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Biomedical subjects

Sadhna Sharma

Publications and source records attributed to Sadhna Sharma.

At least 19 recordsLinked to original sources
PubMed2006

Antimycobacterial activity of econazole against multidrug-resistant strains of Mycobacterium tuberculosis.

This study evaluated the antimycobacterial activity of econazole against multidrug-resistant (MDR) strains of Mycobacterium tuberculosis. The minimum inhibitory concentration (MIC(90)) and minimum bactericidal concentration (MBC(>99.99)) against MDR strains were found to be 0.120-0.125 microg/mL and 0.125-0.150 microg/mL, respectively, demonstrating the antimycobacterial potential of econazole.

Antitubercular Agents↗
PubMed2006

Pharmacokinetic and pharmacodynamic behaviour of antitubercular drugs encapsulated in alginate nanoparticles at two doses.

This study was designed to evaluate the pharmacokinetics and tissue distribution of free and alginate-encapsulated antitubercular drugs in mice at different doses. Alginate nanoparticles encapsulating isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB) were prepared by controlled cation-induced gelification of alginate. The formulation was orally administered to mice at two dose levels (D1 and D2). A comparison was made in mice receiving free drugs at equivalent doses. Drugs were analysed by high performance liquid chromatography (HPLC). The average size of alginate nanoparticles was found to be 235.5+/-0.0 nm with a polydispersity index of 0.44; drug encapsulation was 70-90% for INH and PZA, 80-90% for RIF and 88-95% for EMB. In the free drug groups, plasma levels of RIF and INH were higher and PZA and EMB levels were lower in the D1 group (per body surface area of mice) compared with the D2 group (recommended human dose). The plasma drug levels of all drugs were higher in the D1 encapsulated group compared with D2, resulting in higher values of area under the plasma drug concentration-time curve (AUC(0-infinity)). The relative bioavailabilities of all drugs encapsulated in alginate nanoparticles were significantly higher compared with free drugs. Drug levels were maintained at or above the minimum inhibitory concentration (MIC(90)) until Day 15 in organs after administration of encapsulated drugs, whilst free drugs stayed at or above the MIC(90) up to Day 1 only irrespective of dose. The levels of drugs in various organs remained above the MIC at both doses for equal periods, demonstrating their equiefficiency. Alginate nanoparticles hold great potential in reducing dosing frequency of antitubercular drugs.

Alginates↗
PubMed2006

The potential of azole antifungals against latent/persistent tuberculosis.

The aim of the present study was to evaluate the chemotherapeutic potential of econazole against latent tuberculosis. The activity of econazole and clotrimazole was tested against the latent bacilli (Mycobacterium tuberculosis H(37)Rv) developed by nutrient starvation under in vitro conditions and by drugs under in vivo conditions. The latent bacteria developed under in vitro latent conditions were acid-fast negative, nonreplicating, resistant to conventional antitubercular drugs and showed low respiration rates. Econazole as well as clotrimazole were found to have strong antimycobacterial potential against latent Mycobacterium tuberculosis under in vitro conditions as seen by reductions in colony-forming units. Further, econazole prevented the formation of drug-induced latency and significantly reduced bacterial burden from lungs and spleens of latent tuberculosis-infected mice. We conclude that azole drugs bear significant therapeutic potential against latent tuberculosis.

Animals↗
PubMed2006

Azole antifungals as novel chemotherapeutic agents against murine tuberculosis.

The present study was designed to evaluate the in vivo antimycobacterial potential of econazole alone and in combination with antitubercular drugs against tuberculosis in mice. Econazole was found to reduce bacterial burden by 90% in the lungs and spleen of mice infected with 1 x 10(7) cells of Mycobacterium tuberculosis and was found to be equipotent to rifampicin. Further, our results indicate that econazole can replace rifampicin/isoniazid as well as both rifampicin and isoniazid in chemotherapy of murine tuberculosis. Econazole alone or in combination with antitubercular drugs did not produce any hepatotoxicity in normal or M. tuberculosis-infected mice.

