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NEW DRUG DEVELOPMENT Moderator – Dr.Amitabh kumar , Professor Presenter – Dr.Sriharsha Rayam

new drug development by harsha

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Page 1: new drug development by harsha

NEW DRUG DEVELOPME

NT

Moderator – Dr.Amitabh kumar , Professor

Presenter – Dr.Sriharsha Rayam

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INTRODUCTION

• Average time to develop new drug is 10 -12 years.• On an average out of 10,000 – 30,000 potential

substances only 1 could make it to the market.• As per 2006 estimates, the cost of bringing a new

drug could vary from 500 million to 2,000 million USD.

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unmet medical need;

new diseases ( AIDS, Alzheimer’s; obesity);

low efficacy (dementia, cancer);

side effects (antidepressants, antipsychotics)

cost of therapy; (Interleukins)

costs to individual/country; (Alzheimer’s; spinal

injury, depression)

sustain industrial activity ( pharmaceutical industry

employs thousands and makes a massive contribution

to overseas earnings); patent expiry

WHY ARE NEW DRUGS NEEDED?

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• Folk medicine - natural product remedies

• Early 19th century - extraction of compounds from plants (morphine, cocaine )

History of Drug Discovery….

• James Lind – Citrus fruits – Scurvy – clinical trail

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1909 - First rational drug design. • Goal: safer syphilis treatment than Atoxyl.

• Paul Erhlich and Sacachiro Hata wanted to maximize toxicity to pathogen and minimize toxicity to human (therapeutic index).

• They found Salvarsan (which was replaced by penicillin in the 1940’s)

H2N

AsHO O

O

Atoxyl

As AsHO OH

ClH.H2N NH2.HCl

Salvarsan

Na+

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• Mid to late 20th century - understand disease states, biological structures, processes, drug transport, distribution, metabolism. Medicinal chemists use this knowledge to modify chemical structure to influence a drug’s activity, stability, etc.

• procaine = local anaesthetic; Procainamide = antirhythmic

H2N

O

NHCH2CH2N(C2H5)2H2N

O

OCH2CH2N(C2H5)2

Procaine Procainamide

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Drug development process – 3 main phases

• 1.drug discovery phase• 2.preclinical phase • 3.clinical trial phase

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Drug discovery phase

1. Random screening

2. Serendipity ( By chance )

3. Rational drug designing

4. Designing of a prodrug or an active metabolite as a drug

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1.RANDOM SCREENING

• Blind hitting procedure where new chemical entities are subjected to pharmacological screening procedures

• Studies on animal models , isolated tissues etc • It is time consuming, expensive, inefficient in

providing fruitful results ,burdensome• Ex:• Morphine, Atropine , digitalis, Quinidine,

cyclosporine

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2.SERENDIPITY (BY CHANCE / HAPPY OBSERVATION)

• New use from old drug or its side effects

• Lignocaine & Phenytoin

• Methotrexate – psoriasis

• Cyclophosphamide & Azathioprine – Graft rejection

• Penicillin 1928, Fleming studied Staph, but contamination of plates with airborne mold. Noticed bacteria were lysed in the area of mold. A mold product inhibited the growth of bacteria: the antibiotic penicillin

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3.RATIONAL DRUG DESIGNING

• A. compound centered approach

: from natural products – Pencillin,paclitaxel,cyclosporine

DA – complex molecules – difficult to synthesized

: from synthetic products – from pharmacological data

Ex: Based on proponolol structure- B blokers

H2 blockers - modifying structure of histamine

• Molecular modification ended up in molecular manipulation

New drugs are serving as me too drugs , no added advantage

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B. Target centered approach

* Biochemical or molecular targets Ex: ACE blockers or AT II blockers -Now a days large number of drugs this way -Promising agents for lead optimisation

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4. DESIGNING OF A PRODRUG OR AN ACTIVE METABOLITE AS A DRUG

• Administered as the precursor of a drug and is converted into active therapeutic agent Ex; Levodopa

• Paracetamol, an active metabolite of phenacetin

• N-acetyl procainamide, an active metabolite of procainamide does not cause SLE

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Drug sources

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• After the synthesis or isolation of the compound =

• Purity by physico chemical and analytical studies Then these are subjected to biological screening LEAD COMPOUND - which have a potential of becoming

new drug

•compounds can elicit a positive response in a particular assay, which is called a hit.

