NEW USES OF OLD DRUGS

Dr.Biswajit Kalita

Tutor

Department of Pharmacology

DRAWBACKS IN BRINGING A NEW DRUG

THE COST OF BRINGING A NEW DRUG TO THE MARKET IS AROUND ONE BILLION WHICH INCLUDE PRECLINICAL AND CLINICAL COSTS .

THE PROCESS OF APPROVAL MAY TAKE UPTO 15 YEARS.

IT MAY PRODUCE UNACCEPTABLE ADVERSE REACTIONS OR TOXICITY IN EARLY YEARS OF MARKETING LEADING TO LOSS.

APPROXIMATELY 90% OF EXPERIMENTAL DRUGS IN THE INDUSTRY FAIL.

USING OLD DRUGS USED NEW INDICATIONS

• The adverse effect of the old is already known

The cost of such drug is 20 to 30% less than that of a newly discovered drug

These drugs are often used off-label(unapproved). In USA 40% to 50% of all prescriptions are written for

unapproved/unlabelled purpose.

Serendipity plays an important role in identification of such new uses of old drugs.

Drug repositioning

Also known as Drug repurposing, Drug reprofiling, Therapeutic switching and Drug retasking

It is the application of known drugs and

compounds to new indications (new diseases).

• Using drug repositioning, pharmaceutical companies have achieved of number successes, for example– Pfizer's Viagra in erectile dysfunction and

– Celgene's thalidomide in severe erythema nodosum leprosum

• Advantage of drug repositioning over traditional drug development– Repositioned drug has already passed a significant number of toxicity and

other tests,

– Its safety is known

– The risk of failure for reasons of adverse toxicology are reduced.

ADDITIONAL USE OF FEW DRUGS DISCOVERED DURING CLINICAL USAGE

DRUG INITIAL USE ADDITIONAL OR NEW PRIMARY USE

ALLOPURINOL ANTINEOPLASTIC GOUT

AMANTIDINE ANTIVIRAL ANTIPARKINSONISM

AMPHETAMINE STIMULANT HYPERKINESIS IN CHILDREN

ATOMOXETINE ANTIDEPRESSANT ADHD

CHLORDIAZEPOXIDE MUSCLE RELAXANT TRANQUILIZER

METRONIDAZOLE ANTITRICHOMONAL ANTIBACTERIAL

PEMETREXED MESOTHELIOMA LUNG CANCER

RALOXIFENE CONTRACEPTIVE OSTEOPOROSIS

SILDENAFIL ANGINA ERECTILE DYSFUNCTION

NEW USES OF OLDER DRUGS

DRUG MECHANISM OF ACTION NEW USES

ANGIOTENSIN CONVERTING ENZYME INHIBITOR &ANGIOTENSIN RECEPTOR BLOCKER

DECREASES ANGIOTENSINII→ALTERED CEREBRAL VASOREACTIVITYACT ON AT1 RECEPTOR ON BRAINCOMPONENTS OF RENIN ANGIOTENSIN SYSTEM PRESENT ON EYE:PLAY A ROLE IN AQUEOUS HUMOR PRODUCTION,RETINAL BLOOD FLOWDECREASES IOP BY PROMOTING FORMATION OF PROSTAGLANDINS AND ENHANCING UVEOSCLERAL OUTFLOW

MIGRAINE

•GLAUCOMA

ANTI TNFαeg etanercept,infliximab

TNFα ACT ON TNF RECEPTOR PRESENT ON NEUTOPHIL,FIBROBLAST,ENDOTHELIAL CELL:AMPLIFIES TISSUE CYTOKINES,ENZYMES LIKE COLLAGENASES AND METALLOPROTEINASES

