1 | P a g e
NAMAN SHAH POLY ID-0396904
Discovery and Development of “Jainin” for the treatment of Pulmonary
Tuberculosis caused by Mycobacterium tuberculosis
Abstract/Summary: Pulmonary tuberculosis is the cause behind the death of 1.7 million people every year. The standard
treatment spans for 6 long months with stringent regimen. Patient compliance is difficult to achieve
which many times result in incomplete course of the medicine. This results in drug resistance in the
patients. As such Mycobacterium tuberculosis is a very hardy bacterium and drug resistance makes it
more difficult in treating the disease successfully. Moreover, the side effects of existence drugs are
unfathomable and give great mental and physical pain to the patient.
“Jainin” is the drug developed to counter all these and make the treatment of pulmonary tuberculosis
viable, successful and more generous on the patient. The treatment time reduces to about 4 months
with little or no side effects and virtually 100% curability.
2 | P a g e
Contents
Sr. No. Title Page 1] Brief account on Pulmonary Tuberculosis 3
2] Medical need for a new drug for Pulmonary Tuberculosis 4
3] Target for new drug 5
4] Assay and structure of the lead 6
5] Lead Optimization 7
6] Pharmacological profiling of NCE 8
7] Biomarkers 11
8] Clinical Trials
Phase 1 12
Phase 2 13
Phase 3 14
9] Appendix 18
10] References 20
3 | P a g e
[1] Introduction to TUBERCULOSIS
Tuberculosis is primarily caused by aerobic bacterium-Mycobacterium tuberculosis
SYMPTOMS AND PROGRESSION [21, 22]
Typical symptoms include:
• Fever, chills, chest pain, weakness
• Coughing up of blood
• Night sweats, appetite loss, weight loss
• Tuberculous pleuritis[1]
KIND OF PEOPLE AFFECTED & PREVALANCE OF TUBERCULOSIS [9]
• Annually 8 million people get infected with tuberculosis out of which 2.2 million people
develop tuberculosis.
• Tuberculosis is prevalent among all age groups but the age group of 25-44 has shown
the largest increase.
• Mostly people in the developing countries are at a greater risk.
TREATMENT [5]
• In the short treatment, isoniazid, rifampicin, pyrazinamide and ethambutol is given for
two monthsand then isoniazid and rifampicin are given for 4 months.
• The course runs for 6 months.
• Isoniazid is given for 9 months in latent tuberculosis.[21]
DIAGNOSIS [5]
• Chest X-ray gives a relevant idea of presence of tuberculosis.
• Microbial examinations of the sputum of the patient can also diagnose the disease. The
examinations include fluorescence microscopy.
• Bronchoscopy, biopsy and PCR can also be used to detect M.tuberculosis.[21]
• Tuberculin skin test like Mantoux test and Heaf test are used to detect the presence of
tuberculosis.
4 | P a g e
[2] Is there a medical need to develop a new drug?
Table 1: Comparison of existing drugs in the market
DRUG [15,16,18]
MANUFACTURER[17]
MODE OF
ADMINISTRATION[19]
FREQUENCY[8]
SIDE EFFECTS[18]
ISONIAZID
1)Nydrazid
In
combination
with Rifampin
2)Rifamate
In
combination
with Rifampin
&
pyrazinamide
1)Rifadin
ETHAMBUTOL
1)Myambutol-
along with
isoniazid
Bristol-Myers
Squibb
Aventis
Pharmaceuticals
Aventis
Pharmaceuticals
Elan
pharmaceuticals
Oral
Oral
Oral or Injection IV
Oral
5 mg/kg up to 300mg
in a single dose; or 15
mg/kg up to 900
mg/day 2 or 3 times a
week
2 capsules once daily
10 mg/kg once a day
15mg/kg once a day
1)Severe/fatal
hepatitis
2)Peripheral
neuropathy
3)hypersensitivity
reactions
4)Nausea, vomiting
1)Ataxia, fatigue
2)Diarrhea, nausea
3)Hepatitis
4)Acute renal failure
1)Jaundice
2)Thrombocytopenia
3)Cerebral
hemorrhage
4)Visual
disturbances
1)Decrease in visual
acuity
2)Dermatitis
3)Hypersensitivity
4)Acute gout
MEDICAL NEED:- As it is evident from the side effects caused by the drugs there is an imminent need to develop a new
drug for treating tuberculosis. The standard treatment involves 6 months which is too long. Also, cases
of drug resistance are observed more often than not which compels us to think differently and devise
new drugs which are more effective and consume less time. A finding by WHO indicates that
tuberculosis falls under the neglected diseases as pharmaceutical companies are not that keen to devise
new drugs. Lastly, every year 1.7 million people die due to tuberculosis. So, there is absolutely very dire
need to develop new drug for treating tuberculosis.
