TB

TUBERCLUOSIS

A GREAT HUMAN CONCERN

Discoverer of M.tubercluosis-Robert Koch

Existing TB Vaccine Ineffective

BCG provides unreliable protection against pulmonary TB, which accounts for most TB disease worldwide

BCG is not know to protect against latent TB

BCG is not recommended for use in infants infected with HIV due to increased risk for severe BCG-related complications

Despite wide use, particularly in high burden countries, BCG has had no apparent impact on the growing global TB epidemic

BCG does reduce risk of severe pediatric TB disease, so it should continue to be used until a better TB vaccine is available

BCG introduced in 1921

Goals for Better TB Vaccines Eliminate TB as a public health

threat, in line with global targets (<1 case/million), in conjunction with new drugs and diagnostics

Safe and effective in preventing TB in children, adolescents and adults, including people with HIV (for whom BCG is unsafe)

Protect against all forms of TB – including MDR and XDR

Drug Resistance

WHO estimates 490,000 MDR-TB cases emerge every year, with more than 110,000 deaths

Extensively drug-resistant (XDR) TB has been identified in 57 countries as of November 2009

Treatment for drug-resistant TB is much longer, more complex and more expensive - with much lower success rates

TB -India

370,000 people die of TB in India every year (~ 1000 deaths per day, 2deaths every 3mins)

The estimated incidence of TB in India is 1.8 million new cases annually.India accounts for approximately one fifth of the global TB incidence.

Of world's estimated 450,000 MDR-TB patients 15700 MDR-TB suspects are from India in the past years

Selman Waksman Discoverer of streptomycine - first antibiotic (TB)

1/3 of AIDS patients die due to TB

And many more.........

Aims of Treatment TB

Cure the patient

Prevent Death

Prevent Relapse

Prevent Transmission

Prevent development of drug resistant

TB Drugs First line Drugs: More effective, less toxic. Second line Drugs: less effective than the

first-line drugs but more toxic. Third line drugs: either because they are

not very effective or because their efficacy has not been proven (e.g., linezolid, R207910). Rifabutin is effective, but is not included on the WHO list because for most developing countries, it is impractically expensive.

First line Drugs

Second line Drugs-Aminoglycosides& polypeptides

Second line Drugs:Fluoroquinolones & thioamides

Third line drugs

Other drugs that may be useful, but are not on the WHO list of SLDs:

rifabutin macrolides: e.g., clarithromycin (CLR); linezolid (LZD); thioacetazone (T); thioridazine; arginine; vitamin D; R207910.

Drugs acting at different parts of micobacterium

Current Drugs and limitations

Poor absorbance and toxic

Toxic to liver

CNS side effects

Current Drugs and limitations

Rifampicine and its derivatives showed Decrease in white blood platelet count

Compounds under clinical trail

Compounds under clinical trail

F3C

NO2

S

N

O

N

O

O

BTZ

"Directly Observed Treatment, Short-course"

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.

MDR-TUBERCLUOSIS MDR-TB is TB that is resistant to at

least two of the best anti-TB drugs, isoniazid and rifampicin. These drugs are considered first-line drugs and are used to treat all persons with TB disease.

XDR-Tubercluosis Extensively drug resistant TB (XDR

TB) is which -resistant to isoniazid and rifampicin, plus resistant to any fluoroquinolone and at least one of three injectable 2nd line drugs, i.e amikacin, kanamycin or capreomycin.

XDR-TB in South Africa August 2006

53 of 544 patients defined as XDR-TB cases.

52 of the 53 patients died within 25 days

XDR-TB likely in bordering in afro-asian countries.

The first XDR-TB case in India is reported in King Georg Medical University, Lucknow September 2007.

New Chemical Entities

TB •Can be cured with first line drugs

MDR •Treatable with second line drugs

XDR •Treatment options strictly restricted

DR-TB •Complete drug resistant TB??•So what's next???????

??? •Are we going back to PRE-ANTIBIOTIC era!!!!!!!!!!!!!!!!

GOAL •Let us put some efforts..............

What we can do.......... As an organic chemist synthesize few

libraries and check for the in vivo. If you got reasonable activity, do some

SAR. Pick a candidate do pharmacokinetic

studies.... You may get a lead molecule If you didn't get try again.... Because your efforts will definitely help

them.......see next slide

ALL LIVES HAVE EQUAL VALUE

Thank you