RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE, KARNATAKA.
M PHARM SYNOPSIS
YEAR OF ADMISSION- JUNE 2007.
TITLE OF THE SYNOPSIS
“AN INVESTIGATION OF EFFECT OF CIGARETTE SMOKE ON THE PHARMACOKINETICS OF GATIFLOXACIN IN RABBITS BY
MICROBIOLOGICAL ASSAY”
BY
Mr. VINAY T M
GUIDE
Dr.DAVID BANJI, M.Pharm, Ph.d.,
Professor &principal,
Department of pharmacology,
SREE SIDDAGANGA COLLEGE OF PHARMACY,
TUMKUR-572102.
INSTITUTION
SREE SIDDAGANGA COLLEGE OF PHARMACY,
B. H.ROAD, TUMKUR-572102.
KARNATAKA STATE.
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,BANGALORE, KARNATAKA
PROFORMA FOR REGISTRATION OF SUBJECT FOR
DISSERTATION
1. Name of the candidate : VINAY T M
& Address S/O Mr. T M Panchakshariah
#234/1, Off of Old Bus Stand,
Shanthinivas, P B Road,
Davangere (Dist)
Karnataka-577002.
2. Name of the guide: Dr. DAVID BANJI, M. Pham., PhD.,
Professor & Principal,
Department of pharmacology,
Sree Siddaganga College of pharmacy
Tumkur-572102.
3. Name of intuition: Sree Siddaganga college of pharmacy,
B.H. Road
Tumkur-572102.
4. Course of study: Master of pharmacy (pharmacology)
5. Date of admission: April 2007.
6. Title of the topic: “ AN INVESTIGATION ON THE EFFECT
OF CIGARETTE SMOKE ON THE
PHARMACOKINETICS OF GATIFLOXACIN
IN RABBITS BY MICROBIOLOGICAL
ASSAY”
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BRIEF RESUME OF THE INTENDED WORK
1. GENERAL INTRODUCTION:
The development of chemotherapy during the past 60 years constitutes one of the most important therapeutic advances in the history of medicine. The term chemotherapy was coined by Ehrlich at the beginning of the century to describe the use of synthetic chemicals to destroy infective agents.1Drugs in this class differ from all others in that they are designed to inhibit/kill the infecting organism and to have no animal effect on the recipient.2
Antibiotics are the substances produced by various species of microorganisms which include bacteria, fungi, and actinomycetes etc, that suppress the growth of other microorganisms. Common usage often extends the term antibiotics to include synthetic antimicrobial agents such as sulfonamides and quinolones.
Numerous classes of antimicrobial agents have been discovered and literally hundreds of drugs are available for use today. Antibiotics are among the most commonly used of all drugs. Antibiotics differ markedly in physical chemical and pharmacological properties in antibacterial spectra and in mechanism of action knowledge of molecular mechanism of bacterial fungal and viral replication has greatly facilitated rational development of compounds that can interfere with the life cycles of microorganism.
However antimicrobial agents also are among the drugs most commonly misused by physicians although antibacterial agents are universally recognized as having no antiviral activity 50% or more of patients diagnosed with a viral respiratory tract infection are prescribed a course of antibacterial therapy. The inevitable consequence of the widespread use of antimicrobial agents as been the emergence of antibiotic resistant pathogens, fueling an over increasing need for new drugs and contributing to the rising costs of medical care. Moreover pace of antimicrobial drug development has dramatically slowed during the last decade with only a handful of new agents few of which are really novel being introduced into clinical practice each year. If the gains in treatment of infections diseases are to be preserved physicians must be wiser and more selective in the use of antimicrobial agents.3
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2. NEED FOR THE STUDY:
Number of antimicrobial agents are release to market every year & number of antimicrobial agents withdrawn from market every year due to several reasons (i e, safety, bacterial resistance, adverse drug reaction etc.)