CICATRICAL PEMPHIGOIDSUBCORNEAL PUSTULAR DERMATOSISTENSWEET SYNDROMEHYDRAADENITIES SUPPURATIVA

BETA-BLOCKERS G-PROTEIN IN RBC IS USED BY PARASITE TO ENTER IT

TWO MAJOR Gs ASSOCIATED RECEPTORS ARE-BETA ADRENERGIC AND ADENOSINE RECEPTOR.SO BLOCKING OF BETA RECEPTOR PREVENTED INFECTION

MALARIA

BUDESONIDE GLUCOCORTICOID

HIGH TOPICAL:SYSTEMIC ACTIVITY

UNDERGOES RAPID BIOTRANSFORMATION IN LIVER RESULTING IN LOW POTENCY METABOLITE

GVHDOTHER ORAL MUCOSAL DISORDER

CALCIUM CHANNEL BLOCKERS

INHIBIT PLATELET ACTIVATION PROBABLY BY REDUCTION IN CALCIUM INFLUX

IN PREVENTION OF PLATELET ACTIVATION AFTER CORONARY INTERVENTIONAL PROCEDURE

CIMETIDINE H2 ANTAGONIST WITH IMMUNOMODULATORY PROPERTY

INCREASES MITOGEN INDUCED LYMPHOCYTE PROLIFERATION AND INHIBIT SUPRESSOR T-CELL ACTIVITY

HUMAN PAPILLOMA VIRUS INFECTIONEPIDERMODYSPLASIA VERRRUCIFORMIS

CYCLOSPORIN A CALCINEURIN INHIBITOR:REDUCES IL-2DECREASES HISTAMINE AND PGD2 BY MAST CELL

BLOCK ACTIVATION OF T-CELL:ABILITY OF HIV TO INVADE TE CELL IS REDUCED.ALSO PREVENT PROPER HIV VIRION MATURATION

KERATCOJUNTIVITISSICCAASTHMAIMPROVEMENT IN LUNG FUNCTION WITH FEWER EXACERBATIONSINVESTIGATED FOR USE IN HIV-RESULT IS CONFLICTING

COX-2 INHIBITOR COX-2 CAUSES PRE-RETINAL NEOVASCULARISATION MEDIATED BY PGE2 WHICH ACT ON EP3 RECEPTOR(PROSTAGLANDIN ERECEPTOR 3)

ACIVATE PEROXISOME PROLIFERATIOR NUCLEAR TRANSCRIPTION FACTOR-g: NEGATIVE REGULATOR OF MACROPHAGE ACTIVATION

PROTECT NEURON BY DECREASING RESPONSE TO GLUTAMATE BY ACTING ON CALCIUM DEPENDENT GLUMATE SIGNALLING PATHWAY

THERE IS INCREASED COX-2 EXPRESSION ON MALIGNANT MELANOMA CELL

RETINOPATHY

ALZHEIMER’S DISEASE

CANCER CHEMOPROPHYLAXIS IN MELANOMA

FILGRASTIM(G-CSF RECOMBINANT)

STIMULATE PROLIFERATION AND DIFFERENTIATION OFNEUTOPHIL PROGENITOR CELL AND ALSO PROLONGS ITS CIRCULATION

SEVERAL CYTOKINES AND GROWTH FACTORS INCLUDING G-CSF HAVE A KEY ROLE IN HOST’S ATTEMPT TO RESTORE HOMEOSTASIS IN SEVERE SEPSIS.INHIBIT PRODUCTION OF INFLAMMATORY CYTOKINES AS WELL AS EXPAND T-HELPER CELL LYMPHOCYTE RESPONSE THAT MIGHT INCREASE PRODUCTION OF SPECIFIC ANTIBODIES TO NEUTRALIZE MICROBIAL PATHOGEN

