Download 6.2 review of literature

“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
1
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA
ANNEXURE-II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
Name of the candidate and address
Mr. UMESH.BS
S/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.
1
5
Title of the topic
“Influence of alcoholic extract of
Cinnamomum cassia on anti-diabetic
effect of glibenclamide, metformin and
their combination”
2
6.
7.
Brief resume of intended work
6.1 Need of the work
Enclosure I
6.2 Review of Literature
Enclosure II
6.3 Objectives of the study
Enclosure III
Materials & Methods
7.1 Source of data
Enclosure IV
7.2 Methods of collection of data ( Enclosure V
Including sampling, procedure if any)
7.3 Does the study
investigation on animals?
If yes give details
require
Enclosure VI
7.4 Has ethical clearance been
obtained from your institution in case Yes (Applied for clearance)
of 7.3
8.
List of references
9.
Signature of the candidate
Enclosure VII
10. Remarks of the guide
3
Name & Designation of
11. 11.1 Guide
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.
11.2 Signature of Guide
11.5 Head of the Department
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.
11.6 Signature of HOD
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.
4
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 longterm 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.
5
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 antidiabetic effect of glibenclamide, metformin and their combination.
6
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 the bark 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, and breaks
with a shorter fracture. It has a stronger, more pungent and astringent but less sweet and
grateful taste, and though of a similar odor, is less agreeably fragrant.
7
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.
8
Therapuetic uses with scientific support: 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, 18αGL 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.
 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.
 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.
 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.
 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.

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.
 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.
 It showed that, taking cinnamon powder over a 40-days period, reduced mean fasting
serum glucose, triglyceride, LDL cholesterol, and total cholesterol levels12.
 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.
 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
9
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
.
 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.
 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.
 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.
 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.
 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.
 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.
 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
.
 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.
10
 Metformin did not appear more effective than lifestyle intervention in ameliorating
levels histology in these children with nonalcoholic fatty liver disease 23.
 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.
 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.
 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.
 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.
 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.
11
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.
12
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.
13
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.
Laboratory work:Animals
Rats of Wistar strain (150-250 g) will be selected for anti-diabetic activity. They will be
housed in cages on a 12-h light: 12-h dark cycle and will be allowed free access to
laboratory diet.
Solvents used:Ethanol.
Chemicals and reagents used:Alloxan monohydrate, Glibenclamide, Metformin, Ethanol, Commercial assay kit.
Phytochemical analysis:Phytochemical constituents will be detected by phytochemical tests as described by
Kokate C.K 10.
Pharmacological studies:Animal experimental models will be devised to assess the anti-diabetic activity.
Data analysis:Statistical analysis of the data will be evaluated by analysis of variance (ANOVA).
14
Methodology:(1) Extraction:The dried powdered stem barks of Cinnamomum cassia will be extracted twice
(each time for 3 h followed by heating) with ethanol in a soxhlet apparatus. The extract
will be subjected to dryness and the dry extract will be used for determination of the
activity 11.
(2) Pharmacological study design:-
Evaluation of Anti-diabetic activity on alloxan induced diabetic rats:Rats of Wistar strain weighing 150–250 g are injected I.P with 100–125 mg/kg
of alloxan. Rats showing fasting blood glucose level above 150 mg/dL will be selected
for the study.
Toxicity study:Acute toxicity study will be conducted as per OECD guidelines 420.
Rats will be divided into twelve groups each consisting of six animals.
Group 1: Normal control.
Group 2: Diabetic control.
Group 3: Glibenclamide.
Group 4: Metformin.
Group 5: Alcoholic extract of Cinnamomum cassia low dose.
Group 6: Alcoholic extract of Cinnamomum cassia high dose.
Group 7: Alcoholic extract of Cinnamomum cassia low dose + glibenclamide.
Group 8: Alcoholic extract of Cinnamomum cassia high dose + glibenclamide.
Group 9: Alcoholic extract of Cinnamomum cassia low dose + metformin.
Group 10: Alcoholic extract of Cinnamomum cassia high dose + metformin .
Group 11: Alcoholic extract of Cinnamomum cassia low dose + glibenclamide and
metformin.
Group 12: Alcoholic extract of Cinnamomum cassia high dose + glibenclamide and
metformin.
15
ESTIMATION OF BIOCHEMICAL PARAMETERS:Following Bio-chemical parameters will be estimated using commercial assay
kit:
Blood glucose level.

Total cholesterol.

HDL.

LDL.

VLDL.

Triglycerides.

Serum albumin.

Total protein.

Body weight.
16
ENCLOSURE – VI
7.3 Does the study require any investigation or intervention to be conducted on
patients or other humans or animals? If so, please describe briefly.
Yes, the above study requires investigation on animals.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
The study is cleared from Ethical Committee of the institution. (Applied for
clearance).
17
ENCLOSURE – VII
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18
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20
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21