5 | P a g e
[3] TARGET for the new drug: My target is Isocitrate lyase which is the enzyme involved in the Glyoxylate cycle in
M.tuberculosis
Role of Isocitrate lyase:
• It has been found out through various transcriptional studies that M.tuberculosis
depends more on the fatty acids for survival rather than the carbohydrates in the host
body.
• The bacterium has several enzymes which are related to fatty acid metabolism-34 acyl-
CoA synthases, 34 acyl-CoA dehydrogenases, 21 enoyl CoA hydratases, six 3-
hydroxyacyl-CoA dehydrogenases and six acetyl-CoA C-acetyltransferases.
• It contains more than 250 lipid metabolizing enzymes which show the importance of
fatty acid metabolism in the bacterium.
• Isocitrate lyase is also required for the fatty acid catabolism and virulence in the
organism.
• Individual deletion of the genes coding for the 2 isoforms of the enzyme does not have
any effect on the catabolism but simultaneous deletion of the genes results in total
impairment of intracellular replication.
Isocitrate lyase as a target: • Glyoxylate cycle is very important in bacteria for their metabolism.
• A knockout of enzyme Isocitrate lyase can completely impair the glyoxylate cycle in the
organism.
• Due to this, there occurs a problem in the glyoxylate pathway which ultimately results in
the disruption of the metabolism of fatty acids.
• As a result, the organism cannot maintain its regular physiological processes and
ultimately dies.
• A drug can be devised which specifically targets this lyase.
• As a result the enzyme is denatured and the organism is killed.
Advantages of this drug as compared to the marketed drugs: • Currently available drugs in the market are highly efficient but lead to fatal side effects.
• Also, there is a high rise in the cases of resistance against these drugs which is posing a
big problem in successfully treating the disease.
• Also, current drugs find it difficult to treat the dormant bacteria in the granulomas.
• The new drug implies a new target which can successfully counter the resistance aspect.
• Moreover, it might be able to cure the disease in a short period as compared to current
drug time span as it is also effective on the dormant bacteria which are enclosed in the
granulomas. In fact it is more effective on the dormant bacteria as they live in hypoxic
conditions and hence need fatty acid metabolic pathways more than the bacteria in the
blood stream.
• Also, Isocitrate lyase is specific for the glyoxylate cycle which is not present in humans.
Due to this there is no effect on human beings. The drug will only act on ICL and nothing
else, so the possibility of side effects is greatly reduced.
6 | P a g e
[4] Assay for evaluating Inhibitor of Isocitrate Lyase for developing anti-
tuberculosis drug:- Reagents and Materials required: M.tuberculosis culture, Pfu DNA Polymerase, DNA Ligase, dNTP,
Isocitrate Lyase, Inhibitory compound derived from Itaconic anhydride, 96-well plate, Biomek FX [1]
Assay for checking the inhibitory effect: The assay is divided into 2 parts-1) Checking the enzymatic
activity, 2) Checking the inhibitory effect of the compound under study. [1]
1) Checking the enzyme activity [1]
:
• The formation of glyoxylate-phenylhydrazone was checked in presence of phenylhydrazine and
isocitrate lyase when the enzyme was incubated at 370C.