Animals↗
PubMed2006

Oral poly(lactide-co-glycolide) nanoparticle based antituberculosis drug delivery: toxicological and chemotherapeutic implications.

The present study reports on the detailed toxicological and chemotherapeutic evaluation of antituberculosis drug loaded nanoparticles in mice. A single oral dose administration of poly(lactide-co-glycolide) (PLG, a synthetic polymer) nanoparticles containing rifampicin+isoniazid+pyrazinamide+ethambutol could maintain drug levels in various tissues for 9-10 days and did not elicit any adverse response even when administered at several fold higher than the recommended therapeutic dose. However, dosing with conventional free drugs at the equivalent higher doses was lethal. Despite multiple oral dosing with the formulation at every 10th day, no toxicity was observed on the completion of subacute (28 days) or chronic (90 days) toxicity studies based on survival, gross pathology, histopathology, blood biochemistry and hematology. In mice harboring a high mycobacterial load (mimicking human tuberculosis), two independent chemotherapeutic regimens, i.e. 5 doses of PLG nanoparticles encapsulating (rifampicin+isoniazid+pyrazinamide+ethambutol) administered 10 days apart, or 2 doses of the 4-drug formulation followed by 3 doses of 2-drug formulation (rifampicin+isoniazid) resulted in undetectable bacilli. Further, the efficacy was comparable to 46 daily doses of oral free drugs. Therefore, the experimental evidence suggests that PLG nanoparticle-based antituberculosis drug delivery system is safe and well suited for prolonged and intermittent oral chemotherapy.

Administration, Oral↗
PubMed2005

Oral solid lipid nanoparticle-based antitubercular chemotherapy.

The present study was planned to evaluate the chemotherapeutic potential of oral solid lipid nanoparticles (SLNs) incorporating rifampicin, isoniazid and pyrazinamide against experimental tuberculosis. The SLNs were prepared by the "emulsion solvent diffusion" technique with an encapsulation efficiency of 51+/-5% for rifampicin, 45+/-4% for isoniazid and 41+/-4% for pyrazinamide. Following a single oral administration to mice, therapeutic drug concentrations were maintained in the plasma for 8 days and in the organs (lungs, liver and spleen) for 10 days whereas free drugs were cleared by 1-2 days. In M. tuberculosis H37Rv infected mice, no tubercle bacilli could be detected in the lungs/spleen after 5 oral doses of drug loaded SLNs administered at every 10th day whereas 46 daily doses of oral free drugs were required to obtain an equivalent therapeutic benefit. Thus, SLN based antitubercular drug therapy forms a sound basis for reducing dosing frequency and improving patient compliance for better management of tuberculosis.

Administration, Oral↗
PubMed2005

In vitro and ex vivo antimycobacterial potential of azole drugs against Mycobacterium tuberculosis H37Rv.

The antimycobacterial activity of two clinically approved antifungal azole drugs, clotrimazole and econazole, was evaluated against Mycobacterium tuberculosis H37Rv under in vitro and ex vivo conditions. The minimum inhibitory concentration (MIC90) was 0.120 microg ml(-1), whereas the minimum bactericidal concentration and effective concentration was 0.125 microg m l(-1) for both the drugs demonstrating their potent antimycobacterial activity. Further, the azole drugs exhibited a synergistic activity with either rifampicin or isoniazid as evaluated on the basis of reduction of colony forming units. The results suggest that azole compounds bear the potential to enhance the efficacy of currently prescribed antitubercular drugs.

Anti-Bacterial Agents↗
PubMed2005

Nano-encapsulation of azole antifungals: potential applications to improve oral drug delivery.

