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Pharmaceuticals, Volume 5, Issue 11 (November 2012) – 5 articles , Pages 1147-1264

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325 KiB  
Review
The Biological Role of PI3K Pathway in Lung Cancer
by Evangelos G. Sarris, Muhammad W. Saif and Kostas N. Syrigos
Pharmaceuticals 2012, 5(11), 1236-1264; https://doi.org/10.3390/ph5111236 - 20 Nov 2012
Cited by 92 | Viewed by 12758
Abstract
Lung cancer is the primary cause of cancer-related mortality worldwide and although improvements in treatment have been achieved over the last few years, long-term survival rates for lung cancer patients remain poor. Therefore, there is an imperative need for molecularly targeted agents that [...] Read more.
Lung cancer is the primary cause of cancer-related mortality worldwide and although improvements in treatment have been achieved over the last few years, long-term survival rates for lung cancer patients remain poor. Therefore, there is an imperative need for molecularly targeted agents that will achieve long-term disease control. Numerous downstream molecular pathways, such as EGF/RAS/RAF/MEK/ERK and PI3K/AKT/mTOR are identified as having a key role in the pathogenesis of various forms of human cancer, including lung cancer. PI3K/AKT/mTOR signal pathway is an important intracellular signal transduction pathway with a significant role in cell proliferation, growth, survival, vesicle trafficking, glucose transport, and cytoskeletal organization. Aberrations in many primary and secondary messenger molecules of this pathway, including mutations and amplifications, are accounted for tumor cell proliferation, inhibition of apoptosis, angiogenesis, metastasis and resistance to chemotherapy-radiotherapy. In this review article, we investigate thoroughly the biological role of PI3K pathway in lung cancer and its contribution in the development of future therapeutic strategies. Full article
(This article belongs to the Special Issue PI3 Kinase Inhibitors)
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517 KiB  
Review
The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance
by Jansy Passiflora Sarathy, Véronique Dartois and Edmund Jon Deoon Lee
Pharmaceuticals 2012, 5(11), 1210-1235; https://doi.org/10.3390/ph5111210 - 9 Nov 2012
Cited by 81 | Viewed by 16318
Abstract
In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may [...] Read more.
In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may contribute to the development of phenotypic drug tolerance and induction of drug resistance. M. tuberculosis is intrinsically recalcitrant to small molecule permeation thanks to its thick lipid-rich cell wall. Passive diffusion appears to account for only a fraction of total drug permeation. As in other bacterial species, influx of hydrophilic compounds is facilitated by water-filled open channels, or porins, spanning the cell wall. However, the diversity and density of M. tuberculosis porins appears lower than in enterobacteria. Besides, physiological adaptations brought about by unfavorable conditions are thought to reduce the efficacy of porins. While intracellular accumulation of selected drug classes supports the existence of hypothesized active drug influx transporters, efflux pumps contribute to the drug resistant phenotype through their natural abundance and diversity, as well as their highly inducible expression. Modulation of efflux transporter expression has been observed in phagocytosed, non-replicating persistent and multi-drug resistant bacilli. Altogether, M. tuberculosis has evolved both intrinsic properties and acquired mechanisms to increase its level of tolerance towards xenobiotic substances, by preventing or minimizing their entry. Understanding these adaptation mechanisms is critical to counteract the natural mechanisms of defense against toxic compounds and develop new classes of chemotherapeutic agents that positively exploit the influx and efflux pathways of mycobacteria. Full article
(This article belongs to the Special Issue Antituberculosis Drugs)
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526 KiB  
Review
Improving the Endosomal Escape of Cell-Penetrating Peptides and Their Cargos: Strategies and Challenges
by Alfredo Erazo-Oliveras, Nandhini Muthukrishnan, Ryan Baker, Ting-Yi Wang and Jean-Philippe Pellois
Pharmaceuticals 2012, 5(11), 1177-1209; https://doi.org/10.3390/ph5111177 - 1 Nov 2012
Cited by 311 | Viewed by 21069
Abstract
Cell penetrating peptides (CPPs) can deliver cell-impermeable therapeutic cargos into cells. In particular, CPP-cargo conjugates tend to accumulate inside cells by endocytosis. However, they often remain trapped inside endocytic organelles and fail to reach the cytosolic space of cells efficiently. In this review, [...] Read more.
Cell penetrating peptides (CPPs) can deliver cell-impermeable therapeutic cargos into cells. In particular, CPP-cargo conjugates tend to accumulate inside cells by endocytosis. However, they often remain trapped inside endocytic organelles and fail to reach the cytosolic space of cells efficiently. In this review, the evidence for CPP-mediated endosomal escape is discussed. In addition, several strategies that have been utilized to enhance the endosomal escape of CPP-cargos are described. The recent development of branched systems that display multiple copies of a CPP is presented. The use of viral or synthetic peptides that can disrupt the endosomal membrane upon activation by the low pH of endosomes is also discussed. Finally, we survey how CPPs labeled with chromophores can be used in combination with light to stimulate endosomal lysis. The mechanisms and challenges associated with these intracellular delivery methodologies are discussed. Full article
(This article belongs to the Special Issue Cell-penetrating Peptides 2012)
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488 KiB  
Review
Cyclooxygenase (COX) Inhibitors and the Newborn Kidney
by Francine G. Smith, Andrew W. Wade, Megan L. Lewis and Wei Qi
Pharmaceuticals 2012, 5(11), 1160-1176; https://doi.org/10.3390/ph5111160 - 25 Oct 2012
Cited by 16 | Viewed by 10458
Abstract
This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI) in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can [...] Read more.
This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI) in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2) plays a more important role in during fetal development and influences kidney function early in life is not known, though evidence points to a predominant role for COX-2. Clinical implications of the use of COXI in pregnancy and in the newborn infant are also evaluated herein, with specific reference to the potential effects of COXI on nephronogenesis as well as newborn kidney function. Full article
(This article belongs to the Special Issue Cyclooxygenase(COX) Inhibitors)
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506 KiB  
Article
Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse
by Amy L. Palmer, Virginia L. Leykam, Andrew Larkin, Sharon K. Krueger, Ian R. Phillips, Elizabeth A. Shephard and David E. Williams
Pharmaceuticals 2012, 5(11), 1147-1159; https://doi.org/10.3390/ph5111147 - 25 Oct 2012
Cited by 15 | Viewed by 8946
Abstract
Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in [...] Read more.
Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA. Full article
(This article belongs to the Special Issue Antituberculosis Drugs)
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