PNEUMONIA

SEPSIS

GABAPENTINE INCREASES GABA IN CNS

DECREASES GLUTAMATE

BLOCK Na AND Ca CHANNEL

DECREASES PAIN THROUGH DECENDING INHIBITORY MECHANISM AND CHANGES IN SYMPATHETIC SYSTEM

NEUROPATHIC PAINSACRAL PERINEURAL CYST INDUCED PAIN

INHALED FUROSEMIDE

IT MAY ACT AS BRONCHODILATOR.THE EXACT MECHANISM IS NOT KNOWN

ASTHMA

GLUCOCORTICOID LOW DOSE HYDROCORTISONE ACT AS ANTIINFLAMMATORY AND IMMUNE BALANCING ROLE IN ACUTE SEPSIS→DECREASES PROINFLAMMATORY CYTOKINES(IL-6,IL-8) AND TNFα

ACT SYNERGISTICALLY WITH INTERFERONS TO PRODUCE Fc RECEPTORS ON HUMAN MONOCYTE AND PERITONEAL MACROPHAGES WHICH CORRELATED WITH INCREASED PHAGOCYTOSIS

SEPTIC SHOCK

LEVAMISOLE ANTIHELMINTHIC DRUG

NICOINIC RECEPTOR ANTAGONIST

ACT AS T-CELLSTMULATOR→SO IT ACTS AS IMMUNOSTIMULANT

PEDICULOSISSLOW SPEADING VITILGO

LIDOCAINE STEROID DEPENDENT BRONCHIAL ASTHMA AS NEBULIZED LIDOCAINE

MAGNESIUM SULPHATE BLOCK CALCIUMMEDIATED SMOOTH MUSCLE CONTRACTION:RESULT IN BRONCHODILATATION

COMPETE WITH CALCIUM ENTRY IN MUSCLE CELL

ASTHMA

TOCOLYTICS

MENATETRENONE(VIT K2) ACTIVATE OSTEOBLAST AND PROMOTE BONE FORMATION

ALSO INHIBIT BONE RESORPTION THROUGH INCREASED OSTEOCLAST APOPTOSIS AND DECREASED OSTEOCLAST FORMATION

PREVENT PREDNISOLONE INDUCED BONE LOSS

METHOTREXATE(MTX) PROMOTE EXTRACELLULAR ADENOSINE RELEASE→BIND TO ADENOSINE RECEPTOR ON TARGET CELL→INHIBIT PROINFLAMMATORYAGENTS LIKE LTB4,TNFα

IN MACROPHAGE IT INHIBIT EXPRESSION OF TNFα,IL-6,IL-8

CROHNS DISEASEPALMOPLANTAR POMPOLYXMYCOSIS FUNGOIDESASTHMA

METRONIDAZOLE DECREASES OXIDATIVE STRESS BY INHIBITING NEUTROPHIL GENERATED INFLAMMATORY MEDIATORS

SUPRESSES T-CELLMEDIATED IMMUNITYIMMUNOMODULATORY EFFECT ON LEUCKOCYTE CHEMOTAXIS

SEBORRHEIC DERMATITIS

NITOGEN MUSTARD(MECHLORETHAMINE)

