“Influence of alcoholic extract of Cinnamomum cassia on anti-diabetic effect of glibenclamide, metformin and their combination”
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore –560041.
By
Mr.UMESH.BS B.Pharm
Under the Guidance of
Dr. KALYANI DIVAKAR, M.Pharm. Ph.D.
H.O.D OF PHARMACOLOGY
Department of Pharmacology,
Acharya & B.M.Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post),
Hesaraghatta Main Road, Bangalore – 560090
2008-09
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 / Name of the candidate and address / Mr. UMESH.BSS/O Siddaramappa.B
Aishwarya nilaya, Venkatanarasappa badavane, I-Cross, Chikkasandhra,
Sapthagiri college road,
Hesaragatta main road,
Bangalore-560057.
2 / Name of the institution / Acharya & B.M. Reddy College Of Pharmacy.
Soldevanahalli, Hesaraghatta Road, Chikkabanavara (Post),
Bangalore -560090
Phone No: 080-65650815
3 / Course of study and subject / M. PHARM.
PHARMACOLOGY.
4 / Date of admission / JUNE - 2008.
5 / Title of the topic / “Influence of alcoholic extract of Cinnamomum cassia on anti-diabetic effect of glibenclamide, metformin and their combination”
6. / Brief resume of intended work
6.1 Need of the work
6.2 Review of Literature
6.3 Objectives of the study / Enclosure I
Enclosure II
Enclosure III
7. / Materials & Methods
7.1 Source of data
7.2 Methods of collection of data ( Including sampling, procedure if any)
7.3 Does the study require investigation on animals?
If yes give details
7.4 Has ethical clearance been obtained from your institution in case of 7.3 / Enclosure IV
Enclosure V
Enclosure VI
Yes (Applied for clearance)
8. / List of references / Enclosure VII
9. / Signature of the candidate
10. / Remarks of the guide
11. / Name & Designation of
11.1 Guide
11.2 Signature of Guide
11.5 Head of the Department
11.6 Signature of HOD / Dr. Kalyani Divakar M.Pharm. Ph.D
H.O.D, Department of Pharmacology,
Acharya & B.M.Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post),
Hesaraghatta Main Road, Bangalore – 560 090.
Dr. Kalyani Divakar M.Pharm. Ph.D.
H.O.D, Department of Pharmacology,
Acharya & B.M.Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post),
Hesaraghatta Main Road, Bangalore– 560 090.
12. / Remarks of the Principal
12.1 Signature of the principal / PRINCIPAL
Dr. DIVAKAR GOLI M.Pharm.Ph.D.
Acharya & B. M. Reddy College of pharmacy,
Soldevanahalli, Hesaraghatta Main Road,
Chikkabanavara (Post),
Bangalore-560090.
Enclosure - I
6. BRIEF RESUME OF INTENDED WORK
6.1 NEED OF THE WORK:-
The increasing worldwide incidence of diabetes mellitus in adults is a global public health burden. It is predicted that by 2030, India, China and United States will have the largest number of people with diabetes. By definition, diabetes mellitus is categorized as metabolic disease characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both 1.
The WHO estimated that 19.4 million individuals were affected by this deadly disease in India in 1995, it is likely to go up to 57.2 million by the year 2025. The revised figures are 80.9 million by the year 2030. Every 5th diabetic patient in the world is in India and every 5th adult in Indian urban area is diabetic 2.
Glibenclamide is a sulfonylurea oral hypoglycemic agent which is widely used for the treatment of type 2 diabetes mellitus. It produces the hypoglycemic effect primarily by stimulating insulin secretion from β cells of pancreatic islets. It was reported that glibenclamide was metabolized mainly in liver by cytochrome P-450(CYP) 3A4 3.
Metformin, a member of the biguanide class, reduces blood glucose in patient with type 2 diabetes mellitus. This drug has been reported to exert its effects primarily on the liver, by inhibiting gluconeogenesis and reducing hepatic glucose output. Metformin has also been reported to increase glucose uptake in skeletal muscle and adipose tissue. As the effect of metformin is peripheral, no insulin secretion is stimulated and the hyperinsulinemia and insulin-resistance induced by some other antihyperglycemic drugs are not seen with metformin. Because of this, metformin is considered to be a safe and effective drug for the treatment of type 2 diabetes 4,5.
Aggressive glycemic control has been demonstrated to decrease the risk of long-term microvascular and macrovascular complications such as nephropathy, retinopathy and myocardial infarction. Therefore effective treatment often requires therapy directed at both abnormalities. There is an evidence which shows that glycemic control can be improved by early use of combinations of agents for simultaneously improve of insulin secretion and to reduce insulin resistance 6.
Drugs are used to prevent, diagnose, treat, or cure many diseases or disorders. However, they must be used safely with precaution to ensure that they are safe and effective. Many drugs undergo interaction with the body in different ways, like with our daily diet or lifestyle, which has great significant impact on a drug's ability to show its effects which may be enhanced or decreased.
