Leprosy+(Mycobacterium+leprae)

__**Disease/Drug of interest** : __ //** Mycobacterium leprae **//** (erythema nodosum leprosum or ENL) **** / **** Thalidomide ** Figure 1. Suspension of M. //leprae// derived from the footpad of a nude-mouse under a scanning electron microscope at approximately x12, 000 magnification. Like other Mycobacteria, //M. leprae// tends to cluster together [1].

**Motivation and Background** :
Between Thalidomide's controversial history in the 1960s that highlighted the importance of drug testing and the fact that //Mycobacterium leprae //is near impossible to cultivate in the lab, results have been limited as different concentrations of Thalidomide result in different effects on the protein TNF-α. If carefully regulated and patients properly educated, Thalidomide could be used to treat a whole range of diseases- c urrent research has led to hopeful results in the treatment of Multiple Myeloma (in combination with dexamethasone), various cancers, some symptoms of HIV/AIDS, Crohn’s disease, sarcoidosis, and rheumatoid arthritis [16]. With more research into this drug, there is a potential for this drug to overcome its past and be able to help a lot of people.


 * References: See bottom of page **

**External links:**
__ Target Information** : ** __ **TNF-α** Figure 2. A model of molecular basis for //Mycobacterium leprae// interaction with peripheral nerves. It is believed that //M. leprae// interacts with receptors on Schwann cells via a component of the basal lamina called Laminin-2 [8].


 * Size ** : 25,644 Da [1]


 * Location ** : is secreted mostly by macrophages and causes the activation of other macrophages and T-cells [10]


 * Function in a normal cell ** : plays a major role in nonspecific inflammation and innate resistance and is a cytokine that makes up the acute phase reaction [1] [11]

__**Drug Information**** : **__ Figure 3. Molecular diagram of two optical isomers of Thalidomide. S-thalidomide (left) is a teratogen, the one that causes birth defects, while R-thalidomide (right) is an effective sedative [15].
 * Formula ** : C13H10N2O4


 * Molecular weight ** : 258.2296 g/mol


 * CAS Number ** : 50-35-1 [12]


 * Delivery method ** : pill orally
 * Side effects ** : include but are not limited to damage to peripheral nerves, fatigue, skin rash, blood clots, stroke and heart attack. Those that are pregnant or want to become pregnant are not allowed to take Thalidomide due to severe birth defects in infants [13]


 * Other names ** : Thalidomid, Contergan, Distaval, and Softenon; however, survivors from the Thalidomide scandal are determined to have the drug be marketed as Thalidomide instead of under a trade name so patients are aware of the potential effects [17].


 * Maker or company ** : First marketed by Grünenthal  but since the patent expired there are many companies making it [13]


 * Is it patented ** ? not anymore
 * Clinical Trials Info ** : When Thalidomide was first released researchers had ignored the drug's effect in the fetal development of pregnant mice that had been given Thalidomide. After Thalidomide came back from being banned from the market, it became one of the most strictly regulated drugs in history. There are very few studies being done on this specific drug pair due to the fact that //M. leprae// very difficult to grow in the lab.

__** Origin ** : __<span style="font-family: Calibri,sans-serif; font-size: 11pt;"> neutral racemic compound derived from glutamic acid


 * Alternatives to this drug ** : <span style="font-family: Calibri,sans-serif; font-size: 11pt;">current multi-drug treatment made of Clofazimine, rifampicin, and dapsone as its three main drugs [12].

<span style="font-family: Calibri,sans-serif; font-size: 11pt;">Current research has led to hopeful results in the treatment of Multiple Myeloma (in combination with dexamethasone), various cancers, some symptoms of HIV/AIDS, Crohn’s disease, sarcoidosis, and rheumatoid arthritis [16]
 * Other uses ** : can this drug be used to treat other diseases/conditions?

<span style="font-family: Calibri,sans-serif; font-size: 11pt;">**References**:
[1] Scollard, D.; Adams, L.; Gillis, T.; Krakhenbuhl, J.; Truman, R.; Williams, D., The Continuing Challenges of Leprosy. //Clinical Microbiology Reviews// **2006**. 19 (2). 338-81.