IMMUNOMODULATOR EFFECT ON T-CELL→SPECIFIC CYTOTOXIC EFFECT ON PATHOGENIC INFILTRATING T-CELL

MAY ACT AS TOPICAL IMMUNOGEN LIKE DIPHENCYPRONE

ALOPECIA AREATA

OCTREOTIDE ANALOGUE OF SOMATOSTATIN

IT SLOWS GASTRIC EMPTYING,INHIBIT INSULIN RELEASE

DECREASES PEPTIC SECRETION

INCREASES GUT TRANSIT TIME

DUMPING SYNDROME

PACLITAXEL ANTIPROLIFERATIVE AGENT

PROMOTE POLYMERISATION OF α and ß SUBUNIT OF TUBULIN→STABILIZE MICROTUBULE

PREVENT RESTENOSIS AFTER CORONARY ANGIOPLASTY

RETINOID IT HAS ANTIPROLIFERATIVE, DIFFERENTIATING, APOPTICWITH MODERATE ANTITUMOUR ACTIVITY

AIDS-RELATED KAPOSI SARCOMA

STATIN INCREASES BONE VOLUMEINCREASES RATE OF BONE FORMATION

OSTEOPOROSIS

TETRACYCLIN INHIBIT PHOSPHOLIPASE A2→DECREASES PRODUCTION OFLIPOOXYGENASE,CYCLOXYGENASE

DECREASEPROINFLAMMATORY MEDIATORS

INCREASE INHIBITOR OF MATRIX METALLOPROTEINASES

OSTEOARTHRITISAS A DMARD

THALIDOMIDE IMMUNOMODULATOR AGENT WITH ANTIANGIOGENIC,ANTIINFLAMMATORY PROPERTIES

IT CAN INDUCE G1 GROWTH ARREST AND APOPTOSIS

DOWNREGULATE TNFα

MAY DECREASE EXPRESSION OF ADHESION

MOLECULE ON MYELOMA AND MARROW STROMAL CELLS

ANTIRETROVIRAL EFFECT AS ARESULT OF INHIBITORY EFFECT ON PRODUCTION OF TNFα

SARCOIDOSISAPTHOUS ULCER IN HIVBECHET DISEASECHRONIC GVHDPLASMA CELL DISORDER LIKE MYELOMAOROFACIAL GRANULOMATOSIS AND ORAL MANIFESTATION OF CROHN’S DISEASEDISCOID LUPUS ERYTHROMATOSUSCOMPLEX REGIONAL PAIN SYNDROMEKAPOSI’S SARCOMA

ZILEUTON INHIBIT PRODUCTION OF LTB4→IT IS NATURAL LIGAND FOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR-gamma WHICH REGULATE LIPOPROTEIN METABOLISM,INFLAMMATORY RESPONSE,CELL PROLIFERATION,DIFFERENTIATION AND APOPTOSIS IN CELLS INCLUDING SEBACEOUS GLAND CELL

IT REVERSES AIRWAY CONSTRICTION AND NUMBER OF INFLAMMATORY CELLS IN LUNG

ACNE

RSV INFECTION

SIROLIMUS(RAPAMYCIN,RAPAMUNE)

IT INHIBIT ACTIVATION OF mammalian TARGET OF RAPAMYCIN(mTOR)→BLOCK THE PROGRESSION OF CELL CYCLE FROM G1→S PHASE SO T-CELL ARE ARRESTED IN G1 PHASE

ANTITUMOUR AGENT

Autoimmune LymphoproliferativeSyndromelymphangioleiomyomatosis, a rare lung disease

COLESEVALAM BILE ACID BINDING RESIN INITIALLY USED FORFAMILIAL HYPERCHOLESTEROLAEMIAIT HAS GAINED APPROVAL TO IMPROVE GLYCEMIC CONTROL IN TYPE 2 DIABETES

CONCLUSION

WITH THE ADVANCEMENT IN OUR KNOWLEDGE IN VARIOUS FIELDS OF MEDICAL SCIENCES,WE CAN MAKE USE OF TIME TESTED DRUGS IN DIVERSE AREAS OF CLINICAL PRACTICE FOR THE BENEFIT OF THE PATIENT.

PHARMACEUTICAL MARKETING PRACTICES AND PHYSICIAN DISSATISFACTION WITH CURRENTLY AVAILABLE TREATMENTS MAY BE KEY FACTORS IN PRESCRIBING THE DRUG FOR OFF-LABEL(UNAPPROVED) INDICATIONS.

HOWEVER UNETHICAL PROMOTIONAL OF IRRATIONAL USE OF DRUGS FOR BENEFIT OF PHARMACEUTICAL COMPANIES NEED TO BE CURBED.

IT IS IMPORTANT THAT OFF-LABEL USE OF COMPOUNDS BE BROUGHT UP-TO-DATE WITH CURRENT FDA POLICIES AND TO EMPHASIZE THE RESPONSIBILITY OF PRESCRIBING PHYSICIAN IN USE OF THESE COMPOUNDS.