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-existing drugs 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 in

the US accounting for 21% of outpatient prescription.

ASPIRIN
Primary pharmacological actions of aspirin are analgesic, antiinflammatory and antipyretic. (Beaver,
1965)

Also inhibit platelet aggregation.

In 1988, US-FDA proposed using aspirin to reduce the risk of recurrent myocardial infarction and to prevent recurrent transient

strokes in men.

ASPIRIN contd
Aspirin has been shown to be effective in reducing cardiovascular morbidity and mortality in high-risk

patients 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 the

prevention of colon cancer, esophageal cancer, and other diseases. (Sirven, 2010)

Beta-blockers in malaria
World wide, there has been a resurgence of malaria 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 blood cells. Two major Gs-associated receptors, the betaadrenergic and the adenosine receptors, are known 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 2 subunit of voltagedependent calcium channels. (Gee et al, 1996)

Magnesium sulphate for asthma and tocolysis

Magnesium sulphate, blocks calcium-mediated

smooth-muscle contraction, resulting in bronchodilatation. It was suggested that it binds competitively with calcium-storage sites in the endoplasmic reticulum and thereby uncouples the activation of actinmyosin unit. Intravenous magnesium sulphate therapy may be considered in patients with severe asthma exacerbation. Tocolysis may be another potential use of magnesium.

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, can alleviate dumping. In particular, it has been demonstrated to be effective in patients refractory to standard therapy. Administration of octreotide 30 min before, or immediately after a meal offers a practical and effective approach to the treatment of early and late dumping syndrome.

Paclitaxel for preventing restenosis

The taxanes are potent antiproliferative

agents used in cancer chemotherapy. They promote polymerization of the alpha and beta subunits of tubulin and thereby stabilizes the microtubules. In randomized controlled trials, stents coated with paclitaxel has been found to significantly reduce the restenosis rates after coronary angioplasty.

THALIDOMIDE
Thalidomide (-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 for treating morning sickness. (James, 1993; Sirven, 2010)
Was taken off market in 1961 because of its potent teratogenicity. (Lenz, 1988; 1992)

THALIDOMIDE contd
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 contd
A few decades later, the teratogenic effect of

thalidomide was exploited for its antineoplastic properties. (Rajkumar, 2004)

Several major trials led to its approval for the treatment of multiple myeloma and several related plasma cell disorders. (Rajkumar, 2004)

THALIDOMIDE contd
Other promising uses still under investigation

include:
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)

THALIDOMIDE contd
Mechanism of action is still unclear
Inhibition of TNF-. (Sampaio et al, 1991; Moreira et al, 1993) Promotion of the activity of T cells and natural killer

cells. 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, hyperkeratotic

inflammatory skin disorders especially psoriasis seem to respond to LTB4 inhibitors. Recently potential involvement of arachidonic acid pathway has been documented in the development of acne and provides logical support for use of LTB4 inhibitors in acne treatment. Its role is also coming up in the treatment of airway obstruction after respiratory syncytial virus (RSV) infection.

Conclusion
Although a large number of old drugs with new

potential uses have been discussed here, still the list cannot be claimed to be complete. With advancement in our knowledge we can make use of these time-tested drugs in diverse areas of clinical practice. However, unethical promotion of the irrational use of drugs for economic benefits by the pharmaceutical companies needs to be curbed. Neverthless, these initial findings discussed here need to be pursued by more researches so that the potential benefits could be passed on to the patients.

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: the role 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/author s/?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. Edward Arnold; 1993. p. 1-11.
6.Stitzel RE, McPhillips JJ. Transitions and progress in therapeutics. In: Craig CR, Stitzel RE, editors. Modern Pharmacology with Clinical Applications. 5th ed. New York: Pub. Little, Brown and Company (Inc.); 1997. p. 85-91.

THANK YOU