[2] Monot, M.; Honore, N.; Garnier, T.; Araoz, R.; Coppee, J.; Lacroix, C.; Sow, S.; Spencer, J.; Truman, R.; Williams, D.; Gelber, R.; Virmond, M.; Flageul, B.; Cho, S.; Ji, B.; Paniz-Mondolfi, A.; Convit, J.; Young, S.; Fine, P.; Rasolofo, V.; Brennan, P.; Cole, S., On the Origin of Leprosy. //Science// **2005**. 308 (5724). 1040-42.

[3] Cole,S.; Eiglmeier, K.; Parkhill, J.; James, K.; Thomson, N.; Wheeler, P.; Honoré, N.; Garnier, T.; Churcher, C.; Harris, D.; Mungall, K.; Basham, D.; Brown, D.;Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Duthoy, S.; Feltwell, T.; Fraser, A.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Lacroix, C.; Maclean, J.; Moule, S.; Murphy, L.; Oliver, K.; Quail, M.; Rajandream, M.; Rutherford, K.; Rutter, S.; Seeger, K.; Simon, S.; Simmonds, M.; Skelton, J.; Squares, R.; Squares, S.; Stevens, K.; Taylor, K.; Whitehead, S.; Woodward J.; BarrellB., Massive gene decay in the leprosy bacillus. //Nature// **2001**. 409.1007-11.

[4] Mira, M.; Alcais, A.; Nguyen, V.;Moraes, M.;Di Flumeri, C.; Vu, H.;Mai, C.; Nguyen, T.; Nguyen, N.; Pham, X.; Sarno, E.; Alter, A.; Montpetit, A,.; Moraes, M.; Moraes, J.; Doré, C.; Gallant, C.; Lepage, P.; Verner, A.; Van De Vosse, E.; Hudson, T.; Abel, L.; Schurr, E., Susceptibility to leprosy is associated with PARK2 and PACRG. //Nature// **2004**, 427 (6975), 636-40.

[5] Ridley, D.; Jopling, W., Classification of leprosy according to immunity. A five-group system. //International Journal of Leprosy and other mycobacterial diseases// **1966.** 34 (3). 255-73.

[6] Truman, R.; Krahenbuhl, J., Viable M. leprae as a research reagent. //International journal of leprosy and other mycobacterial diseases// **2001**. 69 (1). 1-12.

[7] Job, C., Nerve damage in leprosy. //International journal of leprosy and other mycobacterial diseases// **1989**//.// 57 (2). 532-9.

[8] Rambukkana, A., How does Mycobacterium leprae target the peripheral nervous system?. //Trends in Microbiology// **2000**. 8 (1). 23-8.

[9] Teo, S.; Resztak, K.; Scheffler, M.; Kook, K.; Zeldis, J.; Stirling, D.; Thomas, S., Thalidomide in the treatment of leprosy. //Microbes and Infection// **2002**. 4 (11). 1193-1202.

[10] Cell Signaling Technology. TNF-a (human). http://www.phosphosite.org/proteinAction?id=8542247 &showAllSites=true (accessed Feb 7, 2016).

[11] Gahring, L.; Carlson, N.; Kulmar, R.; Rogers, S., Neuronal expression of tumor necrosis factor alpha in the murine brain. //Neuroimmunomodulation// **1996**. 3 (5) 289-303.

[12] PubChem Open Chemistry Database. Thalidomide. https://pubchem.ncbi.nlm.nih.gov/compound /thalidomide#section=Top. (accessed Feb 7, 2016).

[13] News Medical. History of Thalidomide. http://www.news-medical.net/health/History-of-Thalidomide.aspx (accessed Feb 7, 2016).

[14] Helix Magazine. The Thalidomide Tragedy: Lessons for Drug Safety and Regulation. https://helix.

northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation. (accessed Feb 7, 2016).

[15] Thalidomide. Optical Isomerism in Thalidomide. http://www.chm.bris.ac.uk/motm/thalidomide /optical2iso.html. (accessed Feb 7, 2016).

[16] Off-Label Drug Use and the Importance of Rigorous Testing. https://tyranessaurusrex.wordpress .com/tag/botox/. (accessed Feb 7, 2016).

[17] Thalidomide. The Reemergence of Thalidomide. http://www.chm.bris.ac.uk/motm/thalidomide /return.html. (accessed Feb 7, 2016).