Synopsis for m. Pharm dissertation submitted to




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Study of Nephroprotective effect of aqueous and ethanol extracts of Nelumbo nucifera gaertn seeds on gentamicin and cisplatin induced nephrotoxicity in animal models”.

SYNOPSIS FOR

M. PHARM DISSERTATION

SUBMITTED TO

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES

BENGALOORU, KARNATAKA.

SUBMITTED BY

RADHAKRISHNA.B

I M. PHARM

DEPARTMENT OF PHARMACOLOGY

P.E.S COLLEGE OF PHARMACY

BENGALOORU – 560050

(2010-2011)

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,


KARNATAKA. BENGALOORU,

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION


1.



NAME OF THE CANDIDATE AND ADDRESS


RADHA KRISHNA.B

S/O B.S. BASAVARAJ

#89, Venkataswamy layout Subbana playa

ITC road , M.S.Nagar post

Bengalooru -33



2.




NAME OF THE INSTITUTION


PES COLLEGE OF PHARMACY

50 FEET ROAD, HANUMANTHNAGAR

BENGALOORU-50



3.




COURSE OF STUDY AND SUBJECT


M-PHARM

PHARMACOLOGY


4.



DATE OF ADMISSION TO COURSE


15th JUNE 2010


5.




TITLE OF THE TOPIC :

Study of Nephroprotective effect of aqueous and ethanol extracts of Nelumbo nucifera gaertn seeds on gentamicin and cisplatin induced nephrotoxicity in animal models”.









6.0

7.0

8.0




BRIEF RESUME OF THE INTENDED WORK:

6.1 GENERAL DISCUSSION

Kidneys are the primary organs of the urinary system, which purifies the blood by removing wastes from it and excreting them from the body in urine. Every day, the kidneys filter about 45 gal (180 L) of blood, about four times as much as the amount that passes through any other organ. Because of this high volume, the kidneys are more often exposed to toxic substances in the blood and are very vulnerable to injury from those sources. 1

Nephrotoxic injury is damage to one or both of the kidneys that results from exposure to a toxic material, usually through ingestion. Nephrotoxic injury can lead to acute renal failure, in which the kidneys suddenly lose their ability to function, or chronic renal failure, in which kidney function slowly deteriorates. If unchecked, renal failure can result in death. Chronic exposure to drugs, occupational hazards, or environmental toxins can lead to chronic interstitial renal diseases. The following are the major causes of chronic interstitial renal diseases, occupational exposure to heavy metals, chronic intake of mesalazine for intestinal disorders, lithium for depression, and cyclosporine in renal and nonrenal diseases, and environmental or iatrogenic exposure to fungus or plant nephrotoxins (ochratoxins, aristolochic acids)2.

Several drugs causes nephrotoxicity which includes antibiotics, primarily aminoglycosides ,sulphonamides, amphotericin B, polymyxin, neomycin, bacitracin, rifampin, trimethoprim, cephaloridine, methicillin, oxy- and chlorotetracyclines , analgesics, including acetaminophen, NSAIDS (e.g. aspirin, ibuprofen), all prostaglandin synthetase inhibitors3 contrast agents used in some diagnostic tests, such as sodium iodide, anti-cancer drugs (cyclosporine , cisplatin, and cyclophosphamide,) methemoglobin-producing agents, solvents and fuels such as carbon tetrachloride, methanol, amyl alcohol, and ethylene glycol herbicides and pesticide

Several in vivo and in vitro studies have demonstrated that reactive oxygen metabolites including free radical species, superoxide, hydroxyl radical anion and hydrogen peroxide are important mediators of tissue injury. Oxygen free radicals have been implicated in several biological processes potentially important in glomerular diseases4, and also their role in neutrophil mediated glomerular diseases. Previous studies have demonstrated, an increase in renal cortical lipid peroxidation in gentamicin treated rats5 and in vitro generation of hydrogen peroxide by renal coritcal mitochondria6.

