new uses for older drugs

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NEW USES FOR OLDER DRUGS

Dr Sanchit Gupta



INTRODUCTION

Introducing a new drug to the market is a costly

affair.

The process may turn futile if it produces any

unacceptable adverse reaction or toxicity.

Discovering new uses for the already-existingdrugs with known adverse drug reaction profile

may prove to be beneficial.

Most of these novel uses are based on the off-label use of the drugs.



Off-label use entails the use of drugs: For unapproved clinical indications (e.g.,

Bupropion for smoking cessation).

In unapproved age group (e.g.,

dextroamphetamine for adult ADHD treatment).

Off-label use is widespread and it is legal inthe US accounting for 21% of outpatientprescription.

http://en.wikipedia.org/wiki/ADHD

http://en.wikipedia.org/wiki/ADHD



Primary pharmacological actions of aspirin are

analgesic, antiinflammatory and antipyretic. (Beaver,

1965)

Also inhibit platelet aggregation.

In 1988, US-FDA proposed using aspirin toreduce the risk of recurrent myocardial

infarction and to prevent recurrent transientstrokes in men.

ASPIRIN



Aspirin has been shown to be effective in reducing

cardiovascular morbidity and mortality in high-riskpatients with myocardial infarction (MI) or stroke(secondary prevention). (Baigent et al, 2009)

Also recommended for prevention of CVD in

diabetics at high risk. (Buse et al, 2007; Pignone et al, 2010)

Other uses explored for aspirin include theprevention of colon cancer, esophageal cancer, andother diseases. (Sirven, 2010)

ASPIRIN cont’d



Beta-blockers in malaria

World wide, there has been a resurgence ofmalaria in recent years, mainly due to the

parasite's growing resistance to drugs.

G-proteins in the red blood cell were shown to

be used by the parasite to enter the red bloodcells.

Two major Gs-associated receptors, the beta-

adrenergic and the adenosine receptors, areknown to be present in red blood cells

The use of beta-receptor antagonists may

provide new approaches for treating malaria.



Gabapentin for pain

Gabapentin was developed as an anticonvulsant.

It has no direct GABAergic action.

In 2002, an indication was added for the

treatment of neuropathic pains. The mechanism of action is not clearly

understood

it is thought to exert its clinical effect by

selective binding of the α2δ subunit of voltage-dependent calcium channels. (Gee et al , 1996)



Magnesium sulphate for

asthma and tocolysis Magnesium sulphate, blocks calcium-mediated

smooth-muscle contraction, resulting inbronchodilatation.

It was suggested that it binds competitively withcalcium-storage sites in the endoplasmic reticulumand thereby uncouples the activation of actin-myosin unit.

Intravenous magnesium sulphate therapy may be

considered in patients with severe asthmaexacerbation.

Tocolysis may be another potential use ofmagnesium.



Methotrexate (MTX)

MTX was first introduced as an anticancer drug,but since the 1960s it has been used to treat

psoriasis and other skin conditions.

Low dose MTX, an antiinflammatory drug, is a

well-established medication for rheumatoid

arthritis and psoriasis.

low-dose methotrexate has also emerged as a

new therapy for chronically active Crohn disease.



Octreotide for dumping

syndrome In the past decade, it has been suggested that

octreotide an analogue of stomatostatin, canalleviate dumping.

In particular, it has been demonstrated to beeffective in patients refractory to standardtherapy.

Administration of octreotide 30 min before,or immediately after a meal offers a practicaland effective approach to the treatment ofearly and late dumping syndrome.



Paclitaxel for preventing

restenosis The taxanes are potent antiproliferative

agents used in cancer chemotherapy.

They promote polymerization of the alphaand beta subunits of tubulin and therebystabilizes the microtubules.

In randomized controlled trials, stents coatedwith paclitaxel has been found to significantlyreduce the restenosis rates after coronaryangioplasty.



