DRUG INTERACTION:Drug interaction can be defined as a modification caused by a substance to the therapeutic outcome of another drug in the body. The interacting substance may be a drug, food or a herb. Interactions between herbs and drugs may increase or decrease the pharmacological or toxicological effects of either component.
Synergistic therapeutic effects may complicate the dosing of long term medications.30 It has become evident that conventional and herbal medicines are often used concomitantly and can result in clinically relevant herb–drug interactions. A methodical strategy is required to reduce the ill- effects of this interactions.313.1.1 Herb-Drug Interaction:The subject of herb-drug interactions is important for both pharmacists and clinicians. Herbs are used for medicinal purposes since ancient times.
Most people believe that herbs are harmless, but many of our drugs (digitalis, morphine, atropine, vincristine, etc.,) have originated from plants. Herbs can affect body functions; therefore, when herbal remedies are taken concurrently with drugs, interactions are possible. There is estimation that, less than one third of the individuals inform their medical practitioners about the concomitant usage of herbs.32 Some reports suggest that herb-drug interactions occur less often than predicted. If an interaction between an herb and a drug occurs, conventional drugs are usually the culprits because they are pharmacologically more active.
The potency of herbs can vary depending on the climate and soil conditions where they were grown that add to the complexity to the assessment. When a drug is prescribed, the dosage and quality of the product is more or less fixed; such is not the case with herbs. The mechanism of action of many herbs is not elucidated. Therefore, the exact mechanisms of drug-herb interaction are also unclear. So far, several pharmacokinetic drug-herb interactions (absorption, distribution, metabolism), and several additive pharmacodynamic interactions have been identified.
For example, psyllium (a herb rich in mucilage) inhibits the absorption of lithium. Similarly, meadowsweet and black willow, which contain pain-reducing salicylates, may displace highly protein-bound drugs such as warfarin and carbamazepine, thus increasing the adverse effects of these drugs.333.
1.2 Chronic Diseases and Polypharmacy:Polypharmacy is defined as “prescription, administration, or use of more medications than are clinically indicated or when a medical regimen includes at least one unnecessaryPh.D. Thesis 2017medication”.
Polypharmacy becomes inevitable while treating chronic diseases due to co morbid conditions. Considering type-2 diabetes, one also needs to institute treatment for dyslipidemia and hypertension. Sometimes the problem gets compounded with other disorders such as hypothyroidism, osteoporosis, heart failure etc, leading to complex drug therapies. The other causes of polypharmacy include multiple prescribers, home remedies and perceiving adverse events as new clinical conditions. The consequences are duplication of therapy, irrationality and drug interactions leading to noncompliance and eventually decreased efficacy and safety. 34The use of herbal medicines is on the rise worldwide. The influence of religious, cultural, socioeconomic issues coupled with tradition and belief are the main reasons for growth in herbal medicines use. The use of herbal medicines is extensive in Chinese, Indian and African societies.
Another reason for the popularity of herbal medicines is the safety profile, as most of the herbal drugs are harmless at the prescribed dose. The increased popularity and use of herbal medicines would obviously enhance the possibility of interactions. Therefore, herb-drug interaction becomes an important consideration for the assessment of safety and efficacy.35The elderly patients, who are generally on polypharmacy, are more susceptible to herb-drug interaction. Medication knowledge and self-management is an important consideration for such patients. As in case of type-2 diabetes mellitus, which generally involves polypharmacy to achieve strict glycemic targets, lack of medication knowledge would lead to adverse events.363.
2 ANIMAL MODELS FOR HYPERGLYCAEMIA:The etiology of type 2 diabetes is complicated involving progressive development of insulin resistance in liver and peripheral tissues associated with a defective insulin secretion from pancreatic beta cells leading to an abnormally high amount of glucose levels in blood. Genetic analysis of diabetes is difficult and not well understood in humans. Moreover, diabetes research in humans has obstacles due to obvious ethical considerations. Animal diabetic models are therefore greatly useful and advantageous in experimental designs because they offer new insights into human diabetes.373.2.1 ANIMALS:Inbred animals, in whom the genetic make-up is homogeneous and environmental factors are controllable, are valuable in the study of multifactorial diseases. Most of the available animalChapter 3 REVIEW OF LITERATUREPh.
D. Thesis 2017models are rodents because of their small size, short reproduction, easy availability and economic considerations.3.