• “Lead” is a hit series for which the structure–activity relationship is shown and activity demonstrated both in vitro and in vivo

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Leads are optimised with respect to

Pharmacodynamic properties-efficacy, potency,

selectivity.

Pharmacokinetic properties- metabolic stability and

toxological aspects

Physiochemical properties

Chemical optimisation-ease of chemical synthesis &

derivation

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PRECLINICAL EVALUATION PHASE ( ANIMAL STUDIES)

Major areas are:

Pharmacodynamic studies In vivo in animals, In vitro preparation

Absorption, distribution , elimination studies (pharmacokinetics)

Acute ,sub acute, chronic toxicity studies (toxicity profile)

Therapeutic index (safety & efficacy evaluation)

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Pharmacodynamic studies •Action relavent to proposed therapeutic use are studied on animals Ex: Antihypertensive activity – dogs,cats,rats To find out – B.P - ECG changes - inotropic & chrinotropic efforts - CO & t.p.r •Once L.C exibits promising results – futhur studies at cellular level •Receptor activity in vitro on cultured cells •Further extended to molecular level to find out receptor affinity & selectivity by performing in vitro studies on cell membrane fractions from organs •Graded response assy or Quantal assay - ED 50 of the drug•

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Pharmacokinetic profile

New compounds subjected in several species of animals.

Studies should establish

a) Relative bioavailability of the compound on oral or parenteral administration

b) Elimination half life for assessment of optimal dosage interval

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Acute toxicity Acute toxicity studies most commonly median lethal

dose

i.e. LD50 is determined. Drug is given in graded doses to at least 2 animal

species by at least 2 routes. To minimize biological variation, animal groups should

be similar. Percentage of animals dying in each group within

specified time (24 hrs) is plotted against the dose. Other toxic symptoms suffered also recorded.

Toxicity profile

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Sub acute toxicity To identify target organs susceptible to drug toxicity. Laboratory studies like hematology, renal ,hepatic

function test are carried out. Animals are maintained at max. tolerated dose for 4 wks

– 3 months & killed for HPE.

Chronic toxicity If drug intended for chronic use in humans. 2 species of animals ,1 rodent and 1 non rodent are

used.

Drug administered for many months (6-24 months),detailed biochemical & histological measurements are made.

To evaluate cumulative toxicity To assist carcinogenic potential Study may run simultaneously with clinical trial.

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Test for fertility & reproductive performance Carried out in rats, treated with new drug before & after

mating period. Effects on early & late stages of embryonic & fetal

development are studied .

Teratogenicity Carried out in 2 animal species to assess the effects of

drug on organogenesis. Drugs given after mating Fetuses are carefully examined for abnormalities.

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Genotoxicity/ Mutagenicity:

It is invivo – invitro test conducted to detects

compounds which induces genetic damage directly or

indirectly. The following standard test is generally expected to be conducted : 1. A test for gene mutation in bacteria – AMES test

2. An invitro test with cytogenetic evaluation of chromosome damage with mammalian cells

3. In vivo test for chromosomal damage using rodent Hematopoietic cells.

Parameters:

Frequency of damage cells ,Total number, types and frequency of metaphase chromosomal aberration

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CARCINOGENECITY :

• for all drugs that are expected to be clinically used for six months as well as for drugs used frequently in an intermittent manner in the treatment of chronic or recurrent condition

• Animals : rodent 2 animal species , same dose of chronic study,

for 2 years.• Parameters : Autopsy and detailed Histopathology of organ and

tissues

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LOCAL TOXICITY:

These studies are required when the new drug is proposed to be used by some special route in human.