Many different chemical agents were used to prevent nephrotoxicity in both animal models and human subjects7. Unfortunately, at present there are not much suitable allopathic medicines in the market to protect nephrotoxicity. So, in drug therapy of nephrotoxicity care should be taken for the dose adjustment in other diseases. In drug therapy of nephrotoxicity, physicians will prescribe drugs like nitrogen supplements, electrolyte supplements, some effective antibiotics and to relive pain in nephrotoxicity analgesics will be administered. Dialysis treatment will also be done. As per our concern at present, the marketed allopathic medicine available is ketosteril tab. Herbal drugs reported to be useful in nephrotoxicity are: grapevine, Indian corn, stroke bill, Stem and roots of banana, Coconut, Fennel, Black cumin, Safranal8 etc. Hence in the present the protective effect, of Nelumbo nucifera seed extracts for nephrotoxicity will be studied.



6.2 NEED FOR THE STUDY

Aminoglycosides and cisplatin have long been one of the commonest causes of the drug induced nephrotoxicity. Aminoglycosides including gentamicin are very important agents for the treatment of gram negative bacterial infections. Nephrotoxicity is the major side effect of aminoglycosides, accounting for 10-15% of all cases of acute renal failure 9. The specificity of gentamicin renal toxicity is apparently related to its preferential accumulation in the renal convoluted tubules and its effect on biological membranes. The incidence of nephrotoxicity from aminoglycosides has increased from 2 to 3% in 1969 to 20% in the past decade10. Despite nephrotoxicity and ototoxicity, the aminoglycosides are continuously being used in clinical practice because of their bactericidal efficacy, synergism with ß-lactam agents, lowcost, limited bacterial resistance, and a post-antibiotic effect.


RENAL HANDLING OF AMINOGLYCOSIDES

Aminoglycosides are polycationic, a property that is responsible for their poor oral absorption, a poor penetration into CSF, and a rapid renal clearance. The polycationic charge also appears to contribute to nephrotoxicity. Aminoglycosides have molecular weight of approximately 500 Dalton and are water-soluble and minimally protein bound. The primary route of elimination from the body is glomerular filtration, which is nearly equal to insulin clearance. A small percentage (approximately 5) of the filtered aminoglycoside gets actively reabsorbed in the proximal tubule. The serum half-life of aminoglycosides is a few hours as compared to 4 to 5 days in proximal tubule cells 11.


CLINICAL FEATURES OF AMINO GLYCOSIDES INDUCED NEPHROTOXICITY

The most common clinical presentation is non-oliguric acute renal failure. The earliest urinary manifestations are: an increase in urine output and the appearance of enzymuria. Enzymuria represents the elimination in the urine of fragments of brush border membrane or lysosomal enzymes. Measuring enzymuria as an early marker of tubular damage. The onset of renal failure is usually slower and the daily rise of serum creatinine tends to be lower than other causes of acute renal failure. Serum creatinine and blood urea nitrogen characteristically increase 7 to 10 days after initiation of aminoglycoside therapy. In more than half of the cases with nephrotoxicity, the decline in renal function occurs only after the therapy has been complete. In patients with underlying chronic kidney disease, recovery in renal function may be incomplete in some. In addition, various tubular dysfunction and electrolyte abnormalities may also occur12.

Cisplatin is a potent and valuable chemotherapy agent used to treat a broad spectrum of malignancies. Renal tubular dysfunction and a cumulative impairment in renal function, as manifested by a decline in the glomerular filtration rate (GFR), can be dose-limiting. The laboratory observation that forced hydration and diuresis may prevent nephrotoxicity facilitated the subsequent clinical development of cisplatin13.Cisplatin is a potent cellular toxin, particularly in a low chloride environment. In the interior of cells, chloride atoms in cisplatin are replaced by water molecules. This hydrolysis product is believed to be the active species, reacting with glutathione in the cytoplasm and DNA in the nucleus. In tumors and other dividing cells, cisplatin-DNA intrastrand crosslinks result in cytotoxicity. These molecular events are thought to be responsible for arresting cancer cell proliferation. More than 50 percent of the drug is excreted in the urine in the first 24 hours following cisplatin administration, and the concentration of platinum achieved in the renal cortex is several folds greater than that in plasma and other organs.Cisplatin primarily injures the S3 segment of the proximal tubule, causing a decrease in the glomerular filtration rate14.