The present study was designed to improve the oral bioavailability of two clinically important antifungal drugs-clotrimazole and econazole. Each drug was encapsulated in nanoparticles of a synthetic polymer (polylactide-co-glycolide, PLG) or a natural polymer (alginate stabilized with chitosan). The nanoparticles were prepared by the emulsion-solvent-evaporation technique in case of PLG and by the cation-induced controlled gelification in case of alginate. Drug encapsulation efficiency was better (>90%) for the alginate formulation compared with the PLG formulation (nearly 50%). The formulations were orally administered to mice and the drugs were analyzed in plasma by a validated HPLC technique. The biodistribution/pharmacokinetic data suggested that there was a controlled drug release for 5-6 days with each of the formulations, compared with unencapsulated drugs, which were cleared within 3-4 h of oral/intravenous administration. There was a striking improvement in the relative and absolute bioavailability of each drug. Further, the drugs were detected in the tissues (lungs, liver and spleen) till 6-8 days in case of nanoparticles whereas free drugs were cleared by 12 h. Overall, the alginate formulation appeared to be better than the PLG formulation. The results emphasize the power of nanotechnology to make the concept of enhancement in oral bioavailability of azole antifungal drugs come to reality.

Administration, Oral↗
PubMed2005

Inhalable alginate nanoparticles as antitubercular drug carriers against experimental tuberculosis.

Pharmacokinetic and chemotherapeutic studies have been carried out with aerosolised alginate nanoparticles encapsulating isoniazid (INH), rifampicin (RIF) and pyrazinamide (PZA). The nanoparticles were prepared by cation-induced gelification of alginate and were 235.5 +/- 0 nm in size, with drug encapsulation efficiencies of 70-90% for INH and PZA and 80-90% for RIF. The majority of particles (80.5%) were in the respirable range, with mass median aerodynamic diameter of 1.1 +/- 0.4 microm and geometric standard deviation of 1.71 +/- 0.1 microm. The relative bioavailabilities of all drugs encapsulated in alginate nanoparticles were significantly higher compared with oral free drugs. All drugs were detected in organs (lungs, liver and spleen) above the minimum inhibitory concentration until 15 days post nebulisation, whilst free drugs stayed up to day 1. The chemotherapeutic efficacy of three doses of drug-loaded alginate nanoparticles nebulised 15 days apart was comparable with 45 daily doses of oral free drugs. Thus, inhalable alginate nanoparticles can serve as an ideal carrier for the controlled release of antitubercular drugs.

Aerosols↗
PubMed2005

Oral therapy using nanoparticle-encapsulated antituberculosis drugs in guinea pigs infected with Mycobacterium tuberculosis.

We evaluated the efficacy of nanoparticle-encapsulated antituberculosis drugs administered every 10 days versus that of daily nonencapsulated drugs against Mycobacterium tuberculosis aerosol infection in guinea pigs. Both treatments significantly reduced the bacterial count and lung histopathology, suggesting that the nanoparticle drug delivery system has potential in intermitted treatment of tuberculosis.

Administration, Inhalation↗
PubMed2004

Lectin-functionalized poly (lactide-co-glycolide) nanoparticles as oral/aerosolized antitubercular drug carriers for treatment of tuberculosis.

OBJECTIVES: This study was carried out to explore lectin-functionalized poly (lactide-co-glycolide) nanoparticles (PLG-NPs) as bioadhesive drug carriers against tuberculosis (TB), in order to reduce the drug dosage frequency of antitubercular drugs and thus improve patient compliance in TB chemotherapy. METHODS: Wheat germ agglutinin (WGA)-coated PLG-NPs were prepared by a two-step carbodiimide procedure. This formulation was administered to guinea pigs through the oral/aerosol route for a detailed pharmacokinetic and chemotherapeutic evaluation. Immunological or hepatotoxic effects of WGA lectin, if any, were also determined. RESULTS: WGA-functionalized PLG-NPs were in the size range of 350-400 nm, with binding of 3-3.5 microg of WGA/mg of PLG-NPs and drug encapsulation efficiency of 54%-66%. Upon administration of lectin-coated PLG-NPs through the oral/aerosol route, the presence of drugs in plasma was observed for 6-7 days for rifampicin and 13-14 days for isoniazid and pyrazinamide. However, upon administration of uncoated PLG-NPs (oral/aerosolized) rifampicin was detectable in plasma for 4-6 days, whereas isoniazid and pyrazinamide were detectable for 8-9 days. All three drugs were present in lungs, liver and spleen for 15 days. Administration of WGA-coated PLG-NPs caused a significant (P < 0.001) increase in the relative bioavailability of antitubercular drugs. Chemotherapeutic studies revealed that three doses of oral/nebulized lectin-coated nanoparticles fortnightly could yield undetectable mycobacterial colony forming units (cfu); this was achievable with 45 doses of oral free drugs. CONCLUSION: WGA-functionalized PLG-NPs could be potential drug carriers for antitubercular drugs through the oral as well as aerosol route for effective TB control.

