.
PPAR Î±/Î³ dual agonist
Glucagon like peptide-1 (GLP-1) hormone
Dipeptidyl peptidase IV inhibitors
Î²3- Adrenoreceptor Agonist
Î± - Lipoic acid
Liver selective glucocorticoid antagonists
A. PPAR Î±/Î³ dual agonist 3
These agents are shown to ameliorate the hyperglycemia and hyperlipidemia associated with Type 2 Diabetes. In addition to their benefit on lipids the activation of PPARÎ± may mitigate the weight gain induced by PPARÎ³ activation .So this dual agonist is supposed to provide additive and possibly synergistic effects.
First literature report of a balanced PPAR Î±/Î³ dual agonist was KRP-297 (MK-767), a TZD derivative that was reported to bind PPARÎ± and PPARÎ³ with an affinity of approx. 0.230 and 0.33 Î¼M respectively and to trans activate PPARÎ± and PPARÎ³ with potencies of 1.0 and 0.8 Î¼M followed by phenylpropionic acid based PPAR Î±/Î³ dual agonists Tesaglitazar (AZ-242) by Astra Zeneca, reportedly in phase III clinical trial, Ragaglitazar (DRF-2725) by Dr.Reddy's Research Foundation, reportedly completed Phase Î™Î™ clinical trial but clinical development being terminated due to an incidence of bladder tumors in rodents. LY-510925 is a result of collaborative effort of Ellily Lilly and Ligand Pharmaceuticals, Muraglitazar (BMS -298585) is disclosed by Cheng et al.
B. Glucagon like peptide-1 (GLP-1) hormone
It is the incretin hormone acting via GLP-1 receptor (a G-protein coupled receptor). When blood glucose levels are high this hormone stimulates insulin secretion and biosynthesis and inhibits glucagon release leading to reduce hepatic glucose output. In addition it serves as an "ileal brake", slowing gastric emptying and reducing appetite. GLP-1 has number of effects on regulation of Î²-cell mass: stimulation of replication and growth and inhibition of apoptosis of existing Î²-cells and neogenesis of new Î²-cells from precursors. Thus, GLP-1 therapy for the treatment of Type 2 Diabetes is an area of active research.
There are two sub-classes of GLP-1 in clinical development .One is natural GLP-1 and the other is exendin-4, a peptide agonist isolated from the venom of lizard and is more potent than natural GLP-1. Some of the compounds developed so far are: Exenatide (AC2993) is under phase Î™II clinical trial developed by Lilly and Amylin, Liraglutide (NN2211), is under phase Î™Î™ clinical trial by Novo Nordisk, CJC1131 is under phase I / Î™Î™ clinical trial by Conjuchem, ZP10 is under phase I / Î™Î™ clinical trial by Zealand.
C. Dipeptidyl peptidase IV inhibitors 8
The role of DPP IV enzyme is to cleave the N-terminal 2 amino acids of active GLP-1 to give the inactive GLP-1 amide so this degradation of GLP-1 leads to decrease in insulin secretion and biosynthesis. Thus the use of DPP IV inhibitors increases the circulating levels of endogenous GLP-1 leading to increase insulin secretion, biosynthesis and inhibits glucagon release.
Preliminary clinical results have been disclosed on three DPP IV inhibitors; Isoleucylthiazolidide (P32/98), DPP-728 and LAF-237. Novartis has recently developed (NBP-LAF-237, LAF-237) as vildagliptin, a potent, selective, stable orally active DPP IV inhibitor with antihyperglycemic properties, currently in phase III clinical trials as potential new treatment for Type II Diabetes. The promise of this treatment remains to be realized as a potent and selective DPP-IV inhibitors progress through clinical studies. 9
D. HGO Inhibitors
Hepatic glucose output is a consequence of two distinct and highly regulated processes gluconeogenesis and glycogenolysis. Inhibition of various enzymes involved in these pathways can lead to regulation of glucose level thus managing Type 2 Diabetes. Metabasis-sankyo has GP3034, a F1, 6Bpase (fructose-1, 6-bis phosphatase) inhibitor in phase II clinical trial. Aventis and Novonordisk have reported compounds that inhibit glycogen phosphorylase. Hoffmann La Roche has reported PEPCK (phosphoenolpyruvate carboxykinase) inhibitor that showed inhibition of glucose production in the liver cell lines.
E. Î²3-Adrenoreceptor Agonist 10
These shows marked selectivity for stimulation of lipolysis and hence oxygen and energy consumption in skeletal muscle and adipose tissue. An initial compound, which shows excellent activity in rodents fail in human trials due to the difference in Î²3 receptor isoforms in different species. Recent cloning of human Î²3 receptor has enabled companies to develop compounds
selective for Î²3 receptor. SR-58611 (Sanofi-Synthelabo) and TAK-677 (Takeda) are some of the compounds in this series undergoing phase II clinical trials.
F. Î±-Lipoic Acid 11
Î±-Lipoic acid (LA) is an eight-carbon fatty acid that is synthesized in trace quantities in organisms ranging from bacteria to man. LA functions naturally as a cofactor in several mitochondrial enzyme complexes responsible for oxidative glucose metabolism and cellular energy production. LA has been prescribed in Germany for over thirty years for the treatment of diabetes-induced neuropathy. Results from several recent controlled clinical studies indicate that this compound is safe, well tolerated, and efficacious.
