Lalit Kumar1*, Rajan1, Vivek Sharma2
1Department of Pharmaceutical Sciences, Vinayaka College of Pharmacy, Kullu, Himachal Pradesh, India
2Department of Pharmacology, Govt College of Pharmacy, Rohru, Distt. Shimla-171207, Himachal Pradesh, India
*Corresponding Author E-mail: firstname.lastname@example.org
Tuberculosis is an infectious disease that affects lungs simple it seems but it is among the first ten leading causes of mortality all over the world. It has been 50 years since the introduction of novel drug candidate for the treatment of tuberculosis and despite many efforts for the development of new antitubercular drug, the pharmaceutical industry has, with few exceptions, indicated little interest in undertaking work in this arena. This lack of interest is due to two key perceptions that currently available drugs are adequate for the control of tuberculosis and that sufficient monetry benefit could not be realized to justify the expense of bringing a new tuberculosis drug to market. This article presents a brief overview of existing drugs and the drug candidates which are under development.
Tuberculosisis an infectious disease caused by bacteria named Mycobacterium tuberculosis. It was first isolated in 1882 by a German physician named Robert Koch who received the Nobel Prize for this discovery. In humans, Mycobacterium tuberculosis is the primary causative bacterium although other Mycobacteria such as Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti, Mycobacterium avium also causes tuberculosis. TB most commonly affects the lungs but also can involve almost any organs of the body. Many years ago, this disease was referred to as “consumption” because without effective treatment, these patients often would waste away. Today, of course, tuberculosis usually can be treated successfully with antitubercular drugs and antibiotics. Tuberculosis has been considered to be a disease of poverty for many years with quite rare occurrence in the developed countries. There is also a group of organisms referred to as atypical tuberculosis. These involve other types of bacteria that are in the Mycobacterium family. Often, these organisms do not cause disease and are referred to as "colonizers" because they simply live alongside other bacteria in our bodies without causing damage. At times, these bacteria can cause an infection that is sometimes clinically like typical tuberculosis.
When these atypical Mycobacteria cause infection, they are often very difficult to cure. Often, drug therapy for these organisms must be administered for one and a half to two years and requires multiple medications.
Types of tuberculosis:
Tuberculosis mainly is of two types and includes:
Pulmonery Tuberculosis: This form of tuberculosis occurs in the lungs and mainly affect the upper lung.
Extrapulmonery Tuberculosis: This form of tuberculosis occurs outside the respiratory tract and affects other body organs.
According to the WHO, there are two types of resistant strains :
v Multidrug-resistant TB (MDR-TB).
v Extensively drug-resistant TB (XDR-TB).
Multidrug-resistant TB (MDR-TB):
Is caused by bacteria that are resistant to the most effective anti-TB drugs (isoniazid and rifampicin). MDR-TB results from either primary infection or may develop in the course of a patient's treatment. WHO estimated that about 3.3% of all new TB cases had MDR-TB globally in 2009. It is estimated that about 440,000 MDR-TB cases are emerged and 150,000 persons with MDR-TB die each year.
Extensively drug-resistant TB (XDR-TB):
Is a form of TB caused by bacteria that are resistant to isoniazid and rifampicin (i.e.MDR-TB) as well as any fluoroquinolone and any of the second-line anti-TB injectable drugs (amikacin, kanamycin or capreomycin). The 69 countries have reported at least one case of XDR-TB (by the end of 2010). There are an estimated 25,000 cases of XDR-TB emerging every year.
These forms of TB do not respond to the standard six month treatment with first-line anti-TB drugs and can take two years or more to treat with drugs that are less potent, more toxic and much more expensive. In 23 countries, funding for MDR-TB care and treatment has increased from US$ 0.1b in 2009 to US$ 0.5b in 2011.
Present Status: 
According to the WHO, In 2008, an estimated 390000–510000 cases of MDR-TB emerged globally (best estimate, 440000 cases). Among all incident of TB cases globally, 3.6% (95% confidence interval (CI): 3.0–4.4) are estimated to have MDR-TB. Almost 50% of MDR-TB cases worldwide are estimated to occur in China and India. In 2008, MDR-TB caused an estimated 150000 deaths. The emergence of drug-resistant TB is an important fact that made the resurgence of TB especially alarming.
World Health Assembly Resolution:
The 2009 resolution urged all WHO Member States “To achieve universal access to diagnosis and treatment of MDR-TB and XDR-TB”.
Signs and symptoms of TB:
Ø Generalized tiredness
Ø Weight loss
Ø Fever and night sweats
Ø Chest pain
Ø Shortness of breath
A person can become infected with tuberculosis bacteria when he or she inhales minute particles of infected sputum from the air. The bacteria get into the air when someone who has a tuberculosis lung infection coughs, sneezes, shouts or spits which is common in some cultures.