Ayurveda, an indigenous system of medicine, offers a vast scope of renal treatment for renal failure. Plants and other natural substances have been used as the rich source of medicine. Also, herbal drugs are more easily accessible & affordable in developing countries like India. This is because; traditional medicines are highly popular in many developing countries due to their firm embedment with in wide belief system.


A decoction of the Nelumbo nucifera extracts (Family: Nymphaeaceae) is being used in the treatment of kidney failure in some parts of Karnataka ( personal communication). However the literature review that, Nelumbo nucifera extracts has not been studied for its nephroprotective activity. The plant is rich in alkaloids, astringent quality, sweet, febrigue, styptic, antioxidant15, property, has been proved which provoked an interest in selecting this plant for the study. Hence, in the present study, the Nelumbo nucifera seed extracts are selected to study its nephroprotective activity on drug induced nephrotoxicity in animal models.
6.3 REVIEW OF LITERATURE16:
Introduction

Nelumbo nucifera, known by a number of names including Indian Lotus, Sacred Lotus, Bean of India, or simply Lotus. This plant is an aquatic perennial. Under favorable circumstances its seeds may remain viable for many years, with the oldest recorded lotus germination being from that of seeds 1300 years old recovered from a dry lakebed in northeastern China. Native to Greater india and Bangladesh. It is commonly cultivated in water gardens, the lotus is the national flower of India .
PLANT PROFILE

Lotus Plant Classification


Kingdom : Plantae

Division: Magnoliophyta

Class: Magnoliopsida

Order : Proteales

Family : Nelumbonaceae

Genus : Nelumbo

Species : N. nucifera

Scientific Name : Nelumbo nucifera
Vernacular names17
Kannada : Kamala,Tavaregadde.
English :East Indian lotus, Sacred lotus, Indian lotus, Egyptian lotus.
Hindi :kamal

Malayalam :Thamara,Senthamara.
Tamil :Ambal,Thamarai.

Bengali : Padma.

Telugu :Kalung, Erra thamara.
ECOLOGY AND DISTRIBUTION.

Native to Greater India and Bangladesh. It is commonly cultivated in water gardens, the lotus is the national flower of India and Vietnam.

PLANT DESCRIPTION17:

Nelumbo nucifera is a perennial aquatic herb, root-stock stout, cylindrical, embedded in the mud.leaves peltate, radiately nerved,margins wavy, petiole long, aculeate, inserted in the middle of the leaf.Flowers large, solitary, handsome and fragrant, rosy or white, carpels numerous, ovoid, fleshy, sunk separately in cavities of receptacle, maturing into nut-like achenes, skin hard and blackish-brown when ripe.

HABITAT: Common, Cultivated in ponds and swamps.

PROPAGATION; By rhizome.

PARTS USED: Leaves, roots, receptacles, filaments, plumules, stamen. The leaves are harvested in autumn and the flowers in summer, the seeds are collected when fully ripe.
CHEMICAL CONSTITUENTS: Plant contains anonaine, pronuciferine, nuciferine, N-nornuciferine, O-nornuciferine, liriodenine, d-methyl coelourine, remerine and dl-armeparine. Leaves contain alkaloids nuciferine, roemerine, non-nuciferine. Petioles, pedicles and seed embryo contains nelumbine. Flowers contain lupeol, α-amyrin, lysine,ß-sitosterol,N-triacontanol, amino acids. Seeds contain oxoushinsunine, N-norarmeparine, isoliensinine, nerferine, armepavine and 4-methyl-N-methylcoclaurine.The plumules yield proteins, sugars and vitamins.The receptacles contain quercetin18
MEDICINAL USES19