Although the exact mechanism of action of LA is unknown, in vitro data from the laboratories of Rudich and others have indicated that LA pretreatment maintains the intracellularlevel of reduced glutathione (the major intracellular antioxidant) in the presence of oxidative stress, and blocks the activation of serine kinases that could potentially mediate insulin resistance. Thus, one potential explanation for the protective effects of LA might be related to its ability to preserve the intracellular redox balance, thereby blocking the activation of inhibitory stress-sensitive serine kinases including IKKbeta. This stress-sensitive kinase is a crucial regulator of the transcription factor nuclear factor-kappaB (NF-kappaB), a major target of hyperglycemia, cytokines, reactive oxygen species, and oxidative stress. The aberrant regulation of NF-kappaB is associated with a number of chronic diseases including diabetes and atherosclerosis. Furthermore, LA and other agents that interfere with the persistent activation of the NF-kappaB pathway appear to be promising approaches to increase insulin sensitivity, and perhaps even as treatments for complications of diabetes in which NF-kappaB activation has been implicated.
G. Liver Selective Glucocorticoid Antagonists 1
Glucocorticoids raise blood glucose levels by functionally antagonizing the action of insulin, thereby inhibiting glucose disposal and promoting hepatic glucose production and
output. So the approaches towards liver selective glucorticoid antagonist have potential role in the management of Type II Diabetes Mellitus. Mifepristone has shown glucocorticoid antagonist action and few other similar compounds have been tested in which A-348441 showed reduction in glucose levels and improved lipid profiles in an animal model of diabetes.
H. Protein Tyrosine Phosphatase 1 B Inhibitors (PTP-1B)
Protein tyrosine phosphatase 1B emerged only four years ago as a new drug target for the treatment of diabetes and obesity.
PTP1B enzyme belongs to the family of tyrosine phosphatase which consists of 90 members. It contain a catalytic cystein residue and localized to the endoplasmic reticulam with its phosphate domain directed towards the cytoplasm. It play an important role in the regulation of signal transduction pathways and the phosphorylation of proteins. PTPase dephosphorylate the activated insulin receptor, attenuating the tyrosine kinase activity and thus involve in Type 2 Diabetes.
PTP1B inhibitors have been shown to increase insulin receptors tyrosine phosphorylation. It exerts insulin like effect invitro and invivo and decreases hyperglycemia in insulin deficient animals. The recent demonstration shows that mice lacking PTP-1B have enhances insulin sensitivity. Furthermore, when fed a high diet, these mice maintained insulin sensitivity and were resistant to obesity, suggesting that inhibition of PTP 1B activity could be a novel way of treating Type 2 diabetes and obesity. Discovery of small-molecule inhibitors has been pursued extensively in both academia and industry and a number of very potent and selective inhibitors have been identified.
PTPase have been inhibited experimentally using a variety of mechanisms and chemical entities. PTPase can be inhibited by chemical inactivation of the active site cysteine residue common to all members of the family. This inactivation may occur via an oxidative mechanism initiated by reactive species such as pervanadate and peroxides e.g., Bis -maltolato vanadium. Most of early PTP1B inhibitors are phosphate-based and the most studied phosphate-based
PTP1B inhibitors are difluorophosphonates e.g., Bis difluorophosphonate-phenylalanine. Thisdifluorophosphonate group was introduced as a nonhydrolyzable phosphotyrosine mimetic in 1992 by Burke and coworkers.2-(Oxalylamino)-benzoic acid (OBA) e.g., Oxalylamino-benzoic acid was identified as a general, reversible and competitive inhibitor of several PTPase using a scintillation proximity-based high throughput screening by workers at Novo Nordisk.
High-throughput screening has allowed the identification of several more PTP-1B inhibitor classes having various mechanisms of action. Pyridazine derivatives such as Pyridazine analogue were identified at Biovitrum potencies in a low micromolar range (5.6Î¼M) and over 20 fold selectivity over TC-PTP. Hydroxyphenylazole derivatives such as Hydoxyphenyl azole, with IC50 value in the micromolar range, were claimed by Japan Tobacco. A series of azolidinediones e.g., Azolidinediones and phenoxyacetic acid based PTP1B inhibitors e.g., Azolidinediones have been reported by American Home Products. More recently a group at Hoffmann-LaRoche described novel pyrimidotriazinepiperidine analogues e.g., Pyrimidotriazinepiperidine with oral glucose lowering effect in ob/ob mice. The inhibition of PTP1B by this class of compounds presumably involves the oxidation of the active site cysteine of PTP1B to the corresponding sulfenic acid
Bis -maltolato vanadium Bis difluorophosphonate-phenylalanine
Oxalylamino-benzoic acid Pyridazine analogue
Hydoxyphenyl azole Azolidinediones
Despite good biological target validation, designing PTP-1B inhibitors as oral agent is challenging because of the highly charged nature of the catalytic domain of the target. Furthermore the development of selective, potent and bioavailable inhibitors of PTP-1B will be a formidable challenge although some of the groundwork has now been laid out.4