Home About us Contact
|
Home About us Contact | ||
|
|
||
Transport Inhibitors (transport + inhibitor)
Selected AbstractsNo pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2009An Thyssen Abstract Objective The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. Methods Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6,mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200,mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. Results Creatinine clearance decreased from 119 to 102,mL,min,1 with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC, by 9%, and t½ by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80,125% range for Cmax, AUClast, and renal clearance. For AUC,, 90% CI was 79.37,101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. Conclusions No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors. Copyright © 2009 John Wiley & Sons, Ltd. [source] Hormonal interplay during adventitious root formation in flooded tomato plantsTHE PLANT JOURNAL, Issue 4 2010Maria Laura Vidoz Summary Soil flooding, which results in a decline in the availability of oxygen to submerged organs, negatively affects the growth and productivity of most crops. Although tomato (Solanum lycopersicum) is known for its sensitivity to waterlogging, its ability to produce adventitious roots (ARs) increases plant survival when the level of oxygen is decreased in the root zone. Ethylene entrapment by water may represent the first warning signal to the plant indicating waterlogging. We found that treatment with the ethylene biosynthesis inhibitor aminoethoxyvinylglycine (AVG) and the auxin transport inhibitor 1-naphthylphthalamic acid (NPA) resulted in a reduction of AR formation in waterlogged plants. We observed that ethylene, perceived by the Never Ripe receptor, stimulated auxin transport. In a process requiring the Diageotropica gene, auxin accumulation in the stem triggered additional ethylene synthesis, which further stimulated a flux of auxin towards to the flooded parts of the plant. Auxin accumulation in the base of the plant induces growth of pre-formed root initials. This response of tomato plants results in a new root system that is capable of replacing the original one when it has been damaged by submergence. [source] Phototropin involvement in the expression of genes encoding chlorophyll and carotenoid biosynthesis enzymes and LHC apoproteins in Chlamydomonas reinhardtiiTHE PLANT JOURNAL, Issue 1 2006Chung-Soon Im Summary Phototropin (PHOT) is a photoreceptor involved in a variety of blue-light-elicited physiological processes including phototropism, chloroplast movement and stomatal opening in plants. The work presented here tests whether PHOT is involved in expression of light-regulated genes in Chlamydomonas reinhardtii. When C. reinhardtii was transferred from the dark to very low-fluence rate white light, there was a substantial increase in the level of transcripts encoding glutamate-1-semialdehyde aminotransferase (GSAT), phytoene desaturase (PDS) and light-harvesting polypeptides (e.g. LHCBM6). Increased levels of these transcripts were also elicited by low-intensity blue light, and this blue-light stimulation was suppressed in three different RNAi strains that synthesize low levels of PHOT. The levels of GSAT and LHCBM6 transcripts also increased following exposure of algal cells to low-intensity red light (RL). The red-light-dependent increase in transcript abundance was not affected by the electron transport inhibitor 3-(3,4-dichlorophenyl)-1,1-dimethylurea, implying that the influence of RL on transcript accumulation was not controlled by cytoplasmic redox conditions, and that a red-light photoreceptor(s) may be involved in regulating the levels of transcripts from specific photosynthesis-related genes in C. reinhardtii. Interestingly, elevated GSAT and LHCBM6 transcript levels in RL were significantly reduced in the PHOT RNAi strains, which raises the possibility of co-action between blue and RL signaling pathways. Microarray experiments indicated that the levels of several transcripts for photosystem (PS) I and II polypeptides were also modulated by PHOT. These data suggest that, in C. reinhardtii, (i) PHOT is involved in blue-light-mediated changes in transcript accumulation, (ii) synchronization of the synthesis of chlorophylls (Chl), carotenoids, Chl-binding proteins and other components