Controlled-release approaches towards the chemotherapy of tuberculosis

Figures & data

Table 1 Structures of first-line antituberculosis drugs

Rifampin (RIF)	Isoniazid	Pyrazinamide	Ethambutol

Figure 1 Detailed structure of a macrophage showing a typical process of phagocytosis.

Meena LS, Rajani. Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS J. 2010;277(11):2416–2427. Reproduced with permission from John Wiley and Sons.⁸

Figure 2 Important factors of the survival mechanisms involved in the phagosome maturation arrest of Mycobacterium tuberculosis inside the macrophages. Meena LS, Rajani. Survival mechanisms of pathogenic Mycobacterium tuberculosis H37Rv. FEBS J. 2010;277(11):2416–2427. Reproduced with permission from John Wiley and Sons.⁸

Abbreviation: TACO, tryptophan aspartate-containing coat.

Table 2 Side effects of first-line antituberculosis drugs

Drug	Major adverse effects	Rare adverse effects
Isoniazid	Peripheral neuropathy, skin rash, hepatitis, sleepiness and lethargy	Convulsions, psychosis, arthralgia, anemia
Rifampin	Gastrointestinal abdominal pain, nausea, vomiting, hepatitis, generalized cutaneous reactions, thrombocytopenic purpura	Osteomalacia, pseudo-membranous colitis, pseudo-adrenal crisis, severe renal stoppage, hemolytic blood paucity
Pyrazinamide	Arthralgia, hepatitis, gastrointestinal problems, eg, stomach upset, nausea, poor appetite and abdominal pain	Cutaneous reaction, sideroblastic anemia
Streptomycin	Vestibular and auditory nerve damage renal breakage, cutaneous allergic reaction	Pain, rash at injection site, numbness around the mouth and tingling soon after the injection
Thiacetazone	Skin rash that sometimes has mucosal involvement	Acute hepatic failure, exfoliative dermatitis

Reproduced with permission of the European Respiratory Society. Breathe. 2005;2:69–73.¹⁸

Table 3 Side effects of second-line antituberculosis drugs

Drug	Major adverse effects	Rare adverse effects
Kanamycin	Vestibular (vertigo) and auditory nerve damage	Cutaneous hypersensitivity
Amikacin	Vestibular damage (vertigo) and auditory nerve damage	Clinical renal failure
Capreomycin	Nephrotoxicity
Ethionamide (prothionamide)	Gastrointestinal anorexia, nausea, diarrhea, abdominal pain, hepatotoxicity	Convulsions, mental symptoms, impotence, gynecomastia
Fluoroquinolones	Gastrointestinal anorexia, nausea, vomiting	Anxiety, dizziness, headache, convulsions, rupture of the Achilles tendon
Cycloserine	Dizziness, headache, depression, psychosis, convulsions	Suicide, generalized hypersensitivity, hepatitis
Para-aminosalicylic acid	Gastrointestinal anorexia, nausea, vomiting, hypersensitivity reactions (fever, rash, pruritus)	Hypothyroidism, hematological reactions

Reproduced with permission of the European Respiratory Society. Breathe. 2005;2:69–73.¹⁸

Figure 3 Structure of capreomycin.

Figure 4 Scanning electron micrograph of spray-dried capreomycin dry powder. Note: Scale bar = 5 μm.

Garcia-Contreras L, Fiegel J, Telko MJ, et al. Inhaled large porous particles of capreomycin for treatment of tuberculosis in a guinea pig model. Antimicrob Agents Chemother. 2007;51(8):2830–2836. Reproduced with permission from American Society for Microbiology.³⁸

Figure 5 Top: Schematic representation of rifampin (Rif) (red circles) loaded into glucan particles (GPs) and sealed with a hydrogel. Bottom: bright-field microscope images of an empty GP (left) and a GP-Rif sample (right).

Reproduced from Soto E, Kim YS, Lee J, Kornfeld H, Ostroff G. Glucan particle encapsulated rifampicin for targeted delivery to macrophages. Polymers. 2010; 2(4):681–689.⁴⁴

Figure 6 Different forms of zein.

Global Protein Products, Inc. Zein: a natural biopolymer from a renewable resource [web page on the Internet]. Fairfield, ME: Global Protein Products, Inc; 2011. Available from: http://www.globalprotein.com/zein.html. Reproduced with permission from Global Protein Products Inc.⁷¹

Table 4 Advantages and disadvantages of different drug-delivery systems

Drug-delivery system	Advantages	Disadvantages/suggestions
Large porous particles of capreomycin	Elimination of injection, reduces the side effects of drugs, biodegradable, increased bioavailability, controlled release of drug^Citation24	–
Microparticles of rifampin-containing mannitol	Easy to prepare, targeted, and effective; pro-release of the drug into the lungs^Citation58	Uncontrolled release of drug^Citation58
Microparticles of poly (D-L-lactic acid)	Direct delivery to the lungs and microparticles phagocytized rapidly by alveolar macrophages; multiple drug encapsulation, maintaining a higher drug concentration than the drug given by intravascular means^Citation28,Citation42	In vivo analysis needs to be done
Tunable systems for controlled release into the lungs	Monomers are already in medical application, controlled release of drugs, can be tuned to target side of interest^Citation23	–
Targeted delivery of glucan particles to macrophages	Glucan particles are easily taken in by macrophages, controlled release of drug, and good targetability; therapeutic effect can be maintained with a lower concentration than the minimum inhibitory concentration; reduces adverse effects of rifampin, such as hepatotoxicity^Citation33	Encapsulated amount of drug was below the minimum inhibitory concentration and glucan-chitosan particles dissolve at pH 5 and result in quick drug release^Citation33
Plant proteins: zein	Multiple drug encapsulation and safe to use^Citation51	Sustained release needs to be improved
Gelatin nano-vehicles	Biocompatible, biodegradable, low antigenicity, low cost, numerous available active groups for attaching targeting molecules, uniform distribution of the particles, extended controlled release, nontoxic compared with free drug, improved pharmacokinetics, have the potential to reduce dosing frequency^Citation53^–^Citation55	–
Chitosan-montmorillonite hydrogel	Good targetability and controlled release at lower pH; improved encapsulation properties^Citation57,Citation58	In vitro and in vivo analysis for the evaluation of the therapeutic effect and cytotoxicity needs to be done
Nanocomposite hydrogels of poly (vinyl alcohol) and sepiolite	Improves the water solubility of drugs, especially that of rifampin^Citation64	Swelling behavior and crystallinity of the hydrogels are not fully understood and in vitro and in vivo analysis for the evaluation of therapeutic effect needs to be done^Citation64

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