• The reaction mixture of buffer and isocitrate lyase and phenyl hydrazine was kept for 10
minutes for incubation and then the absorbance was measured at 324 nm after the addition of
isocitrate.
• Buffer was composed of potassium phosphate, MgCl2, phenylhydrazine, and cysteine.
2) HTS checking of the inhibitory effect of the compound under study [1]
:
• 10 micro liter of the inhibitory substance was added into a 96-well plate. Into that, 178 micro
liters of reaction buffer, 10 micro liters compound solution, 2 micro liters recombinant protein
ICL solution and 10 micro liter of isocitrate solution was added. It was allowed to incubate for
some time. Then absorbance was measured at 324 nm.
• The activity of the enzyme was determined by change in the absorbance values.
Inhibitory substance+ Reaction buffer+ ICL +Isocitrate+ Phenyl hydrazine Glyoxylate-
Phenylhydrazone
Change in Absorbance
Lead Structure [1, 13]
:
OH
C NH2
H2C C O
CH O
HOOC
Figure 1
7 | P a g e
[5] Lead Optimization and Selection of animal model:- The NCE structures are as follows:
OH
HO
CH2
NH2
OH
O
ClHO
O
HS
OH
NH2
Cl
CH2
NH2
OH
O
ClOH
Br
CH2
OH
O
ClHO
OH
N
Cl
Figure 2 (a, b, c, d)
Animal model [2, 3, 4]
:-
There are basically 4 models available for the study of Tuberculosis. They are-
Table 2: Animal model selection
MICE RABBIT GUINEA PIG RHESUS MONKEY
Mode of infection is
subcutaneous or
intravenous
Shows a spectrum of
disease-represent
specific stages of
human disease
Highly susceptible
towards the disease.
Susceptibility and
progression of disease
is like humans
Low cost Low-medium cost High cost High cost
Aggregation of the
lymphocytes is towards
the center in the
granuloma
The inbred are more
susceptible compared
to outbred.
They granulomas
exhibit many similarities
to human granulomas.
The granulomas are
similar to humans
Has innate resistance
towards tuberculosis
which is a negative
point for studies.
Has Innate resistance
towards tuberculosis
No resistance-Show
lung tissue necrosis,
lose weight, die-like
humans
Many reagents to study
pathological
parameters.
Easily available Large numbers required High rearing cost can be
countered by high
susceptibility
Can spread infection to
other monkeys.
Animal of choice: - Rhesus monkeys with SCID are best suited for the studies as they resemble the
humans very closely as far as the disease progression and symptoms are concerned. Also, there are
8 | P a g e
many reagents to study the pathological parameters which are not available in other models. Other
close contender is the guinea pig which shows exceptional susceptibility towards the disease. But the
monkey is chosen ahead due to its similarity and efficacy of the drug in it. Mice and rabbits show innate
resistance which is not useful. Monkeys might spread infection but it can be dealt with. The cost is little
higher but the results are worth the cost. So, Rhesus monkey with SCID is the animal of choice.