Dermal toxicity Vaginal toxicity Rectal tolerance test Ocular toxicity

1. Dermal toxicity: Animals: rabbit & rat Parameters: erythema & edema2. Vaginal toxicity: Animals: rabit & dog Parameters: swelling, closure of introitus & histopathology

of vaginal wall.

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3. Rectal tolerance test-

Animals: rabbit & dog

Parameters: sign of pain, blood/mucus in faeces, histopathology of rectal mucosa.

4. Ocular toxicity-

Animals: rabbit

Parameters: Slit Lamp Test & Fluroscent Dye Test

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3.Therapeutic index Relative margin of safety of a drug

TI =LD50/ED50• Maximum Tolerated Dose • No Adverse Effect Dose • Human Equivalent Dose

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REDUCING ANIMAL USAGE

• About 2.6m animals/y used in procedures in UK (11.6m in Europe)

• Likely to increase; more research, more targets, genetic capability

• 3Rs -- 3Rs -- 3Rs

• REPLACEMENT: use non-animal tests if possible (cheaper, less trouble, less variable but not possible for everything at this time)

• REDUCTION: get the statistics right, don’t replicate work unnecessarily, don’t overbreed

• REFINEMENT: reduce suffering and severity of procedure, pay attention to housing, stress, husbandry and rich environments, proper analgesia and pre- and post- operative care

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CLINICAL TRIAL PHASE(HUMAN PHASE)

• To determine safety & efficacy of a new drug in humans

• Good clinical practices (GCP) by international Conference on Harmonization (ICH) and declaration of Helsinki.

• It provides details about – designing the trail

- collection of data

- recording of information

- statistical analysis

- documentation & reporting

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IND APPLICATION

• When the new compound passes the preclinical phase , manufacturer may file a Investigational New Drug (IND) application to authorized drug control body

• In INDIA - drugs controller general,Govt.of india,Delhi

• It contains information about the test drug –

- source,structure,manufacturing data

- preclinical data

- dosage forms,investigational protocol

- details about investigators

- agreement from the sponsers

- certification that Informed Consent will be obtained from volunteers

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Eight basic elements of informed consent purpose of the research risks or discomforts any benefits to the subject which may reasonable be expected from

the research Any alternative procedures or treatment that may be available to the

subject confidentiality of records identifying the subject will be maintained any compensation and whether any medical treatments are

available if injury occurs An explanation of whom to contact for answers to questions about

the research and research subjects’ rights A statement that participation is voluntary

Informed consent

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Ethics committee & its responsibilities

• At the institutional level – independent E.C to ensure rights & welfare of the participants

• Responsibilities - review protocol - safeguard the rights , safety of trail subjects - periodical review – SOPs • 7 members – Member secretary - chair person (outside) - medical & non medical persons

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ROLE OF PLACEBO

• Placebo controls – on healthy volunteers – Appetite stimulant or new vaccine

• No place – Pt suffering from a disease – effective drug already available

• Ethics – consent is taken

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PHASES OF CLINICAL TRIALS

• 4 phases

phase I

phase II

phase III

phase IV

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PHASE 1 CLINICAL TRIALS :

• Begins after 30 days of filing IND.• Drug given to 20-100 healthy volunteers

• Duration could vary from 1 month to 1 year. • Following is studied here :

• Drug absorption/Metabolism in human. • Effect on organs and tissues. -Side affect of different

dosages. • Thus early evidences on effectiveness are achieved*NON BLIND OR OPEN LABEL TRAIL

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Phase I studies are carried out in 2 stagesSingle rising doseRepeat administration

Each volunteer given a single dose of drug/placebo. Dose-escalating study design. Initial dose and route of administration decided from existing

pre-clinical data. 8 -12 volunteers . 2-4 volunteers receive placebo and 6-8 volunteers receive drug

under study.

STAGE 1–SINGLE RISING DOSE

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Started after single dose administration results assessed.

