Side Effects of TB Therapy and Recent Therapeutic Approaches for Tuberculosis Management

 

Harshada R Bandgar

Bharati Vidyapeeth’s College of Pharmacy, Sector - 8, C.B.D Belapur, Navi Mumbai, 400614.

*Corresponding Author E-mail: harshadabandgar200@gmail.com

 

ABSTRACT:

Tuberculosis or TB caused by the micro-organism Mycobacterium tuberculosis is a highly contagious and the second most fatal disease after AIDS. It is estimated that it will soon surpass the deaths caused by HIV.BCG is the only vaccine available to prevent TB, however it is not effective in case of adult pulmonary TB which is actually the most common type of TB. The currently used treatment regimen in most developing countries is a single tablet with fixed dose combination of four drugs- Isoniazid (INH), Rifampicin, Ethambutol and Pyrazinamide which are 1st line anti-tubercular drugs. This combination reduces the risk of development of multi-drug resistant (MDR) Mycobacterium. But this drug combination is known to have various severe side-effects, which if not taken into consideration might lead to fatal reactions. MDR-TB treatment involves the use of 2nd line drugs which are less potent and more toxic compared to 1st line drugs. Increasing number of MDR strains of mycobacterium and failure of these conventional regimens to treat them is a huge challenge. Also, these side-effects associated with anti-TB drugs are a major reason for patient non-compliance and non-adherence to the treatment. Treatment discontinuation leads to increased risk of mortality and morbidity due to TB. Thus, it is very important to develop new therapeutic approaches towards the treatment of this disease which provide a better cure without relapse, lesser side-effects and prevents formation of drug resistant strains. The article reviews the various side-effects associated with the Anti-Tubercular drugs that are currently used and discusses certain newer, nanoparticle-basedapproaches to overcome the shortcomings of the current conventional therapy.

 

KEYWORDS: Tuberculosis, Side-effects, Multi-drug resistant, Adult pulmonary TB, Nano-particles.

 

 


INTRODUCTION:

In underdeveloped and developing countries, TB has a very big impact. Along with lack of knowledge and lesser penetration of proper health facilities in the remote areas, it is a very big challenge for these countries to control this disease.1,2 A lot of adverse effects associated with the existing anti-TB drugs is a reason for treatment discontinuation by patients.3 This increases the risk of multi drug resistant TB which cannot be treated using these 1st line drugs.4,5

 

Though these adverse effects are manageable, it is important to recognize them on time and provide appropriate solutions like altering dosages, adding ancillary drugs to treat adverse effects, discontinuation of the drugs if needed, and development of a personalized patient centered approach for the treatment of tuberculosis.6 Treatment interruption may also lead to formation of multi drug resistant bacteria which is difficult to treat. This stimulates the search of new and unique alternative therapeutic drugs and dosage forms.6,7,22,23

 

·       Bacteriology:

Mycobacterium tuberculosis is a large, slow growing, nonmotile, Gram positive, non-spore forming, catalase positive, rod-shaped bacteria that causes tuberculosis. Since it is an obligate aerobe, it is prominently found in the oxygenated environment of the upper lobes of human lungs. It is also found to be resistant to dehydration as a result of which it can even survive in the expectorated sputum.

 

The bacterial cell wall is made up of an array of complex lipids such as mycolic acid and fatty acids. They facilitate its acid-fast characteristics. Wax-D and phosphatides are responsible for clinically relevant feature of caseating necrosis.8

·       Diagnosis:

Clinically TB can be diagnosed by carrying out chest radiography and by skin reactivity testing i.e., tuberculin (Mantoux) skin testing.9 Another method would be the interferon-gamma release assay (IGRA) that measures the level of interferon-gamma upon exposure of blood to an antigen obtained from M. tuberculosis. BCG immunization does not have any influence on this test. A positive test result indicates that the individual is infected with M. tuberculosis.10

·       Treatment:

Patients with latent tuberculosis, who have the bacteria in their bodies but do not present with any symptoms, are treated with drugs like INH, rifampicin and rifapentine.11 While for non-resistant tuberculosis the treatment involves the use of a several drugs that are taken over a period of about 6-9 months.12 There are 10 FDA approved drugs that are currently used for the treatment out of which the 1st line drugs- INH, rifampicin, ethambutol, and pyrazinamide, form the core of the treatment regimen for tuberculosis.13

 