TB can be diagnosed in several different ways including:
Ø Chest X-rays
Ø Analysis of sputum
Ø Skin tests
Current therapy for TB (antitubercular drugs):
v First line drugs
v Second line drugs
v Third line drugs
It was the first chemotherapeutic agent introduced for the treatment of TB was discovered in 1944 by Waksman and Schats. It is an aminoglycoside antibiotic isolated from Streptomyces griseus. It is a bactericidal to the rapidly multiplying tubercle bacilli. Due to many toxic manifestations on peripheral, central nervous system and hypersensitivity reactions it is not the drug of popular choice.
2) Isoniazid (INH, Isonicotinic acid hydrazide): Discovered by Domagk in 1952. It is one of the most effective antitubercular agent used today. It is a prodrug that requires activation before acting. It is orally active and exhibits bacteriostatic actions on the resting bacilli and is highly active against the M. tuberculosis complex (M. tuberculosis, M. bovis, M. africanum, M. microti and M. avium). It acts by preventing the mycolic acid biosynthesis present in the tubercle bacilli by affecting an enzyme mycolate synthetase, unique for mycobacteria.
It is a complex macrocyclic antibiotic and is bactericidal to tubercle bacilli including dormant bacilli. It is also effective against many other gram positive and gram negative bacteria. It acts by inhibiting DNA dependent RNA polymerase which prevents formation of protein synthesis. It is widely used antitubercular agent with INH.
Ethambutol was synthesized by Wilkinson in 1961 is a synthetic amino alcohol, orally effective bacteriostatic agent. It is effective against all types of Microbacterium strains. It acts by interfering with mycolic acid biosynthesis in cell wall.
Pyrazinamide is a structural analogue of Nicotinamide. It is also active against semidorminant bacilli not affected by any other drug and has strong synergy with INH and Rifampicin and shortens the therapy period to 6 months. The drug has no significant bactericidal effect and is thought to act by sterilizing effect.
Second line drugs:
There are six classes of second line drugs (SLDs) used for the treatment of TB. A drug may be classed as second line instead of first-line for one of two possible reasons:
Ø Less effective than the first-line drugs.
Ø It may have toxic side-effects or it may be unavailable in many developing countries.
Third line drugs: They are some newer agents for tuberculosis treatment. They includes rifabutin, clarithromycin, linezolid, thiocetazone, etc.
Bacille Calmette Guerin (BCG) is the current vaccine for tuberculosis. It was first used in 1921. BCG is the only vaccine available today for protection against tuberculosis. It is given throughout many parts of the world. It is derived from an atypical Mycobacterium but offers some protection from developing active tuberculosis, especially in infants and children.
Bacille Calmette Guerin (BCG) containes a live attenuated (weakened) strain of Mycobacterium bovis. It was originally isolated from a cow with tuberculosis by Calmette and Guren who worked in Paris at the Institute Pasteur. This strain was carefully subcultured every three weeks for many years. After about thirteen years the strain was seen to be less virulent for animals such as cows and guinea pigs. During these thirteen years many undefined genetic changes occurred to change the original stain of M. bovis. This altered organism was called BCG. In addition to the loss of virulence, other changes to BCG were noted. These included a pronounced change in the appearance of colonies grown in the laboratory. Colonies of M. bovis have a rough granular appearance whereas colonies of BCG are moist and smooth.
Management of TB:
Common antitubercular regimens:
v Isoniazid + rifampin daily for 9-12 months out of which third drug is pyrazinamide or ethambutol for first 2 months.
v Isoniazid + thiacetamide or ethambutol for 12-18 months.
v Isoniazid + rifampin + pyrazinamide daily plus ethambutol or streptomycin for two months, then isoniazid + rifampin for 4 months, or isoniazid + thiacetazone for 6 months.
DOTS stands for "Directly Observed Therapy, Short-course" and is a major plank in the WHO global TB eradication program. The DOTS (Directly Observed Treatment Short-course) strategy of tuberculosis treatment recommended by WHO was based on clinical trials done in the 1970s by Tuberculosis Research Centre, Chennai, India. The DOTS strategy focuses on five main points of action. These include government commitment to control TB, diagnosis based on sputum-smear microscopy tests done on patients who actively report TB symptoms, direct observation short-course chemotherapy treatments, a definite supply of drugs, and standardized reporting and recording of cases and treatment outcomes. The WHO advises that all TB patients should have at least the first two months of their therapy observed (and preferably the whole of it observed): this means an independent observer watching patients swallow their anti-TB therapy. The independent observer is often not a healthcare worker and may be a shopkeeper or a tribal elder or similar senior person within that society. The WHO extended the DOTS program in 1998 to include the treatment of MDR-TB (called "DOTS-Plus").
The need for new tuberculosis drugs:
There are three main reasons usually given for needing new tuberculosis drugs:
Ø To improve current treatment by shortening the total duration of treatment and/or by providing for more widely spaced intermittent treatment.
Ø To improve the treatment of MDR-TB.
Ø To provide more effective treatment for latent tuberculosis infection (LTBI) in programs that are able to implement this practice.