Drug / placebo given repeatedly for 1 or more weeksE. g. Antibiotics given for 5-7 daysAnticonvulsants tested for 4 weeks or more

Interval between doses is usually one half life. Kinetic data obtained from blood and urine sample

collected after 1st and last dose

STAGE 2 REPEATED ADMINISTRATION

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PHASE 2 CLINICAL TRIALS :

• Therapeutic exploratory trial• First time in patients

• Less than 300 patients• Doses are usually less than the highest doses

used in phase I *SINGLE BLIND TRAIL

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1. Efficacy in patients

2. Safety issues

3. Optimum dose finding Dose efficacy relationship Therapeutic dose regimen Duration of therapy Frequency of administration Therapeutic window

OBJECTIVES

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PHASE II DIVIDED INTO EARLY & LATE PHASE

• EARLY PHASE II

small number of pts – upto 200

detail therapeutic benefited & ADR

idea to establish dose range

SINGLE BLIND STUDY

• LATE PHASE II

large number of pts – 200-400

DOUBLE BLIND STUDY

third party holds the code identifying studies

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PHASE 3 CLINICAL TRIALS :

• By several physicians at many centres• Large scale – 1000 to 5000 plus• To further establish the safety & efficacy • Long term side effects in patients• Duration could vary from 5 years to 6 years. • DOUBLE BLIND CROSS OVER design • At end of trail statistical analysis of data is

performed

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Pts groups Week 1 Week 2 Week 3

ISTANDARD DRUG

PLACEBO NEW DRUG

IIPLACEBO NEW DRUG STANDARD

DRUG

IIINEW DRUG

STANDARD DUG

PLACEBO

Double-Blind Cross Over design

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NDA

• NDA Refers to New Drug Application • Formal proposal for the FDA to approve a new drug for

sale • Sufficient evidences provided to FDA to establish:

• Drug is safe and effective. • Benefits outweigh the risks. • Proposed labeling is appropriate.

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PHASE IV

• launched to the Market • Post marketing surveillance – field trails • No fixed duration • To discover relatively rare side effects(congenital effects) or

drug interactions• From hundreds to thousands of people• Usually takes place after drug is approved to provide additional

information on the drug’s risks, benefits and optimal use

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PERIODIC SAFETY UPDATE REPORT (PSUR)• Report any new information about the new drug & its

safety

• Every 6 months for 2 yrs & annually next 2 yrs

Where the drug fails ?

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EXAMPLE: THALIDOMIDE

Thalidomide was developed by German pharmaceutical company Grünenthal. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to pregnant women, as an antiemetic to combat morning sickness and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.

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Birth defects

caused by use of thalidomide

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EXAMPLE: THALIDOMIDE

From 1956 to 1962, approximately 10,000 children were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy. In 1962, in reaction to the tragedy, the United States Congress enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S.

Phocomelia presents at birth very short or absent long bones and flipper-like appearance of hands and sometimes feet.

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Pharmacovigilance

• Pharmakon – a drug , vigilare – to be observant • Continuous monitoring for unwanted effects & other

safety related aspects of marketed drugs • Thalidomide, Isotretinoin , • Fenfluramine & Phentermine – PHTN & valvular H.D• Troglitazone – liver toxicity

• WHO – safety monitoring of medical products - setting a P.V centre in every country

• P.V – Detection,Assessment, Understanding and Prevention (DAUP) of ADR

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• INDIA ,National P.V centre – AIIMS, New Delhi by central drug standard control organization (CDSCO)

• 2 zonal , 8 regional & 28 peripheral P.V centres• Generated data – global P.V database at WHO-Uppsala

monitoring centre-Sweden• Reporting ADR includes: -drug interaction -death -life-threatening reaction -hospitalization -disability -congenital abnormality

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• Pharmaceutical companies are commercial enterprises• Pharmaceutical companies will, therefore, tend to avoid

products with a small market (i.e. a disease which only affects a small subset of the population)

• Pharmaceutical companies will also avoid products that would be consumed by individuals of lower economic status (i.e. a disease which only affects third world countries)

Choosing a Disease

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Most research is carried out on diseases which afflict “first world” countries: (e.g. cancer, cardiovascular diseases, depression, diabetes, flu, migraine, obesity).

