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      Investigation of the antibacterial activity of pioglitazone

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          Abstract

          Purpose:

          To evaluate the antibacterial potential of pioglitazone, a member of the thiazolidinediones class of drugs, against Gram-positive ( Streptococcus pneumoniae) and Gram-negative ( Escherichia coli and Klebsiella pneumoniae) bacteria.

          Methods:

          Susceptibility testing was done using the antibiotic disk diffusion method and the minimal inhibitory concentration (MIC) of pioglitazone was measured according to the broth micro incubation standard method.

          Results:

          Pioglitazone induced a dose-dependent antibacterial activity in which the optimal concentration was 80 μM. Furthermore, results indicated that while E. coli was sensitive (MIC = 31.25 ± 3.87 mg/L) to pioglitazone-induced cytotoxicity, S. pneumoniae and K. pneumoniae were resistant (MIC = 62.5 ± 3.77 mg/L and MIC = 62.5 ± 4.14 mg/L, respectively). Moreover, pretreatment of bacteria with a suboptimal concentration of pioglitazone (40 μM) before adding amoxicillin, cephalexin, co-trimoxazole, or ciprofloxacin enhanced the antibacterial activity of all agents except co-trimoxazole. This enhancing effect was particularly seen against K. pneumoniae.

          Conclusion:

          These results indicate the possibility of a new and potentially important pioglitazone effect and the authors’ ongoing studies aim to illustrate the mechanism(s) by which this antibacterial effect is induced.

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          Most cited references 18

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          Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands: a review.

          Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of a class of nuclear hormone receptors intimately involved in the regulation of expression of myriad genes that regulate energy metabolism, cell differentiation, apoptosis and inflammation. Although originally discovered as a pivotal regulator of adipocyte differentiation, the roles that this transcription factor play in physiology and pathophysiology continue to grow as researchers discover its influence in the function of many cell types. This review highlights the roles that PPARgamma play in the regulation of gene expression associated with normal cell physiology as well as the pathophysiology of multiple diseases including obesity, diabetes and cancer. Additionally, naturally occurring and pharmaceutical ligands for the receptor as well as the potential role of PPARgamma as the receptor responsible for fatty acid-induced effects on gene expression will be described.
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            The pharmacokinetics of pioglitazone in patients with impaired renal function.

            To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M-III and M-IV with impaired renal function and normal renal function. In a phase-I, open-label, parallel-group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min-1), nine patients with moderate renal impairment (creatinine clearance 30-60 ml min-1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min-1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M-III and M-IV were assessed for the first and last dose administered (day 1 and day 12, respectively). Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M-III and M-IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration-time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; -23%; confidence interval (CI) -57, 38), M-III metabolite (13 394 vs 15 071, P = 0.841; -11%; CI -74, 194) and M-IV metabolite (27 991 vs 49 856, P = 0.006; -44%; CI -62, -17). After repeated oral doses of pioglitazone, mean AUC values (microg.h l-1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; -40%; CI -57, -16), M-III (3991 vs 7,289, P = 0.0009; -45%; CI -60, -25) and M-IV (21 080 vs 25 706, P = 0.181; -18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups. Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.
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              Pioglitazone: mechanism of action.

               U. Smith (2001)
              Thiazolidinediones, such as pioglitazone, are synthetic ligands for peroxisome proliferator-activated receptors (PPARs). They alter the transcription of genes influencing carbohydrate and lipid metabolism, resulting in changed amounts of protein synthesis and, therefore, metabolic changes. Pioglitazone improves glycaemic control in people with Type 2 diabetes by improving insulin sensitivity through its action at PPAR gamma 1 and PPAR gamma 2, and affects lipid metabolism through action at PPAR alpha. The results of these interactions include increases in glucose transporters 1 and 4, lowered free fatty acids, enhanced insulin signalling, reduced tumour necrosis factor alpha (TNF alpha) and remodelling of adipose tissue. Together, these can increase glucose uptake and utilisation in the peripheral organs and decrease gluconeogenesis in the liver, thereby reducing insulin resistance.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2011
                27 September 2011
                : 5
                : 421-425
                Affiliations
                [1 ]Department of Pharmaceutical Technology;
                [2 ]Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
                Author notes
                Correspondence: Majed M Masadeh, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan, Tel +962 27 201000, Fax +962 27 201075, Email mmmasadeh@ 123456just.edu.jo
                Article
                dddt-5-421
                10.2147/DDDT.S24126
                3210070
                22087061
                © 2011 Masadeh et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Original Research

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