The Sacred water lotus has been used in the Orient as a medicinal herb for well over 1,500 years. All parts of the plant are used as astringent, cardiotonic, febrifuge, hypotensive, resolvent, stomachic, styptic, tonic and vasodilator, treatment of sunstroke. Lotus seeds are classified as astringents, being sweet and neutral, and benefiting the spleen, kidney, and heart. The astringent quality helps prevent loss of kidney essence. seed contains several medically active constituents, including alkaloids and flavonoids. It is hypotensive, sedative and vasodilator, lower cholesterol levels and to relax the smooth muscle of the uterus, used in the treatment of poor digestion, enteritis, chronic diarrhoea, spermatorrhoea, leukorrhoea, insomnia, palpitations , thirst in high febrile disease, hypertension, and restlessness,abdominal cramps, bloody discharges ,haemostatic,It is used in treating bleeding gastric ulcers, excessive menstruation, post-partum haemorrhage, urinary frequency, premature ejaculation, haemolysis, epistasis and uterine bleeding, agitation, fever, root is tonic. The root starch is used in the treatment of diarrhoea, dysentery etc, a paste is applied to ringworm and other skin ailments. It is also taken internally in the treatment of haemorrhages, excessive menstruation and nosebleeds,nasal bleeding, haemoptysis, haematuria and functional bleeding of the uterus. The plant has a folk history in the treatment of cancer, modern research has isolated certain compounds from the plant that show anticancer activity.


TRADITIONAL MEDICINAL USES19
Rhizome-sunstroke, fever, diarrhoea, dysentery, dizziness, vomiting of blood, haemorrhoids.

Flower- Cough, Fever, Skin eruptions, Biliousness

Whole plant- Haemorrhage, Sterility, skindiseases, bleeding piles, menorrhagia, ulcers, thirst.

Seeds:Diabetes dysuria and hyperdipsia


REPORTED ACTIVITIES OF NELUMBO NUCIFERA GAERTN :

The analgesic activity of lotus seeds ( Nelumbo nucifera) was reported in Albino rats20.

Effects Nelumbo nucifera seeds on reproductive organs of female rats were reported21. Anti-obesity effect of Nelumbo nucifera leaves extract was reported in mice and rats22.The anti-diarrhoeal activity of Nelumbo nucifera rhizome extract was evaluated23. The antisteroidogenic effect of the seed extract of Nelumbo nucifera in the testis and the ovary of the rat was studied24. Attenuation of acute and chronic stress-induced perturbations of Nelumbo nucifera were reported in experimental animals25. Cytoprotective activity of lotus (Nelumbo nucifera Gaertner) leaf extracts on the mouse embryonic fibroblast cell was reported26. Synthesis of silver nanoparticles using Nelumbo nucifera leaf extract and its larvicidal activity against malaria and filariasis vectors were reported27. The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine genes expression, and cell proliferation in human peripheral blood mononuclear cells was reported28. Water extracts from nelumbo nucifera leaf reduced plasma lipids and atherosclerosis in cholesterol-fed rabbits was reported29. Effect of Nelumbo nucifera rhizome extract on blood sugar level in rats were reported30.Antioxidant activities of various extracts of lotus (Nelumbo nuficera Gaertn) rhizome were reported31. The psychopharmacological effects of Nelumbo nucifera Gaertn rhizome extract were reported32.
6.4. OBJECTIVE OF THE STUDY:

To study the nephroprotetive effect of aqueous and ethanol extracts of Nelumbo nucifera seeds on gentamicin and cisplatin induced nephrotoxicity in experimental animal models.


1.Collection and authentification of Nelumbo nucifera

2. Extraction of plant material by water (aqueous) and ethanol using Soxhlet apparatus.

3.Determination of LD50 of the aqueous and ethanol extract of “Nelumbo nucifera” as per

OECD guidelines.

4. To establish the pharmacological profile of prepared extracts for its nephroprotective activity in gentamicin and cisplatin induced nephrotoxicity.

MATERIAL AND METHODS:
7.1 SOURCE OF DATA:

Whole work is planned to generate data from laboratory studies i.e, experiments are performed as described in reference, experimental studies in journals and in textbooks available with college and various institutions like :-



IISc library, Bengalooru.

PESCP library, Bengalooru.

RGUHS digital library (Helinet), Bengalooru.

Websites: www.sciencedirect.com

www.ncbi.nlm.nih.gov/pubmed/

www.google.com

www.ijp-online.com

Above sites will be used to obtain related information regarding this research protocol.