[6] Pharmacological profiling of NCE [10]
:
LEAD
NH2
Cl
CH2
NH2
OH
O
ClHO
O
HS
OH
OH
HO
CH2
NH2
OH
O
ClHO
O
HS
OH
NCE1 NCE 2
NH2
Cl
CH2
NH2
OH
O
ClOH
Br
CH2
OH
O
ClHO
OH
N
Cl
NCE 3 NCE 4
Figure 3 (a, b, c, d, e)
9 | P a g e
Table 3: Structural formula of NCEs
R1 R2 R3
Lead
NCE(1)
NCE(2)
NCE(3)
NCE (4)
-H
NH2
Cl
OH
OH
NH2
Cl
N
H
-H
-O-CH2-SH
-O-CH2-SH
Br
Cl
-H
-NH2
-NH2
-NH2
-H
Table 4: Pharmacological profiling
Absorption rate by
Caco-2 screening
assay (cm sec-1
)[4]
P450 Inhibition
(%)[4]
% GSH depletion[4]
IC50[16]
NCE 1 12 x 10-6
8 4 1.2 uM
NCE 2 9 x 10-6
40 27 7 uM
NCE 3 8 x 10-6
72 53 3.2 uM
NCE 4 6 x 10-6
24 37 4.1 uM
10 | P a g e
Conclusion: From the pharmacokinetic values, NCE 1 is the best suited NCE to choose for animal
studies as it can be seen that, in all the 4 screens that are selected as testing parameters, the values of
NCE 1 are good. The absorption rate obtained by Caco 2 assays suggest that the absorption of NCE 1 is
better. The %P450 inhibition of NCE 1 is 8 which shows that it is better. The % GSH inhibition is also low
which suggests that NCE 1 is less toxic. The IC50 value is 1.2 uM which is good because at that low
concentration 50% of enzyme gets inhibited. In case of other NCEs the IC50 values are high which is not
good.
Also, the molecular weight is 459.34, LogP is 2.57 and N+O is 7 which follows the Lipinski rule.
The presence of –Cl, NH2, OH, COOH, SH groups makes it hydrophilic while the presence of 2 benzene
ring structures makes it hydrophobic. So stronger binding can be achieved.
Hence, it can be seen that NCE 1 is good enough and should proceed ahead with animal studies.
Route of Administration of drug:
Based on the studies performed on animal model, the route of administration of the drug will be oral
for all further studies.
Patent of NCE:
The most effective NCE determined through in vitro pharmacological profiling and animal studies is
patented under the patenting regulatory authority.
Summary of Pre-IND activities:
Duration: 3 years
� Research to generate Lead
� Efficacy and mechanism of action studies
� Animal model selection-SCID Rhesus monkey(dose exposure, metabolism) & route of
administration-oral
� Kinetic studies to check drug-drug metabolism, effect on enzymatic activity
� Safety pharmacology study (Pharmacological profiling-ADMET studies)
� Toxicology under GLP
� Single dose toxicity study
� Safety studies including range finding
� Genotoxicity study
� Drug impurity determination
� IND filing
11 | P a g e
[7] Biomarkers used for clinical trials of pulmonary tuberculosis:
CD11c [7]
:
CD11c is involved in phagocytosis of M.tuberculosis by macrophages. Tuberculosis patients
have an elevated level of CD11c on blood monocytes as compared to normal and healthy
people. When anti-tuberculosis treatment is done then the levels of CD11c come down. So,
CD11c can be used as a biomarker for evaluating the efficacy of the drug.
sIL-2Rα, sTNF-R1, sTNF-R2 [8]
:
sIL-2Rα, sTNF-R1 and sTNF-R2 can be used as biomarkers for testing the efficacy of the
tuberculosis treatment. Before treatment the levels of all the 3 are relatively high in the
patients. After subsequent treatment, the levels of these biomarkers go down even in slow
treatment responders.
So, the above mentioned biomarkers can be used as efficacy biomarkers in monitoring the
efficacy of the drug for treatment of tuberculosis.
12 | P a g e
[8]Phase 1 clinical trial for study of Isocitrate lyase inhibitor for treatment of
tuberculosis [15]
Purpose: This study is targeted to find out the safety and tolerability of an increasing dose of
Isocitrate lyase inhibitor by administering it into adult volunteers.
Condition: Tuberculosis
Intervention: Isocitrate lyase inhibitor
Phase: Phase-1
Study type: Interventional
Study design: Safety and efficacy study, Dose comparison, treatment
ELIGIBILITY
Age: 18 to 60 years
Gender: Both
Healthy Volunteers: No
Number of volunteers: 90
Doses taken of NCE:
From the results obtained from the trials on animal model the range of dose is selected. The
minimum effective dose was 10mg/kg and maximum tolerated dose was 200 mg/kg. 1/10th
of
this MTD was taken in the clinical trials which turned out to be 20 mg/kg.