There were 121 safety related withdrawals world wide between 1960 and 1999. During 1990 to 2001 in U K 21 drugs were withdrawn due to safety reasons including antibiotics. For example temofloxacin & grepafloxacin fluoroquinolone antibiotics are withdrawn from the market due to severe hemolytic anemia and fatal heart rhythm activity respectively.
There is very limited information available on adverse drug reaction [ADRS] in India and therefore many undesirable effects of drugs are unreported. New drugs, developed in elsewhere are being regularly introduced in Indian market. Forty-five new drugs including antibiotics were approved and marketed in India between January and June 2004.4
Once the drugs has been selected it should be used high enough doses for long enough periods to eradicate even the more resistance pathogenic mutants that may be present. Low doses may let these organisms live & rapidly become the dominant strains. Hospitals should reserve potent and new antibiotics for use in severely ill patients with serious infections which don’t respond to established drugs.5
Also sedentary life style, environmental causes, lack of exercise, diet, and alcohol consumption, cigarette smoking and drug interactions affect the pharmacokinetics of the drug.
Environmental and occupational health encompasses the diagnosis, treatment and prevention of injuries and illnesses resulting from exogenous chemical and physical agents such exposure may occur in the work place or people may voluntarily expose themselves to these hazards, for example by abusing drugs ethanol and smoking cigarettes.5
People are often confused about the magnitude of the adverse health effects of exogenous physical and chemical agents. There is a wide spread concern about the potential chronic are delayed effects of exposure to contaminants in water, food and air.
Air pollution is a serious problem in many industrialized countries. The major source of air pollutants are ; combustion of fossil fuels, photochemical reactions, power plants, waste incenarators,industry ,smelters, automobiles and cigarette smoking. Also raising energy costs during the past 30 years have lead to increase insulations and decreased ventilations of homes are elevates the level of indoor air pollutants.
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Other sources of indoor air pollutants are gas cooking, stoves and furnaces, wood stoves, construction materials, furniture, radon, allergens associated with pets, dust mites and fungal spores and bacteria.
Use of tobacco products including cigarettes, cigars, pipes, snuffs is associated with more mortality and morbidity than any other personnel environmental or occupational exposure.
Mainstream cigarette smoke inhaled by the smokers is exposed of a particulate phase and gas phase. Tar is the total particulate phase with out water or nicotine. There are 03-3.3 billion particles per milliliter of main stream smoke and more than 4000 constituents including 43 known carcinogens such as polycyclic aromatic hydrocarbons, polonium210, N1-nitrosonornicotine, 4-aminobiphenyl, 2-napthylamine etc in addition to these chemicals carcinogens, cigarette smoke contains carcinogen metals such as arsenic, nickel, Cadmium and Chromium; irritants such as nitrogen di oxide and formaldehyde; cilia toxins such as Hydrogen cyanide and carbon monoxide.6
When person begins to smoke, the risk if he/she contracting cardiac, pulmonary and cancerous diseases also begins and chases him to catch up with every inhalation. The thousands of chemicals besides the soot of cigarette inhaled for decades keep on acting on the various tissues and body systems causing changes in them ultimately leading to the irreparable deformity of the organ causing failure of the systems to function normally.7
Cigarette smoke also responsible for drug interactions. Cigarette smoke has been shown to increase hydrocarbon inducible enzymes in the lungs, liver, intestine and in the placenta of human cigarette smokers and to decrease the action and /or stimulate the metabolism of several drugs. The following effects of cigarette smoking have been reported.
· Lowered blood levels of phenacetin, theophylline and imipramine and antipyrine
· Decreased urinary excretion of nicotine.
· Decreased effectiveness of pentazocin and propoxyphene
· Decreased drowsiness from chlorpromazine, diazepam and chlordiazepoxide8
The main aim of this work is to investigate the pharmacokinetics of Gatifloxacin in experimental animal expose to cigarette smoke. Though the pharmacokinetic of gatifloxacin has been studied the pharmacokinetics of gatifloxacin in cigarette smoking has not yet been studied, so we have chosen this topic for our dissertation work.
