Tuberculosis Chemotherapy-Perspective For Advancements
Tuberculosis (TB) Polymeric drug carriers Polymers
are the most versatile class of materials and are widely used in
pharmaceutical ,medical ,biomedical engineering, food and cosmetic
industry. When a polymer is judiciously combined with a drug or other
active agents in such a way that this active agent is released from the
drug in a pre designed manner, a controlled drug delivery system is
obtained.
The major
advantages that polymeric drug carriers offer can be listed as:
· Decrease
in dosage frequency and increased patient compliance
· Localized drug delivery
· Reduced toxicity
· Increased drug absorption
· Protection of drug in physiological environment
The
polymeric drug carriers can be broadly classified into natural and
synthetic drug carriers based on their origin.
is a disease of antiquity and civilization. It still remains one of the
top three fatal infectious diseases, together with AIDS and malaria.
Despite medical progress in fighting tuberculosis, the disease remains a
major health problem, especially in developing countries that are being
ravaged by the AIDS scourge.
The
World Health Organization (WHO) has identified tuberculosis as one of
the most important emerging global health threats, with an estimated
one-third of the world population infected with the causative agent.
Despite the existence of effective treatment, the disease burden remains
high due to logistic and operational problems, including those related to
access to TB services. Roughly 80 percent of all active tuberculosis cases
are found in Asia and sub-Saharan Africa. Southern Africa has the highest
rate in Africa of people suffering from both TB and HIV, with more than 9
million people infected. Of the 13 million tuberculosis patients who are
also HIV-positive on the continent, about 9,5 million of them are believed
to be in southern Africa, which calls for greater efforts to expand the
control programmes.
WHO states
that at least 8 million people acquire tuberculosis while two million
deaths as a result of the disease are recorded every year worldwide.
Virtually wiped out in the so-called developed world, tuberculosis has for
sometime been regarded as a largely Third World disease. Chemotherapy of
tuberculosis As mankind has been afflicted by tuberculosis from
pre-historic times, a plethora of treatments, ranging from traditional
healing to surgery has been described, however, it was not until 1943,when
Selman Waksman discovered streptomycin, that physicians had at their
disposal as a powerful antituberculosis agent with scientifically proven
activity. Shortly afterwards, in 1946, para-aminosalicylic acid was shown
by Jorgan Lehmann to be active against M.tuberculosis and in 1952, three
pharmaceutical companies simultaneously announced the discovery of highly
effective antitubercular drug, isoniazid (INH). In the early days of
tuberculosis chemotherapy, these drugs were used individually and in many
cases, despite good initial response, the patients developed drug
resistance. Consequently, regimens were developed in which streptomycin
was associated with another drug. The duration of treatment lasted from
12-18 months.
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This
research culminated in the first generation of multidrug treatment
regimens for tuberculosis. These were subsequently improved and
strengthened as new drugs, such as ethambutol and rifampicin were
introduced in1962 and 1967 respectively. Pyrazinamide compound, which is
bactericidal at acidic pH and acts on intracellular bacteria, was found to
be of great value.
Short
course chemotherapy of tuberculosis
As a result of much research and many controlled clinical trials, the
current regimens for short course chemotherapy were evolved (WHO, 1983).
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The treatment lasts for
6-8 months and consists of two phases(Table 2)
i.e.Intensive phase which lasts for 2 months aimed at sputum
negativization and prevention of selection of resistant strains and
continuous phase aimed at sterilization and relapse free resolution.These
short course treatment regimens are able to cure multibacillary forms of
tuberculosis after as little as 6 months of treatment and have become the
standard care throughout the world.
