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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.

 

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).

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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