of the photosynthetic apparatus is achieved, at least in part, through PHOT-mediated signaling, and (iii) a red-light photoreceptor can also influence levels of certain transcripts associated with photosynthetic function, although its action requires normal levels of PHOT. [source] Serotonin decreases generation of dopaminergic neurons from mesencephalic precursors via serotonin type 7 and type 4 receptorsDEVELOPMENTAL NEUROBIOLOGY, Issue 1 2007J. Parga Abstract Inductive signals mediating the differentiation of neural precursors into serotonergic (5-HT) or dopaminergic neurons have not been clarified. We have recently shown that in cell aggregates obtained from rat mesencephalic precursors, reduction of serotonin levels induces a marked increase in generation of dopaminergic neurons. In the present study we treated rat neurospheres with antagonists of the main subtypes of 5-HT receptors, 5-HT transport inhibitors, or 5-HT receptor agonists, and studied the effects on generation of dopaminergic neurons. Cultures treated with Methiothepin (5-HT1,2,5,6,7 receptor antagonist), the 5-HT4 receptor antagonist GR113808;67:00,.or the 5-HT7 receptor antagonist SB 269970 showed a significant increase in generation of dopaminergic cells. Treatment with the 5-HT1B/1D antagonist GR 127935, the 5-HT2 antagonist Ritanserin, the 5-HT transporter inhibitor Fluoxetine, the dopamine and norepinephrine transport inhibitor GBR 12935, or with both inhibitors together, or 5-HT4 or 5-HT7 receptor agonists induced significant decreases in generation of dopaminergic cells. Cultures treated with WAY100635 (5-HT1A receptor antagonist), the 5-HT3 receptor antagonist Ondasetron, or the 5-HT6 receptor antagonist SB 258585 did not show any significant changes. Therefore, 5-HT4 and 5-HT7 receptors are involved in the observed serotonin-induced decrease in generation of dopaminergic neurons from proliferating neurospheres of mesencephalic precursors. 5-HT4 and 5-HT7 receptors were found in astrocytes and serotonergic cells using double immunolabeling and laser confocal microscopy, and the glial receptors appeared to play a major role. © 2006 Wiley Periodicals, Inc. J Neurobiol 67: 10,22, 2007 [source] No pharmacokinetic interaction between paliperidone extended-release tablets and trimethoprim in healthy subjects,HUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 7 2009An Thyssen Abstract Objective The effect of trimethoprim, a potent organic cation transport inhibitor, on the pharmacokinetics (PK) of paliperidone extended-release tablets (paliperidone ER), an organic cation mainly eliminated via renal excretion, was assessed. Methods Open-label, two-period, randomized, crossover study in 30 healthy males. Single dose of paliperidone ER 6,mg was administered either alone on day 1 or day 5 during an 8-day treatment period of trimethoprim 200,mg twice daily. Serial blood and urine samples were collected for PK and plasma protein binding of paliperidone and its enantiomers. The 90% confidence interval (CI) of ratios with/without trimethoprim for PK parameters of paliperidone and its enantiomers calculated. Results Creatinine clearance decreased from 119 to 102,mL,min,1 with trimethoprim. Addition of trimethoprim increased unbound fraction of paliperidone by 16%, renal clearance by 13%, AUC, by 9%, and t½ by 19%. The 90% CIs for ratios with/without trimethoprim were within the 80,125% range for Cmax, AUClast, and renal clearance. For AUC,, 90% CI was 79.37,101.51, marginally below the lower bound of the acceptance range. Paliperidone did not affect steady-state plasma concentrations of trimethoprim. Conclusions No clinically important drug interactions are expected when paliperidone ER is administered with organic cation transport inhibitors. Copyright © 2009 John Wiley & Sons, Ltd. [source] Expression of Mouse Osteoclast K-Cl Co-Transporter-1 and Its Role During Bone Resorption,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 7 2006Hiroshi Kajiya PhD Abstract To assess the role of Cl, transport during osteoclastic bone resorption, we studied the expression and function of K+/Cl, co-transporters (KCCs). KCC1 and chloride channel-7 were found to be expressed in mouse osteoclasts. The KCC inhibitor, R(+)-butylindazone (DIOA), KCC1 antisense oligo-nucleotides, and siRNA suppressed osteoclastic pit formation. DIOA also decreased Cl, extrusion and reduced