Table 2
Short course treatment of tuberculosis
Phase Duration Drugsadministered Dose (mg/Kg b.w.) Aim
Intensive(Bactericidal) 2 months INHRIFPZAEMB 51015-3015-25 Reduces
clinical symptoms, risk of transmission and emergence of drug resistance
Continuous(Sterilizing) 4-6 monthsDrugs employed in tuberculosis
chemotherapy
Numerous antibiotics with antituberculous activity are available,
including natural products such as aminoglycosides and
cycloserine;synthetic compounds such as nicotinamide analogues and
semisynthetic compounds such as rifamycins. These have been classified as:
Firstline drugs- These combine the greatest level of efficacy with an
acceptable degree of toxicity; these include isoniazid, rifampicin,
pyrazinamide, ethambutol and streptomycin.
Secondline drugs -As drug resistance is very frequent in tuberculosis,
it may be necessary to resort to al;ternative drugs including ofloxacin,
ciprofloxacin, ethionamide, para-aminosalicylic acid, cycloserine,
amikacin, kanamycin and capreomycin.
For TB
treatment to be successful a number of requirements are to be met:
· Antibiotics must be given for a long period of 6-8 months to prevent
relapse after treatment is stopped
· Antibiotics must be given in combination to prevent selection of mutant
strains
· Clinician and patient compliance must be ensured.
` When administered appropriately, combination therapy can be highly
effective owing to:
· Regimens employing firstline agents are orally bioavailable
· The therapy is relatively cheap
· Cure rates exceeding 85% are possible
Drawbacks of chemotherapy
of tuberculosis
In spite of having an immense chemotherapeutic efficacy the conventional
chemotherapy of tuberculosis is associated with certain inherent
drawbacks: Patient non-compliance-The
current regimens of antiTB therapy are complex and lengthy. Adherence
to 6-8 month chemotherapy with a combination of drugs is often difficult.
Moreover, treatment programmes require substantial supervision to
monitor intake and tolerability of drugs, which is often difficult
Drug
resistance-Inadequate drug intake is often associated with emergence and
expansion of multidrug resistant strins thereby further complicating the
therapy of tuberculosis. Drug
toxicity-For the most part, TB chemotherapy is well tolerated. However,
the potential for drug toxicity has been highlighted by several reports on
the rates of adverse reactions during routine curative treatment (Chaisson
et al, 2003) and by unanticipated hepatotoxicity of antitubercular drugs
Drug-drug
interaction-Complex drug-drug interactions particularly between the rifamycins and antiretroviral drugs (antiprotease drugs) may also
complicate the chemotherapy of tuberculosis.
Drug
dilution-The administration of antitubercular drugs in free form causes
their dilution and premature metabolic degradation (Deol et al, 1997).The
drugs that reach the target site is therefore lower than the effective
concentration required, which might result in the primary resistance of
drugs.
Numerous
strategies are being employed for improving the chemotherapy of
tuberculosis including:
New drug development- numerous new drugs with diverse
antimycobacterial activities are in the pipeline including
flouroquinolones ,oxazolidones ,nitroimidazopyran and thiolactomycins.
Newer
drug targets- Several enzymes being encoded by mycobacterial genes
have been recently reported to play an important role in virulence and
persistence (Mckinney et al, 2000), enzymes involved in polyketide
synthesis like polyketide synthase (George et al, 1999).
Although,
the development of improved antimycobacterial drugs and drug targets is an
important issue to the scientific community the currently used
antitubercular drugs still hold a great chemotherapeutic strength. Since
compliace is a major issue in battle against tuberculosis,improved and
efficient methods for the effective delivery of antiTB drugs should be a
key issue in regard to the therapy aimed at :
· Achieving
therapeutically active levels of antitubercular drugs alongwith reduced
dosing regimens for addressing the issues related to
compliance(Barrow,2004).
· Directing the sustained delivery of drugs constantly towards the
intracellular pathogen
INHRIF 510 Reduces the risk of relapse.
Contributing Author: Anjali Sharma, I am a Ph.D.
student of Biochemistry working in PGIMER. I am a national fellowship
holder with a very good academic record and 3 international research
publications.
anjs108@yahoo.co.in
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