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3. REVIEW OF LITERATURE:
GATIFLOXACIN:
Gatifloxacin is an advanced-generation, 8-methoxy fluoroquinolone oral derivative characterized by an activity against a broad spectrum of against gram-positive and gram-negative organisms, including obligate anaerobes. The antibiotic activity of gatifloxacin against Streptococcus pneumoniae, Mycoplasma, Chlamydia, and Legionella and mycobacteria, Streptococcus aureus. Like other quinolones, gatifloxacin penetrates well into leukocytes, which can deliver active drug to sites of infection and play an important role in the treatment of intracellular pathogens. Gatifloxacin drug has high oral bioavailability (96%) and broad tissue distribution and is primarily excreted unchanged (70%) in urine.9
Gatifloxacin tablets are indicated for the treatment of adults with mild to moderate infections caused by susceptible strains of the microorganisms in the infection listed below
· For treatment of bacterial infections, including chronic bronchitis.
· Acute sinusitis.
· Community-acquired pneumonia.
· Uncomplicated and complicated Urinary tract infection.
· Pyelonephritis.
· Uncomplicated urethral and cervical gonorrhea.
· Uncomplicated rectal infections in women.
· Bacterial conjunctivitis (ophthalmic).
Adverse effects:
The most common adverse reaction includes the gastrointestinal tract, abdominal pain, constipation, dyspepsia, glossitis, stomatitis, vomiting, nausea, diarrhea, anorexia.
CNS side effects Abnormal dream, insomnia, parenthesia, tremors, vasodilatation, vertigo, agitation, anxiety, confusion, headache, dizziness, asthenia.
Rashes, sweating, pruritus, dryskin, conjunctival irritation, conjunctival hemorrhage, increased lacrimation.10
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4. OBECTIVE OF THE STUDY:
· To study the effect of cigarette smoking on the pharmacokinetics of gatifloxacin in experimental animals by microbiological assay.11
tmax [Time of peak concentration]
Cmax [Peak plasma concentration]
t1/2 [Absorption half life]
Ka [Absorption rate constant]
AUC [Area under curve]
Cl [Total body clearance]
Vd [Volume of distribution]
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5. MATERIALS AND METERIALS:
A. SOURCE OF GATIFLOXACIN:
We are trying to get pure gatifloxacin from the pharmaceutical company as a gift sample.
B. EXPERIMENTAL ANIMALS:
Adult healthy albino rabbits of either sex weighing 2-3kg will be used. The animal will be fed with commercial rabbit feed and will be given water ad libitum and housed under standard animal room conditions.
C.GROUP OF ANIMALS:
Two group of animals. Each group contains 6 animals:
GROUP I - will be supplied with the normal diet and treated with gatifloxacin. This
group serves as CONTOL group.
GROUP II - will be supplied with the normal diet and treated with gatifloxacin. Also
this group is exposing to cigarette smoke for 1,7,15,30,45 and 60 days.
This group serves as TREATED group
D. SMOKING CHAMBER:
The animals are exposing to cigarette smoke by keeping bottom less rectangular wooden chamber on the top of the metal cage containing rabbits. The wooden container contains two holes of about 3cm diameter, one in the front and the other at the back of the container. A burning cigarette is introduced through one hole and air through another hole. The animals are exposing to the smoke of burning cigarette for 15min, twice daily, at the same time every day, morning and evening [10.0AM AND 4.00PM]. 12, 13.
E. BLOOD WITHDRAWAL AND MEASUREMENT:
In this study gatifloxacin administered orally as per body weight of serial samples of blood are collected from the ear vein of each animal at different time intervals in heparinaized centrifuge tubes.14 The plasma is collecting after centrifugation, at Gatifloxacin in plasma samples is determining by microbiological assay using agar diffusion method.
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F. SELECTION OF MICROBE:
We are going to select the suitable microbial strain for this work by doing bacteriological sensitivity test in our laboratory. However, the sensitive strains of microorganisms as per literature are Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Haemophilus influenza, Neisseria gonorrhea, Pseudomonas aeruginosa, Chlamydia trachomatis, Proteus mirabilis, Haemophilus influenza, etc.