The initial phase of treatment for non-resistant tuberculosis involves the use of INH, rifampicin and pyrazinamide for the 1st2-month regimen followed by the administration of INH and rifampicin for the next 4 months.14 If this treatment is not completed it may lead to development of bacteria resistant to these 1st line drugs. A long period of treatment regimen is also one of the significant reasons for patient non-adherence. Another critical reason for treatment non-adherence is the adverse effects caused by anti-TB drugs (ATD).15,16

 

They are mainly classified into major and minor adverse effects. Minor adverse effects are seen in 5-20% cases and they do not require any immediate modification in the standard treatment regimen and can be taken care of at primary care clinics. Whereas major adverse effects occur in about 3-8% cases and they need immediate treatment modification along with specialized care.17

 

There can be various factors for these adverse effects like age, dose, body weight etc. The adverse drug effects include gastrointestinal, neurological, immune-mediated, and hepatic side effects.18 Gastrointestinal adverse effects mainly include nausea, vomiting, diarrhea. Immune mediated adverse effects include fever, Herpes zoster, oral candidiasis, Kaposi’s sarcoma, and immune reconstitution inflammatory syndrome.19-21 Hepatic adverse effects are the most common type and include hepatotoxicity, hepatitis, jaundice etc. Slow N-acetyl transferase acetylators have higher risk for hepatic adverse effects. Arthralgia, exanthema, kidney disorders, hearing loss etc. are certain other adverse effects. Pyrazinoicacid, which is a metabolite of pyrazinamide, inhibits renal tubular secretion of uric acid which causes joint pain.

 

In order to eliminate or reduce these adverse effects of the conventional therapeutic agents and to prevent the development of MDR-TB and to ultimately increase treatment adherence at large, research has been carried out for replacing the administration of these antibiotics.22,23

 

·       Nano technology-based approach:24-27

Nanobead delivery provides a slow, sustained, and controlled drug release. Nano particles are also taken up more effectively by body cells than other larger molecules. Thus, they can be used as carriers that can provide a sustained drug release from the matrix.

Nano particle-based drug delivery system (DDS) provides the following advantages:

·       Multiple drugs can be encapsulated in the same matrix

·       Lesser adverse effects compared to conventional methods

·       Improved patient compliance

·       Increased bioavailability

 

1.     Oral delivery of nano particles:

INH, rifampicin, and pyrazinamide were encapsulated in PLG NPs by double emulsion process. To reduce the dosing frequency and duration of chemotherapy, PLG-NPs encapsulated ethambutol was added to the regimen along with the other three encapsulated front-line drugs.

 

2.     Pulmonary delivery of nano particles:

Pulmonary TB is the most common form of the disease, and this route of administration (ROA) provides a unique way of delivering drugs directly to the lungs. It reduces the systemic toxicity and helps to accomplish higher drug concentration at the site of infection.

 

Inhalable nano particles have an enhanced ability to bind to the mucus layer and provide better particle delivery.

 

3.     Intravenous (IV) delivery of Nano-particles:

Among all the injectable drug delivery routes, IV administration of drugs is the fastest ROA. A single subcutaneous injection of PLG nano particle loaded with rifampicin, INH, and pyrazinamide show sustained drug levels in plasma for about 32 days and in lungs or spleen for 36 days.

 

A new anti-TB drug- Clofazimine is shown to have promising effect. However, it has less solubility. To overcome this problem, it was formulated as a nanosuspension, which, upon IV administration shows significant effect.

 

Certain other approaches like liposome or niosme based anti-TB DDS can also be used as an alternative to the conventional therapy.

 

CONCLUSION:

In conclusion, the various adverse effects of Anti-TB drugs, treatment nonadherence, patient noncompliance due to a large treatment period, development of multi drug resistant strains and even the lack of knowledge and unavailability of proper health care services are some of the many reasons for increasing number of deaths and infections due TB. To eradicate this devastating infection, it is important to look at alternative methods for its treatment. The use of nanoparticles is one such method that has tremendous potential for tuberculosis treatment due to various advantages like better shelf life, enhanced bioavailability, etc.

 

However, the success of this technology must be tested by appropriate clinical studies. This nanoparticle-based DDS might be the solution to improve the patient compliance in Tuberculosis chemotherapy.

 

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Received on 19.04.2022         Modified on 27.09.2022

Accepted on 08.12.2022   ©Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2023; 13(1):31-33.

DOI: 10.52711/2231-5691.2023.00005