An extensive literature survey from all scientific sources revealed that Cinnamomum cassia has anti-diabetic activity. But the influence of the crude drug with diabetic patients who are under treatment is not clear. Hence, the present study is planned to find out the Influence of alcoholic extract of Cinnamomum cassia on anti-diabetic effect of glibenclamide, metformin and their combination.
Enclosure – II
6.2 REVIEW OF LITERATURE:-
Cinnamomum cassia:-
It consists of dried bark Cinnamomum cassia (Nees) Nees ex Blume belonging to the family Lauraceae 7.
SYNONYMS:-
Bastard Cinnamon, Chinese Cinnamon, Cassia lignea, Cassia bark, Cassia Aromaticum, Canton Cassia.
VERNACULAR NAMES:-
HINDI - DALCHINI
ENGLISH - CINNAMON
SANSKRIT - TWAK
KANNADA - CHAKKE
DESCRIPTION OF THE PLANT:-
The leaves are green, oval oblong blades from 5 to 9 inches long. The fruit is about the size of a small olive. The trees are at their greatest perfection at the age of ten to twelve years, but they continue to spread and send up new shoots. The bark may be easily distinguished from that of cinnamon, as it is thicker, coarser, darker and duller, the flavor being more pungent, less sweet and delicate, and slightly bitter.
The Bark occurs in quills, usually single, sometimes double, very rarely more than double, from 30 to 60 cm. long, 2 to 5 cm. wide, and 0.2 to 3 mm. thick. In some instances thebark is rolled very much upon itself, in others it is not even completely quilled,forming segments more or less extensive of a hollow cylinder. It is of a redder or darker color than the finest Ceylon cinnamon, thicker, rougher, denser, andbreaks with a shorter fracture. It has a stronger, more pungent and astringentbut less sweet and grateful taste, and though of a similar odor, is less agreeably fragrant.
GEOGRAPHICAL DISTRIBUTION:-
Mainly in China, Cochin and also cultivated in Sumatra, Ceylon, Japan, Java, Mexico and South America.
CHEMICAL CONSTITUENTS:-
Cassia bark contains 1-2% of volatile oil and is known as cassia oil. It also contains mucilage, starch, calcium oxalate and tannins. Cassia oil contains not less than 85% of cinnamic aldehyde and very small amount of eugenol. It also contains cinnamyl acetate. The volatile oil is brown in colour 8.
Traditional Therapeutic Uses:-
Cinnamomum cassia is used as Expectorant, anti-cough, anthelmentic, aromatic, carminative, diuretic, anorexia, urinary bladder disorders, dryness of mouth, corzy, diarrhea, haemorrhoids, nausea, spermatorrhoea, bronchial asthma, bronchitis, allide disorders of respiratory system, in pulmonary tuberculosis, in heart troubles, blood impurities, dysuria, enteric fever, abdominal coli, amadosa, grahani, gonorrhea, dysmenorrhoea, uterine disorders, neuralgia; paralysis, poisons, foul taste of mouth and as germicidal.
Therapuetic uses with scientific support:-
Ø Results revealed that 18α-glycyrrhizin led to the enhancement of the hypoglycemic effect of glibenclamide by inhibiting the activity of CYP3A: on the other hand, 18α-GL protected the pancreatic islet of β cells and liver from damage in diabetes which suggested that 18α-GL might be beneficial as an adjuvant drug of glibenclamide in proper dose, especially to the diabetic patients associated with liver dysfunction 3.
Ø Results suggest that metformin may increase LPL production, thereby increasing LDL particle size. These effects might be independent of the hypoglycemic effect of metformin 4.
Ø The results showed that Cysteinyl metformin (CM) corrected the organ edema of the diabetic rats. All these findings suggest that CM is a potential candidate for the future treatment of both type 1 and type 2 diabetes 5.
Ø Both glyburide/meyformin 2.5mg/500mg and glyburide/metformin 5.0mg/500mg combination therapy were efficacious and well tolerated in the treatment of Chinese patients with type 2 diabetes mellitus 6.
Ø Cinnamomum cassia does not produce any changes in the locomoter activity & also shows that it does not produces adverse effects, such as myorelaxant effect and might be an effective anxiolytic agent by regulating the serotonergic & GABAergic system 9.
Ø The cassia oil significantly reduced serum and hepatic urate levels in heperuricemic mice caused by oxonate in a time & dose dependent manner and altered urate levels in liver, but not in serum, with a dose dependent decrease in normal animals 10.
Ø Scanning electron microscope observation revealed that the bacterial cells treated with cinnamic aldehyde suffered from severe damages in their structure. Minimal inhibitory concentration of cinnamic aldehyde was determined to be 250µg ml-1 against E.coli strains 0157:H7 and O26 or 500 µg ml-1 against strains ATCC11105 and 0111 11.