G. MEDIA PREPARATIONS:
Microorganism cultures are maintained in nutrient broth. Stock cultures of microorganisms from the clinical isolates are maintained on nutrient agar plates & stored at 40 c. Before each assay run, the organism is subculture on to nutrient broth. At least two transfers in nutrient broth are made before the test assay. The nutrient broth cultures are kept at 37 0 c for 24hrs.15
Nutrient agar [11.5gm] is dissolved in 500ml of distilled water & PH adjusted to 7.0 using 0.4N Noah solution. The nutrient agar solution is autoclaved for 20min at 15lbs pressure. The agar solution is then brought to 37 0 c to 40 0 c & the organism kept in nutrient broth is seeded. This is then poured in to sterile Petri plate’s wells of 2mm diameter are cut 14.
F. STATISTICAL ANALYSIS:
Statistical analysis of gatifloxacin will be done by using student’s ‘t’ test.
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6. EXPERIMENTAL DESIGN:
Animals used: Rabbits
Route of drug administration: Oral
SLNO / GROUP / TREATMENT / DURATION / DOSE
(mg/kg) / NO.OF
ANIMALS / PARAMETERS
01 / I / GATIFLOXACIN / 1st DAY / 40 mg/kg / 6 / tmax
Cmax
t1/2
Ka
K10
AUC
CI
Vd
7th DAY / 40mg/kg
15th DAY / 40mg/kg
02 / II / SMOKING / 1st -60th
DAY / SUITABLE
DOSE / 6
GATIFLOXACIN / 1st DAY / 40mg/kg
7th DAY / 40mg/kg
15th DAY / 40mg/kg
30th DAY / 40mg/kg
45th DAY / 40mg/kg
60th DAY / 40mg/kg
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BIBLIOGRAPHY:
1. Rang HP, Dale MM, Ritter JM. Pharmacology, 4th ed. Edinburgh Churchill Livingstone publication 2003: 648.
2. Tripathi KD. Essentials of medical pharmacology, 5th ed. New Delhi Jaypee Brothers medical publishers (p) Ltd. 2003: 646-652.
3. Joel GH, Limbird LE, Goodman and Gilman’s The Pharmacological basis of therapeutics, 10th ed. India: Mc Graw-hill medical publishing division, New York 2001: 1143-69, 1179-85.
4. Subal C. Basak. Safety issues of drug use: past lessons and present dilemmas, the pharma review 2005; 4: 81-84.
5. Barar FSK. Essentials of pharmacokinetics, 1st ed. New Delhi: S.Chand & company Ltd 2006: 386-338.
6. Kumar, Abbas, Fausto. Robbins and cotran pathologic basis of disease, 7th ed. New Delhi Elsevier publication 2005; 415: 419-430.
7. Bhagavan PS. Pharmacist for tobacco free future, 1st ed. Bangalore Karnataka state pharmacy council publication 2005: 27.
8. William OF. Principles of medicinal chemistry 3rd ed. Bombay Varghese publishing house 1989: 109.
9. http://www.medsafe.govt.nz/profs/datasheet/tequintabinj.htm.
10. http://www.drugs.com/ ppa/gatifloxacin.html.
11. http://aac.asm.org/cgi/reprint/50/6/1931
12. Baskaran S, lakshmi S & Prasad PR. Effect of cigarette smoke of lipid per
oxidation & anti oxidation enzymes in albino rat.
Indian J Exp Biol Dec 1999; 37: 1196-1200.
13. Chitra S, Semmalar R, Shyamaladevi CS. Effect of fish oil on
cigarette smoking induced dyslipidemia in rats.
IJP Apr.2000; 32:114-119.
14. http/aac.asm.org./cgi/reprint/45/3/794. .
15. Chakraborty P. A text book of microbiology 2nd ed: 47-52.
16. http/aac.asm.org./cgi/reprint/46/1/231.