Administration, Oral↗
PubMed2004

Chemotherapeutic efficacy of poly (DL-lactide-co-glycolide) nanoparticle encapsulated antitubercular drugs at sub-therapeutic dose against experimental tuberculosis.

The present study was designed to evaluate the chemotherapeutic efficacy of poly (DL-lactide-co-glycolide) (PLG) nanoparticles (NP) encapsulating three front-line antitubercular drugs (ATDs: rifampicin, RIF; isoniazid, INH and pyrazinamide, PZA) at 2/3rd therapeutic dose. PLG nanoparticles prepared by the double emulsion and solvent evaporation technique were administered orally at 2/3rd therapeutic dose to guinea pigs. A single oral administration of the formulation resulted in sustained drug levels in the plasma for 7-12 days and in the organs for 11-14 days with a significant improvement in mean residence time as well as drug bioavailability. The administration of PLG nanoparticles every 10 days (five doses) to Mycobacterium tuberculosis H(37)Rv infected guinea pigs led to undetectable bacilli in the organs, as did 46 conventional doses. Therefore, nanoparticle based antitubercular chemotherapy forms a sound basis for a reduction in dosing frequency and also offers the possibility of reducing the drug dosage.

Administration, Oral↗
PubMed2004

Induction of nitric oxide release from the human alveolar epithelial cell line A549: an in vitro correlate of innate immune response to Mycobacterium tuberculosis.

In view of the presence of a large number of epithelial cells in the alveoli of the lung and their ability to produce various cytokines and chemokines, the possible role of alveolar epithelial cells in the innate immune response to tuberculosis was examined. The human alveolar epithelial cell line A549 was used as a model. The ability of A549 cells to induce nitric oxide (NO) in response to Mycobacterium tuberculosis infection was taken as an in vitro correlate of innate immunity. M. tuberculosis infection induced A549 cells to produce significant levels of NO and to express inducible nitric oxide synthase mRNA at 48 hr of infection. However, the amount of NO released at this point was not mycobactericidal. Cytokine stimulation (interferon-gamma, tumour necrosis factor-alpha, interleukin-1beta, alone or in combination) of the infected A549 cells induced a higher concentration of NO. The study of colony-forming units (CFU) as a measure of the mycobactericidal capacity of A549 cells revealed a reduction in CFU of M. tuberculosis by 39.29% (from 10.62 +/- 0.48 - 6.392 +/- 0.54) following cytokine stimulation of the infected cells. Interestingly gamma-irradiated M. tuberculosis H37Rv could also induce higher than basal level of NO. Therefore we examined mycobacterial antigenic components for their possible role in NO production. We observed that A549 cells produced significantly higher amounts of NO at 48 hr when treated with mycobacterial whole cell lysates, cell wall or cell membrane preparations. The release of NO and the resultant mycobactericidal activity could be further enhanced by simultaneously conditioning the M. tuberculosis infected A549 cells with cytokine and mycobacterial components. These results suggest that alveolar epithelial cells respond to their microenvironment, which is constituted of various cytokines and macrophage-processed antigens and may contribute to the innate immune response to tuberculosis.

Cell Line↗
PubMed2004

Mycobacterium tuberculosis induces high production of nitric oxide in coordination with production of tumour necrosis factor-alpha in patients with fresh active tuberculosis but not in MDR tuberculosis.