Thalidomide (α-N-[phthalimido] glutarimide) was first synthesized in 1953 by Ciba. (Rajkumar, 2004)

Was introduced into the market in 1957 as a non-addictive, relatively “risk-free” sedative and fortreating morning sickness. (James, 1993; Sirven, 2010)

Was taken off market in 1961 because of itspotent teratogenicity. (Lenz, 1988; 1992)

THALIDOMIDE



Has R- and S- enantiomers

R- enantiomer ----- sedative activities

S- enantiomer ----- teratogenic and antitumor properties. (Stirling, 2000; Eriksson et al , 2001)

It was later re-introduced as treatment for:

Erythema nodosum leprosum [ENL]. (Iyer et al,

1971)

Oral ulcer and wasting associated with HIV.(Youle et al, 1989; Reyes-Teran, 1996)

THALIDOMIDE cont’d



Other promising uses still under investigationinclude:

Kaposi sarcoma (Little et al , 2000)

Renal cell carcinoma (Minor et al, 2002; Motzer et al, 2002) Reflex sympathetic dystrophy syndrome

(Rajkumar, 2004)

Inflammatory bowel disease. (Sirven, 2010)




Mechanism of action is still unclear Inhibition of TNF-α. (Sampaio et al, 1991; Moreira et al, 1993)

Promotion of the activity of T cells and natural killercells.

Inhibition of the release of cytokines. (Hideshima et al,2001; Mitsiades et al, 2002)

Toxicity – peripheral neuropathy, constipation,sedation, deep venous thrombosis,hypothyroidism. (Rajkumar et al, 2000; Osman et al, 2001;

Zangari et al, 2002; Ghobrial & Rajkuymar, 2003)




Zileuton for acne and RSV

Among the several diseases, hyperkeratoticinflammatory skin disorders especially psoriasisseem to respond to LTB4 inhibitors.

Recently potential involvement of arachidonic

acid pathway has been documented in thedevelopment of acne and provides logicalsupport for use of LTB4 inhibitors in acnetreatment.

Its role is also coming up in the treatment ofairway obstruction after respiratory syncytialvirus (RSV) infection.



Conclusion

Although a large number of old drugs with newpotential uses have been discussed here, still the listcannot be claimed to be complete.

With advancement in our knowledge we can makeuse of these time-tested drugs in diverse areas of

clinical practice. However, unethical promotion of the irrational use

of drugs for economic benefits by thepharmaceutical companies needs to be curbed.

Neverthless, these initial findings discussed hereneed to be pursued by more researches so that thepotential benefits could be passed on to thepatients.



References 1.Pharma Times News [homepage on the Internet]. Drug development tops

$897 million. [cited 2003 May 15]. Available from:http://www.ptwebcast.com

2.Ravot E, Lisziewicz J, Lori F. New uses for old drugs in HIV infection: therole of hydroxyurea, cyclosporin and thalidomide. Drugs 1999;58:953-63.

3.Kimberly J, La Pointe. Childrens Hospital of the Kings' Daughters Norfolk,

Virginia, USA. Available from:http://www.dekker.com/servlet/product/DOI/101081EECP120006328/authors/?t=a#0.

4.Esposito S. Off-label prescribing of drugs call FDA role into question.Medical Sentinel 2002;7:24.

5.Newbold BB. How medicines are discovered? In: Burley DM, Clarke JM,Lasagna L, editors. Pharmaceutical Medicine. 2nd ed. London: Pub. EdwardArnold; 1993. p. 1-11.

6.Stitzel RE, McPhillips JJ. Transitions and progress in therapeutics. In: CraigCR, Stitzel RE, editors. Modern Pharmacology with Clinical Applications. 5thed. New York: Pub. Little, Brown and Company (Inc.); 1997. p. 85-91.

http://www.ijp-online.com/article.asp?issn=0253-7613;year=2005;volume=37;issue=5;spage=279;epage=287;aulast=Verma














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