7.2 PLAN OF WORK:

The whole study is divided in the following phases



Phase I: Collection of plant material.

The seeds of the plant Nelumbo nucifera will be procured from the authenticated supplier in Bengalooru and it will be authenticated by the taxonomist, horticulture Department Bengalooru.



Phase II: Preparations of extracts.

Aqueous and ethanol extract of Nelumbo nucifera seeds will be obtained by successive extraction with Soxhlet apparatus. The marc obtained after ethanol extraction was macerated with water to obtain an aqueous extract. The extracts will be preserved in air tight container and will be utilized for the present study.


Phase III: Acute toxicity study.

Determination of LD50 of the aqueous and ethanol extract of Nelumbo nucifera as per OECD guidelines.


7.3 Method 1- Gentamicin induced nephrotoxicity:33
A. Experimental animal

Male Wistar rats weighing 200-250g used for the experiment. The animals are housed under conditions of controlled temperature and 12 hour day-night cycle and are fed standard chow.


B. Selection of the dose: Lower dose and higher dose of Nelumbo nucifera extract will be used.
C. Grouping of animals:

The animals are divided into 6 groups of 6 animal each.



GroupI: Control which receives only normal saline through out the course.

GroupII: gentamicin (80 mg/kg/body wt) i.p. for 8 days.

GroupIII: : Gentamicin (80mg/kg i.p) for eight days + AENNS (Aqueous extract of Nelumbo nucifera seeds) lower dose which is started prior to gentamicin injections and continued with the eight day gentamicin treatment

GroupIV: Gentamicin (80mg/kg i.p) for eight days + AENNS higher dose which is started prior to gentamicin injections and continued with the eight day gentamicin treatment.

GroupV: Gentamicin (80mg/kg i.p) for eight days + EENNS (Ethanolic extract of Nelumbo nucifera seeds) lower dose which is started prior to gentamicin injections and continued with the eight day gentamicin treatment.

GroupVI: Gentamicin (80mg/kg i.p) for eight days + EENNS higher dose which is started prior to gentamicin injections and continued with the eight day gentamicin treatment.

D. Biochemical assay: At the end of the study, the animals will be kept in individual metabolic cage for 24-hour urine collection. Before sacrificing the animal, blood is collected by orbital sinus under ether anesthesia. Estimation of urinary sodium and potassium is done by autoanalyser. Blood urea concentration, Creatinine clearance will be determined by using diagnostic kits. Lipid peroxides are estimated in plasma by using thiobarbituric acid (TBA) method to measure the malondialdehyde (MDA) reactive 33.
E. Histopathological examination: Kidneys from all the six groups will be fixed in 10% neutral buffered formalin and processed to paraffin wax. Sections will be stained with haemtoxyllin and eosin and will be examined under light microscope. They will be evaluated and assigned33, score as follows: Score 0 = normal, 1= areas of focal granulovacoular epithelial cell degeneration and granular debris in tubular lumens with or without evidence of tubular epithelial cell desquamation of small foci (<1% of total tubule population); 2= tubular epithelial necrosis and desquamation easily seen but involving less than half of cortical tubules; 3 = more than half of proximal tubules showing desquamation of necrosis but involved tubules easily found; 4 = complete or almost complete tubular necrosis.
F. Statistical analysis:

Results will be expressed as mean ± SE and data will be subjected to respective statistical analysis.




G.EXPERIMENTAL DESIGN:

Animals used: Male Wistar Rats

Method 1- Gentamicin induced nephrotoxicity:

Group


Treatment


Dose& Route of

Administration


Duration

No. of

animals

Group I

Normal saline



Oral

8 days

6


Group II

Gentamicin



80 mg/kg,i.p

8 days

6

Group III

AENNS +

Gentamicin



Lower dose +

80mg/kg, i.p.



11days

6

Group IV

AENNS+

Gentamicin




High dose +

80mg/kg,i.p.



11days


6

Group V

EENNS +

Gentamicin



Lower dose +

80mg/kg, i.p.



11days

6

Group VI

EENNS+

Gentamicin



Higher dose +

80mg/kg, i.p.