2.1.1 Genetically Modified Animals:Spontaneously diabetic animals of type 2 diabetes may be obtained from the animals with one or several genetic mutations transmitted from generation to generation (e.
g., ob/ob, db/db mice). These animals generally inherit diabetes either as single or multigene defects. The metabolic peculiarities result from single gene defect(monogenic) which may be due to dominant gene or recessive gene (diabetic or db/db mouse, Zucker fatty rat) or it can be of polygenic origin e.g., Kuo Kondo (KK) mouse, New Zealand obese (NZO) mouse.383.2.
2 DIET-INDUCED TYPE 2 DM:3.2.2.
1 High Fat Diet:Obesity is one of the major reasons for the pathogenesis of type-2 diabetes mellitus. For induction of obesity fed mice with high fat diet. The diet was composed of 32% safflower oil, 33.1% casein, 0.5% DL-methionine, 17.6% sucrose, 1.
4% vitamin mixture, 9.8% mineral mixture, and 5.6% cellulose powder. High-fat diet fed mice showed obesity, glucose intolerance and modest increase in GLUT-4 transporters.3.
2.2.2 High Sucrose Diet:Wright et al.
, demonstrated that substitution of sucrose for starch results in hyperinsulinemia and deterioration of glucose tolerance. This study was done on male SD rats. The grouping was done in 42 days old rats and the test group was given customized diet composed of sucrose as a replacement of cornstarch. The diet had about 32% of sucrose and casein 25%, cornstarch 32%, corn oil 5% and vitamins, salt and methionine accounted for the rest. The results showed that sucrose diet fed rats showed significant hyperinsulinemia and glucose intolerance as compared to normal diet.
The animals subjected to exercise showed substantial improvement in glucose tolerance.393.2.2.
3 High Fructose Diet:To induce insulin resistance, Hwang et al., fed SD rats with high fructose diet composed of 66% sucrose, 12% fat, 22% protein and electrolytes constituted the rest of the diet. The rats were fed for two weeks and the required parameters were measured. The rats demonstrated significant hyperinsulinemia and hyper-triglyceridemia.40Chapter 3 REVIEW OF LITERATUREPh.D. Thesis 20173.2.
3 CHEMICAL- INDUCED TYPE 2 DM:22.214.171.124 Alloxan:Alloxan (ALX) is a uric acid analogue and is highly unstable in water at neutral pH, but quite stable at pH 3.
ALX acts by selectively destroying the pancreatic beta islets leading to insulin deficiency, hyperglycemia and ketosis. ALX causes diabetes in many rodent and non-rodent animals and is most preferably used in case of rabbits because of the relative ineffectiveness of streptozotocin (STZ) in rabbits for induction of diabetes and development of well characterized diabetic complications. ALX is disadvantageous as the percentage incidence of diabetes is quite variable and is not proportionately related to increasing doses of ALX.4126.96.36.199 Streptozotocin:Streptozotocin (STZ) is a most popular agent to induce diabetes.
STZ is generally used in the dose range of 40-60 mg/Kg b.w. STZ is used either as a single dose or multiple injections at low dose to induce IDDM. STZ is a light sensitive, unstable drug. It is administered through i.v.
or i.m. route as a solution in citrate buffer at pH 4.5 under low light conditions. It selectively destroys beta cells and brings about type-2 diabetes like conditions. However, extent of destruction is variable. The variability involves spontaneous recovery after showing high plasma glucose values, death to excessive insulin secretion.
4188.8.131.52 Nicotinamide+Streptozotocin:With the consideration of extensive beta cell destruction by STZ at routinely used doses, efforts were made to protect the beta cells partially to achieve a condition similar to that of NIDDM.
Hence, a combination of STZ and nicotinamide was used. Nicotinamide administered before STZ injection, protected the beta cells partially. A study done in three months old Wistar rats, nicotinamide at the dose of 230 mg/kg, i.p. 15 min before STZ administration (65 mg/kg i.
v.) yielded a maximum of animals with moderate and stable hyperglycemia resembling type-2 diabetes.43, 443.2.
3.4 Diet+Streptozotocin:Recently, type-2 diabetes animal models were introduced with the intent of mimicking the metabolic features of human Type-2 diabetes mellitus. The models involved both diet and chemical components. This model involves feeding the animals with high fat/calorie diet till the rodents become obese. This results in impaired glucose tolerance (IGT) and insulinChapter 3 REVIEW OF LITERATUREPh.D.
Thesis 2017resistance. Once IGT is achieved, streptozotocin is administered at low dose/multiple low doses to partially destroy beta cells by low dose (single/multiple) streptozotocin, to reduce insulin secretion.45, 46