Choosing a Disease

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The Orphan Drug Act

• The Orphan Drug Act of 1983 was passed to encourage pharmaceutical companies to develop drugs to treat diseases which affect fewer than 200,000 people

• Because the cost incurred will not be recovered• So rare diseases are left untreated – orphan diseases ,

drugs – orphan drugs • Govt. offered tax relief and exclusive marketing rights • > 300 drugs Ex: factor XIII , Erythropoietin , Atravaquone ,

Antithrombin III , Miltefosine , Acetyl cysteine , Relaxin

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New tools for drug screening

HIGH THROUGHPUT SCREENING

Screening large libraries of 2 lakh compoundsRate of 1,00,000 compounds/day

In HTS chemicals are tested for their ability to modify a target

Methods – screening of combinatorial chemistry ,genomics, proteomics & peptidelibraries

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Drugs are tested for their activity on these molecules using plates wherein a large number of compounds are simultaneously tested.

Screening depends on inhibition of enzymic products which are detected using fluoroscopy or photometry

Instrumentation 24 WELL PLATE. 96 WELL PLATE. - COMPOUND STORAGE. - COMBINATORIAL CHEMISTRY. - SAMPLE COLLECTION. -SCREENING. 384 WELL PLATES. -LOW VOLUME -DNA LIBRARY MANIPULATION. 1536 WELL PLATES.

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Advantages

Lead compound.

Molecular mechanism.

Minimizing cost and maximizing patent life time.

Highly efficient development.

Disadvantages

Availability Of Instruments.

Trained Personnels.

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HTS is a remarkable achievement in drug discovery process

to speed up preclinical discovery process. This automation in

the process is supported by the excellent software packages.

.

The goal of the HTS is to accelerate drug discovery by

screening large libraries at a rate that may exceed 50,000

compounds per week.

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CASSETTE DOSING / N-IN-ONE DOSING

• Elegant, inexpensive , time intensive novel technique – aim to rapidly assess P.K of large number of compounds

• Several compounds(5-10) to single animal & rapid sample analysis by liquid chromatography or mass spectography

• Advantages – to reduce no. of animals

- increased quality of kinetics data

- reduce the amount of the drug

- time minimized

• Disadvantages – drug to drug interactions

- false positives

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Micro dosing / First In Human( FIH) studies /Phase O

•Study of new drug in microdoses to derive PK information in human before undertaking phase I studies is called PHASE 0

•“1/100th or lower of the expected therapeutic dose.”A dose less than 100ug

•(The test compound has no pharmacologic effect at microdose concentrations)

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• Microdosing approach in man could ‘accelerate’ drug development without compromising clinical safety

• Microdosing helps researchers select better drug candidates for clinical trials by providing early human PK and bioavailability data.

• Reduced cost of development• Reduced development time

Objectives Primary:

Determine the pharmacokinetics Determine a non -toxic dose range

Secondary : Determine the safety of an chemical entity

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Limitations ? Predictive accuracy of microdosing

PK at microdose vs. therapeutic dose False positive/ negatives Compound metabolism and solubility (limited solubility at

higher doses; ? Microdose too small) Study mainly based on PK parameters - not efficacy and

safety based

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• 3rd world diseases?• orphan drugs with few users?• improve safety and efficacy records• reduce animal utilisation (cell lines; early

human volunteers, )• new diseases (AIDS; Alzheimer’s; CJ

disease;human BSE variant; obesity; cancer)• new biology - (clone human receptors;

disease model by gene changes)

The future ?

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References :

• Pharmacological basis of Therapeutics – Goodman & Gilman 12th Edition .

• Principles of pharmacology – HL Sharma & KK sharma 2nd edition .• Drug Screening methods – Gupta 2 nd edition

• Experimental Pharmacology – Bikash Medhi

• Text book of pharmacology – K. D. Tripathi.7th Edition.

• Basics & clinical pharmacology – Katzung 11th edition • www.history of clinicaltrails.in

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Thank u