11days

6


Parameters to be Evaluated

  • URINE ANALYSIS

sodium,potassium, glucose,creatinine

  • BLOOD ANALYSIS

Urea, creatinine,MDA

  • BODY WEIGHT

  • HISTOPATHOLOGICAL EXAMINATION



7.4 Method 2-Cisplatin induced nephrotoxicity34 :
A. Experimental animal

Male albino mice weighing 25-30gm will be used for study.


B.Plant material: Naturally occurring Nelumbo nucifera plant will be collected and the aqueous and ethanolic extract of the seeds will be obtained using Soxhlet apparatus.The extract will be suspended in 2% carboxy methyl cellulose and administered orally.

C.Selection of the dose: Lower dose and higher dose of Nelumbo nucifera extract will be used.
D.Grouping of animal:
GroupI: Vehicle (normal saline)as normal.

GroupII: A single dose of cisplatin(12mg/kg i.p.) will be kept as control.

GroupIII: AENNS (lower dose) + cisplatin (12mg/kg i.p.)

GroupIV: AENNS (higher dose) + cisplatin (12mg/kg i.p.)

GroupV: EENNS (lower dose) + cisplatin (12mg/kg i.p.)

GroupVI: EENNS (higher dose) + cisplatin (12mg/kg i.p.)

G.EXPERIMENTAL DESIGN:

Animals used: Male Albino mice are divided into six groups of six animals each.



Group



Treatment



Dose& Route of

Administration


Duration

No. of

animals

Group I


Normal saline

Oral

72h

6

Group II


Cisplatin

12mg/kg i.p.

72h

6

Group III

AENNS +
Cisplatin

Lower dose +
12mg/kg i.p.

72h

6

Group IV

AENNS +
Cisplatin

Higher dose +

12mg/kg i.p.



72h

6

Group V

EENNS +
Cisplatin

Lower dose +
12mg/kg i.p.

72h

6

Group VI


EENNS +
Cisplatin


Higher dose +
12mg/kg i.p.

72h

6

The extract was administered by oral gavage 1 hr before and 24 h and 48 h after cisplatin injection.72 h after the cisplatin injection, animals will be sacrificed using ether-anesthesia; blood samples will be collected by heart puncture for measuring serum urea and serum creatinine levels. Kidneys were quickly removed and washed with ice cold normal saline and homogenates (10% w/v) .A part of homogenate will be used for the estimation of the reduced glutathione (GSH) and lipid peroxidation. The remaining homogenate will be centrifuged at 5000 rpm for 10 minutes at 4 0 C, After removal of the cell debris, supernatant was used for assay of super oxide dismutase (SOD), catalase (CAT), glutathione etc.


Parameters to be Evaluated


  • IN BLOOD

Urea, Creatinine


  • IN KIDNEY

GSH, SOD, CAT, Lipid peroxidase
7.5 Has Ethical Clearance been obtained from your institution in case of 7.3?

Yes, ethical clearance has been obtained.(copy enclosed)



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9.0




NAME OF CANDIDATE


RADHAKRISHNA.B


10.0


SIGNATURE OF THE CNDIDATE




(RADHAKRISHNA)


11.0


REMARKS OF THE GUIDE



RECOMMENDED AND FORWARDED FOR APPROVAL



11.1


NAME AND DESIGNATION OF THE GUIDE




Mr.SHIVALINGE GOWDA.K.P

ASST. PROFESSOR,

DEPT.OF PHARMACOLOGY

P.E.S COLLEGE OF PHARMACY



11.2


SIGNATURE







11.3




HEAD OF THE DEPARTMAENT



Mr.SRINATH.R

HOD& ASST.PROFESSOR

DEPT.OF PHARMACOLOGY

P.E.S.COLLEGE OF PHARMACY.



11.4


SIGNATURE






12.0



REMARKS OF THE PRINCIPAL



FORWARDED FOR APPROVAL



12.1


SIGNATURE


Prof.Dr.S.Mohan
PRINCIPAL AND DIRECTOR

P.E.S.COLLEGE OF PHARMACY

BENGALOORU-560050




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