Mycobacterium tuberculosis is an intracellular pathogen that readily survives and replicates in human macrophages. Host cells have developed various mycobactericidal and immunoregulatory mechanisms, such as the production of nitric oxide and inflammatory cytokines to control intracellular replication of M. tuberculosis. Inducible nitric oxide synthase (iNOS) is transcriptionally under the control of IFN-gamma and TNF-alpha. IL-12 provides a crucial link between activated mononuclear phagocytes and T cells by regulating the production of IFN-gamma. In this study, we investigated the production of nitric oxide (NO), TNF-alpha and IL-12 by the peripheral blood monocytes (PB Mn) of patients suffering from multidrug-resistant tuberculosis (MDR-TB). The cells were infected with M. tuberculosis and stimulated with IFN-gamma or activated with mycobacterial subcellular components. The results were compared with those from cases of newly diagnosed TB and healthy controls. Nitric oxide production was significantly depressed in PB Mn from MDR-TB patients. Infected monocytes from newly diagnosed TB patients produced significantly higher levels of NO as compared to those from MDR-TB patients or normal controls. The subcellular fraction of M. tuberculosis-like whole cell lysate (WCL), culture filtrate protein (CFP) and lipoarabinomannan (LAM) induced higher concentrations of NO release in PB Mn from newly diagnosed TB patients as compared to those from MDR-TB patients. Cell culture supernatant from PB Mn assayed at 48 h after infection or stimulation demonstrated significantly depressed release of TNF-alpha and IL-12 from MDR-TB cases as compared to the fresh cases. We observed a definite correlation between nitric oxide release and TNF-alpha production, irrespective of low or high production in MDR-TB or fresh cases, respectively. The present data suggest that peripheral blood monocytes of MDR-TB patients typically show signs of immunosuppression. Whether such immunodepression is the cause or the effect of MDR-TB merits further investigation.

Adult↗
PubMed2004

Liposome technology for drug delivery against mycobacterial infections.

Mycobacteria are intracellular pathogens that invade and reside inside macrophages. There has been a rapid resurgence in infections caused by the genus mycobacteria. Chemotherapy of mycobacterial infections is prolonged, hepatotoxic and very often inadequate in achieving optimal drug concentrations inside the cells. Recent advances in controlled delivery systems for drugs such as liposomes have sparked a renewed interest in their potential application for the treatment of mycobacterial infections. The versatility of liposomes in incorporation of hydrophilic/hydrophobic components, non-toxic nature, biodegradability, biocompatibility and property of sustained release makes them attractive candidates for the delivery of antitubercular drugs. Liposome research in the area of mycobacterial diseases has evolved and matured through several phases; from the laboratory to the clinics. This review, thus focuses on the use of liposomes for the treatment of various types of mycobacterial diseases.

Animals↗
PubMed2004

Lung specific stealth liposomes as antitubercular drug carriers in guinea pigs.

The problem of patient non-compliance in the management of tuberculosis (TB) can be overcome by reducing the dosing frequency of antitubercular drugs (ATD) employing drug carriers. This study reports on the intravenous (iv) administration of lung specific stealth liposomes encapsulating ATD (rifampicin and isoniazid in combination) to guinea pigs and the detailed pharmacokinetic/chemotherapeutic studies. Following a single iv administration of liposomal drugs, the latter were found to exhibit sustained therapeutic levels in plasma for 96-168 hr with half-lives of 24-70 hr, mean residence time (MRT) of 35-81 hr and organ drug levels up to day 7. The relative bioavailability (as compared to oral free drugs) was increased by 5.4-8.9 folds, whereas the absolute bioavailability (as compared to iv free drugs) was increased by 2.9-4.2 folds. Weekly therapy with liposomal ATD for 6 weeks produced equivalent clearance of Mycobacterium tuberculosis from organs as did daily therapy with oral free drugs. Hence, intravenous liposomal ATD offer the therapeutic advantage of reducing the dosing frequency and improving the patient compliance in the management of TB.

Animals↗