Table 5: Results for Phase-1 trials
Dose (mg/kg) No of Subjects No of Adverse Events Average CD11c level (%) *
20
40
80
30
30
30
1-Nausea
2-Nausea, Fatigue,
3-Nuasea, Vomiting, Fatigue
60
40
6
*100% stands for total amount of CD11c receptors on the Phagocytes before the treatment of
the patient began.
Adverse event: Nausea is seen as a common side effect in majority of patients. It might be
resulting due to the creation of heaviness in the stomach as the drug may draw water from the
cells. This withdrawal of water might be due to the changes in osmotic pressure across the cells
of stomach. Also, vomiting and fatigue are observed.
Conclusion:
From the phase-1 trials the hMTD is 80mg/kg.
The drug is well tolerated as it is not giving major side effects.
13 | P a g e
[9] Phase-2 clinical trial to determine the dosage and safety of Isocitrate lyase
inhibitor [15]
: Purpose: To evaluate safety of the drug and determine its effective dosage.
Study type: Interventional
Study design: Safety and efficacy study, placebo, treatment
Eligibility:
Age: 18 to 60 years
Gender: Both
Healthy volunteers: No
Number of volunteers: 180
Criteria [15]
:
Inclusion criteria:
• Sputum positive patients and patients previously treated for more than 1 month as per RNTCP/WHO
guidelines.
• Radiographic evidence of the disease.
• High WBC count. High WBC count symbolizes mycobacterial infection.
• Microbiological confirmation of Mycobacterial infection.
• Patients with treatment failure, disease relapse as it helps in establishing the superiority of the drug.
Exclusion criteria:
• Subjects below 18 years are not included as the drug might behave differently.
• Pregnant, breast feeding women in order to prevent the drug from going inside the baby.
• Patients with systematic cancer chemotherapy which may result in false side effects.
• Patients who are also infected with HIV, Hepatitis B or C as these infections make treatment difficult.
Table 6: Results for phase-2 trials
Dose (mg/kg) no of subjects No of Adverse events Average CD11c level (%) *
15
30
60
60
60
60
1-Nausea
3-Nuasea,Bowel upset, fatigue
4-Nausea, Indigestion, Fatigue,
Vomiting
65
45
7
*100% stands for total amount of CD11c receptors on the Phagocytes before the treatment of
the patient began.
Adverse events: Apart from the side effects observed in phase 1 trials which were also
observed in phase 2, bowel upset was observed in subjects. In some of the subjects, indigestion
was also observed.
Conclusion:
Phase 1 and 2 trials are giving sufficiently good results with fewer side effects to proceed ahead
with the phase 3 trials. The side effects are very marginal. Dose should be 50mg/kg.
14 | P a g e
Phase 3 clinical trials for Isocitrate lyase inhibitor (Jainin):
Efficacy and safety study of Isocitrate Lyase inhibitor in Pulmonary Tuberculosis patients
Purpose of this study is to evaluate the efficacy, safety, side effects and decrease in daily dosage of drug
for treating pulmonary tuberculosis.
Study design: treatment, safety, efficacy, drug lowering
Study type: interventional
Placebo controlled trial [15]
: Currently there are no drugs being developed which inhibit Isocitrate Lyase.
So my study will tested against a placebo to get a clear idea of the effect of the drug. Drugs for
tuberculosis are known to give various side effects. Also, tuberculosis is a stubborn disease with large
amount of resistance. So a placebo controlled study would be ideal in order to study the side effects as
well as efficacy.
Primary endpoints [15]
:
Number of days required for the sputum culture to turn to negative.
Treatment success rate at the end of 4 months.