Of greatest impact would be new drugs to improve current treatment by providing for regimens that facilitate patient and provider compliance. Shorter regimens and those that require less supervision can accomplish this. Most of the benefit from treatment comes during the first 2 mo, the “intensive” or “bactericidal” phase when four drugs are given together, the bacterial burden is greatly reduced, and patients become non-infectious. The “continuation” or “sterilizing” phase of 4 to 6 months is required to eliminate persisting bacilli and minimize the risk of relapse. A potent sterilizing drug that shortens treatment to 2 months or less would be of great benefit. Drugs that facilitate compliance by providing for less intensive supervision are also of great interest. Obviously, a compound that would reduce both the total length of treatment and the frequency of drug administration would provide the greatest improvement.
Newer drugs for TB:
Ø Triflouperazine: Triflouperazine posses in-vitro antitubercular activity against drug resistance (XDR or MDR) Mycobacterium tuberculosis. It inhibited the invitro growth of drug susceptible & resistance strain of Mycobacterium tuberculosis H37Rv including clinical isolate for TB patient. Triflouperazine has multiple sites of action by inhibiting the lipid synthesis, DNA & protein from their levelled precursor in Mycobacterium tuberculosis.
Drugs under clinical trials for TB :
Currently the global TB development pipeline has nine candidates in different stages of clinical trial. Some of them are active in latent and active form against MDR-TB and XDR-TB. These compounds are:
Ø PNU 100480 (protein synthesis inhibitor)
Ø AZD 5847 (protein synthesis inhibitor)
Ø SQ 109 (cell wall and multitarget inhibitor)
Ø OPC67683 (cell wall and multitarget inhibitor)
Ø PA824 (cell wall and multitarget inhibitor)
Ø Gatifloxacin (DNA gyrase inhibitor)
Ø Moxifloxacin (DNA gyrase inhibitor)
Ø TMC 207 (ATP synthase inhibitor)
Ø Ansudoterb (mechanism still unknown)
Many drugs i.e. first line and second line drugs are available and are in use for many years for the treatment of tuberculosis even then this, not so good side effect profile of drugs and the existing mortality and morbidity due to this dreaded disease is still a concern for the scientific community. Many of the possible drug candidates are currently in different phases of clinical trials, still a continuous and multifaceted approach is required to minimize the suffering because of this dreaded disease.
1. Ilango K, Arunkumar S. Synthesis and antitubercular activity of novel 2-aryl -N-(3,4,5-trihydroxybenzamido)-4-thiazolidinone derivatives. Rasayan J Chem. 3(3); 2010: 493-496.
2. Sivakumar PM, Kumar V, Seenivasan SP, Mohanapriya J, Doble M. Experimental and theoretical approaches to enhance anti tubercular activity of chalcones. WSEAS TRANSACTIONS on BIOLOGY and MEDICINE. 7(2); 2010: 51-61.
3. Bijev A, Georgieva M. The development of new tuberculostatics addressing the return of tuberculosis: current status and trends. J Uni of Chem. Tech. and Metallargy, 45(2); 2010: 111-126.
4. Kishore N, Mishra BB, Tripathi V, Tiwari VK. Alkaloids as potential anti-tubercular agents. Fitoterapia 80; 2009: 149–163.
5. Joint Tuberculosis Program Review, New Delhi. India. World Health Organization. Regional Office for South-East Asia. 2006.
6. Barar FSK. Essentials of pharmacotherapeutics. S Chand & company Ltd, New Delhi. 2006.
7. World Health Organization. Global Tuberculosis Control: Surveillance, Planning, Financing; 2008 (http://www.who.int/tb/publications/global report/2008/summary/).
8. WHO, Tuberculosis MDR-TB and XDR-TB Progress report 2011, WHO, 2011.
9. Tripathi KD. Essential of Medical Pharmacology. Medical publishers Pvt. Ltd, New Delhi. 2011.
10. Rang HP and Dale MM. Pharmacology. Churchill Living Stone. International Publication. New York. 2011.
11. Panda G, Parai MK, Srivastava AK, Chaturvedi V, Manju YK, Sinha S. Design, synthesis and antitubercular activity of compounds containing aryl and heteroaryl groups with alkylaminoethyl chains. Ind. J Chem. 48B; 2009:1121-1127.
13. Budhiraja RD. Textbook of Pharmacotherapeutics. Vallabh Prakashan, New Delhi. 2011.
14. Chakraborty AK. Epidemiology of tuberculosis: Current status in India. Indian J Med Res. 120; 2004:248-276.
15. Gupta RL, Jain S, Talbar V, Gupta HC and Murthy PS. Studies on new antitubarcular drug Triflouperazine. Indian J Clinical Biochemistry. 13(2); 1998: 92-97.
16. Koul A, Arnoult E, Lounis N, Guillemont J, Andries K. The challenge of new drug discovery for tuberculosis. Nature. 469(7331); 2011: 483-490.
Received on 07.05.2012 Accepted on 26.05.2012
© Asian Pharma Press All Right Reserved