Ø It showed that, taking cinnamon powder over a 40-days period, reduced mean fasting serum glucose, triglyceride, LDL cholesterol, and total cholesterol levels12.
Ø Cinnamon supplementation (1.5 g/d) did not improve whole-body insulin sensitivity or oral glucose tolerance and did not modulate blood lipid profile in postmenopausal patients with type 2 diabetes 13.
Ø Treatment with gliclazide resulted in the significant reduction to about 60% of baseline in urinary 8-iso-prostaglandin F2α extraction while no such change was detected in the glibenclamide period. The increase in peak forearm blood flow and flow debt repayment were in parallel with its anti-hyperglycemic effect, but not with antioxidant state. Results suggest that gliclazide and glibenclamide can protect vascular endothelium from hyperglycemia-induced injury in Type 2 diabetic patients 14.
Ø The finding in this study suggest that pioglitazone has anti-arteriosclorisis effects. They conclude that drugs for the treatment of diabetes mellitus should be selected taking into consideration such endpoints as blood sugar control, and also the risk of complications such as cardiovascular events in the future 15.
Ø Rosiglitazone improved insulin resistance while a worsening was seen with glibenclamide. Total: high-density lipoprotein cholesterol ratios were reduced with glibenclamide and unchanged with rosiglitazone. All treatments were generally well tolerated 16.
Ø In the severe injury model, glibenclamide inhibited inflammatory parameters, as assessed by Evans blue extravation, neutrophil influx and haemoglobin content, and increase in TNF-α (tumor necrose factor-α) and IL (interleukin)-6 levels in the intestine and lungs. The drug did not affect the increase in IL-1β and IL-10 levels 17.
Ø Glycosylation proved to be a powerful tool for the development of a high affinity glibenclamide ligand with completely different pharmacodynamics. Therefore, the glucose-conjugate could be potential lead compound for the design of substituted glibenclamide derivatives as islet imaging ligands 18.
Ø When clonidine was administered along with glibenclamide, it not only caused early onset of hypoglycaemia but also produced grater fall in blood sugar than observed with glibenclamide alone. The diuretics did not modify the hypoglycaemic activity of glibenclamide 19.
Ø When phenformin was combined with glybenclamide, the effect was more marked and quicker than with glybenclamide alone. The different sites of action of the drugs may be responsible for this interesting response 20.
Ø Metformin monotherapy and combination therapy with metformin and sulfonylurea were well tolerated and improved the glycemic control and lipid concentration in patients with NIDDM was poorly controlled with diet or sulfonylurea therapy alone 21.
Ø When combined with metformin , sulphonylureas and α-glucosidase inhibitor showed a similar efficacy on HbA1c. The effects of drugs used as add-on metformin monotherapy could be different from those observed in monotherapy22.
Ø Metformin did not appear more effective than lifestyle intervention in ameliorating levels histology in these children with nonalcoholic fatty liver disease 23.
Ø The combination of repaglinide, metformin and bedtime NPH proved safe and effective and it provided better postprandial blood glucose control. The association of metformin and dose of NPH did not obtain suitable control in patients with a long evolution who have already received two or more oral antidiabetic agents 24.
Ø This study reported that the use of pioglitazone in combination with metformin or an sulfonylurea is a safe and effective alternative to a commonly used fixed dose metformin and glibenclamide combination in the treatment of patients with Type 2 diabetes 25.
Ø The Combine treatment with metformin and sulfonylurea was more effective than these drugs alone in improving glycemic control in the type 2 diabetes, while also allowing a reduction of the dosage of each drug 26.
Ø The present findings suggest that switching from a sulfonylurea coadministered with metformin to the glyburide-metformin tablet may improve glycemic control in patients with type 2 diabetes and an AIC>8% 27.
Ø Glimepiride/metformin demonstrated being more efficacious than alibenclamide/metformin at reaching the glycemic control goals with less hypoglycemic events in patients with uncontrolled type 2 diabetes mellitus 28.
Enclosure – III
6.3 OBJECTIVES OF THE STUDY:-
· Extraction of Cinnamomum cassia bark with alcohol (AECC).
· Preliminary phytochemical analysis of AECC.
· To study the influence of AECC on anti-diabetic effect of glibenclamide, metformin and their combination.
enclosure – IV
7. Materials and Methods:-
7.1 SOURCE OF DATA:-
The data will be obtained from experiments which involves:-
(I) Laboratory based studies.
(II) Literature survey, CD ROM, Chemical abstracts.
(III) National & International Journal.
(IV) Text books.
(V) Internet.
(VI) Phytomedicine.
Enclosure – V
7.2 METHOD OF COLLECTION OF DATA
(including sampling procedure if any):-
Field and laboratory studies:-
Field work:-
The bark of Cinnamomum cassia will be collected, and it will be authenticated.