Adverse effects during the study
Secondary endpoints [15]
:
Tuberculosis cure rate
CD4 T Lymphocytes
Dose: 50mg/kg
Eligibility [15]
Age- 18 to 60 years
Sex- Both
Healthy volunteers- No
Inclusion criteria:
• Sputum positive patients and patients previously treated for more than 1 month as per RNTCP/WHO
guidelines.
• Radiographic evidence of the disease.
• High WBC count. High WBC count symbolizes mycobacterial infection.
• Microbiological confirmation of Mycobacterial infection.
• Patients with treatment failure, disease relapse as it helps in establishing the superiority of the drug.
• Ability and willingness to give written consent as it is a high risk study.
Exclusion criteria:
• Subjects below 18 years are not included as the drug might behave differently.
• Pregnant, breast feeding women in order to prevent the drug from going inside the baby.
• Patients with systematic cancer chemotherapy which may result in false side effects.
• Patients who are also infected with HIV, Hepatitis B or C as these infections make treatment difficult.
• Severely malnourished patients as proper nutrition is very essential especially proteins.
Results:
A total of 1200 patients went through phase 3 clinical trials for the drug JAININ against placebo
controlled trial. About 25% were given placebo.
15 | P a g e
About 85% of the patients administered with JAININ showed relief in their tuberculosis symptoms. The
CD11c levels went down which showed successful treatment of tuberculosis.
There were side effects in about 10% of population.
Side Effects [17]
:
Anticipated side effects may not include any specific symptom as the drug targets isocitrate lyase which
is a bacterial specific enzyme and not present in humans. So it is highly unlikely that the drug may cause
any problems in humans. And this property is one of the high points of this drug.
Nausea, weakness or fatigue might be observed.
General energy drinks may be given to remove the weakness or fatigue.
Drug Administration Regimen:
Based on the clinical trials, the dosage for patients of 18 years and older is 50mg/kg tablet every day. For
patients under 18 years-the dosage should be determined by physician depending upon case to case
basis.
16 | P a g e
Summary of Clinical Trials:
Table 7:
Key points for Phase1 Key points for Phase 2 Key points for Phase 3 NDA
Gateway to Phase
1Chemistry,Manufacturing
& Controls:
• Formulation of
drug
• Manufacturing
process on small
scale
• Bioassay, Assay for
purity and potency
• Stability Indicating
assay
Toxicology study
• Genotoxicity study
• Single and repeat
dose studies
• Reproductive &
developmental
toxicity studies.
Starting dose is defined
based on non clinical study
Phase 1 trialsStudy is done
on healthy
indivisuals.Phase 1 study is
randomized, dose
escalation study to
determine Maximum
Tolerated Dose(MTD)
,safety in human and safe
dose range in
human.Human
Pharmacokinetics and
exploratory end points are
also studied
Gateway to Phase 2
CMC-
• characterization of
drug
• Check impurities,
manufacturing
controls, product
release
specifications,
stability(at least 1
year)
Non clinical Toxicology study
• Single and repeat
dose studies
• Genotoxicity study
• Reproductive toxicity
Evaluation of potential for
delayed ventricular
repolarization
Phase 2 trials:
Study is randomized, placebo
controlled,double blind
efficacy study in the subjects
having asthma.
Gateway to Phase 3
CMC
• Manufacturing
process validation
• Product release
specification
validation
• Stability check-at
least for 2 years
Non clinical study:
Exposure of drug for 3
months-need 6 month
rodent & non rodent
Phase 3 trials:
Randomized, placebo
controlled, double blind
efficacy study in subjects
having asthma to know
efficacy and safety profile
on large scale.
Submission to
NDA & decision
2 years
17 | P a g e
NDA Application:
Sufficient data is gathered after successful completion of phase 3 trials for filing of NDA approved
application form.
Life cycle management for JAININ:
� Patent for the chemical structure of the drug will be filed.
� Patent for the most effective NCE will be filed.
� The whole manufacturing process will be filed for patenting after the process is standardized in
the studies.
� Patent will be filed for the dosage after standardizing it in phase 2 studies.
� Application for FDA approval will be filed after successful completion of phase 3 studies.
After approval the drug is ready to be launched.
18 | P a g e
Appendix:
APPENDIX-1
There have been many cases of drug resistance in tuberculosis but still the standard treatment regimen
include the above mentioned drugs as the resistance prevalence is not that much and these drugs can
successfully treat the disease. In some cases multiple drug resistance is observed which is also at a small
scale so the standard treatment is continued.
APPENDIX-2
The present drugs-Isoniazid, Rifampin, Pyrazinamide and Ethambutol are highly effective in treating
Tuberculosis but there is a problem with the side effects that they cause-liver problems being the most
severe.
Moreover, patient compliance is a big issue as the current treatment spans over 6 stringent months.
My target is a new one and currently under study. It is based on a hypothesis, the efficacy of which is
currently under experimental study.
There is a problem with redundancy as there are more than one synthase in the bacterium and
inhibiting one synthase might not be that much useful but a drug can be developed which selectively
inhibits all the synthases or the genes coding for the synthases.
Apart from the TAG synthase, isocitrate dehydrogense inhibition, pantothenate biosynthesis inhibition,
targeting the respiratory chain, ribonucleotide reductase and ATP synthase can be other possible
targets. They are all under experimental study.
APPENDIX-3
19 | P a g e
20 | P a g e
References:
[1] Bing Bai, Jiang-Ping Xie, Ju-Fang Yan, Hong-Hai Wang, Chang Hua Hu. 2006. A High
Throughput Screening Approach to Identify Isocitrate Lyase Inhibitors from Traditional Chinese
Medicine Sources. Drug Development Research 67:818-823.
[2] Dharmadhikari A.J., Nardell E.A. (2008) “What Animal models teach humans about tuberculosis.”
Ernesto J., Upton Anna, Cherian Joseph, McKinney J.D., 2006. Role of Methylcitrate cycle in
Mycobacterium tuberculosis metabolism, intracellular growth and Virulence
[3] Gupta U.D., Katoch V.M. (2009) Animal models of tuberculosis for Vaccine development. Indian J
Med Res 129, pp 11-18
[4] Li. A.P. Screening for human ADME/Tox drug properties in drug discovery. DDT Vol.6, No. 7 (2001)
[5] McMurray D.N. (2001) Disease model: pulmonary tuberculosis
[6] Prescott L, Harley J, Klein D, ed. (1999), Prescott’s Microbiology, McGraw Hill, USA
[7] Rosas-Taraco AG (Rosas-Taraco, Adrian G.), Salinas-Carmona MC (Salinas-Carmona, Mario
C.), Revol A (Revol, Agnes), Rendon A (Rendon, Adrian), Caballero-Olin G (Caballero-Olin,
Guillermo), Arce-Mendoza AY (Arce-Mendoza, Alma Y.) Expression of CD11c in Blood
Monocytes as Biomarker for Favorable Response to Antituberculosis Treatment
[8] S Brahmbhatt, G F Black, N M Carroll, N Beyers, F Salker, M Kidd, P T Lukey, K Duncan, P van
Helden, and G Walzl. Immune markers measured before treatment predict outcome of
intensive phase tuberculosis therapy (2006)
[9] Treatment of Tuberculosis. American Thoracic society, CDC, and Infectious Diseases Society of
America.
[10] www.avert.org
[11] www.bindingdb.org
[12] www.biomedcentral.com
[13] www.bio-medicine.org
[14] www.chexmexper.com
[15] www.clinicaltrials.gov
[16] www.familydoctor.org
[17] www.fda.gov
21 | P a g e
[18] www.healthscout.com
[19] www.pubmedcentral.nih.gov
[20] www.rxlist.com
[21] www.sciencemag.org
[22] www.wikipedia.org
[23] www.wrongdiagnosis.com
Top Related