H+ extrusion activity. These results show that KCC1 provides a Cl, extrusion mechanism accompanying the H+ extrusion during bone resorption. Introduction: Mice with deficient chloride (Cl,) channels, ClC7, show severe osteopetrosis, resulting from impairment of Cl, extrusion during osteoclastic bone resorption. However, the expression and functional role of Cl, transporters other than ClC7 in mammalian osteoclasts is unknown. The aim of this study was to determine expression of K+/Cl, co-transporters (KCCs) and their functional role for bone resorption in mouse osteoclasts. Materials and Methods: Mouse osteoclasts were derived from cultured bone marrow cells with macrophage-colony stimulating factor (M-CSF) and RANKL or from co-culture of bone marrow cells and primary osteoblasts. We examined the expression of Cl, transporters using RT-PCR, immunochemical, and Western blot methods. The effects of Cl, transport inhibitors on H+ and Cl, extrusion were assessed by measuring intracellular H+ ([H+]i) and Cl, ([Cl,]i). The effects of inhibitors, antisense oligo-nucleotides, and siRNA for Cl, transporters on bone resorption activities were evaluated using a pit formation assay. Results and Conclusions: Mouse osteoclasts express not only ClC7 but also K+/Cl, co-transporter mRNA. The existence of KCC1 in the cell membrane of mouse osteoclasts was confirmed by immunochemical staining and Western blot analysis. KCC inhibitors and Cl, channels blockers increased [Cl,]i and [H+]i in resorbing osteoclasts, suggesting that the suppression of Cl, extrusion through KCC and Cl, channels leads to reduced H+ extrusion activity. The combination of both inhibitors greatly suppressed these extrusion activities. KCC inhibitors and Cl, channel blockers also decreased osteoclastic bone resorption in our pit area essay. Furthermore, KCC1 antisense oligo-nucleotides and siRNA suppressed osteoclastic pit formation as well as treatment of ClC7 inhibitors. These results indicate that K+/Cl, co-transporter-1 expressed in mouse osteoclasts acts as a Cl, extruder and plays an important role for H+ extrusion during bone resorption. [source] Differing effects of substrate and non-substrate transport inhibitors on glutamate uptake reversalJOURNAL OF NEUROCHEMISTRY, Issue 6 2001Christopher M. Anderson Na+ -dependent excitatory amino acid transporters (EAATs) normally function to remove extracellular glutamate from brain extracellular space, but EAATs can also increase extracellular glutamate by reversal of uptake. Effects of inhibitors on EAATs can be complex, depending on cell type, whether conditions favor glutamate uptake or uptake reversal and whether the inhibitor itself is a substrate for the transporters. The present study assessed EAAT inhibitors for their ability to inhibit glutamate uptake, act as transporter substrates and block uptake reversal in astrocyte and neuron cultures. lthreo -,-hydroxyaspartate (l -TBHA), dlthreo -,-benzyloxyaspartate (dl -TBOA), ltrans -pyrrolidine-2,4-dicarboxylic acid (ltrans -2,4-PDC) (+/,)- cis -4-methy- trans -pyrrolidine-2,4-dicarboxylic acid (cis -4-methy- trans -2,4-PDC) and lantiendo -3,4-methanopyrrolidine-2,4-dicarboxylic acid (lantiendo -3,4-MPDC) inhibited l -[14C]glutamate uptake in astrocytes with equilibrium binding constants ranging from 17 µm (dl -TBOA and l -TBHA) , 43 µm (cis -4-methy- trans -2,4-PDC). Transportability of inhibitors was assessed in astrocytes and neurons. While l -TBHA, ltrans -2,4-PDC, cis -4-methy- trans -2,4-PDC and lantiendo -3,4-MPDC displayed significant transporter substrate activities in neurons and astrocytes, dl -TBOA was a substrate only in astrocytes. This effect of dl -TBOA was concentration-dependent, leading to complex effects on glutamate uptake reversal. At concentrations low enough to produce minimal dl -TBOA uptake velocity (, 10 µm), dl -TBOA blocked uptake reversal in ATP-depleted astrocytes; this blockade was negated at concentrations that drove substantial dl -TBOA uptake (> 10 µm). These findings indicate that the net effects of EAAT inhibitors can vary with cell type and exposure conditions. [source] Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorptionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2001Alekha K. Dash Abstract Creatine is a nutraceutical that has gained popularity in both well-trained and casual athletes for its performance-enhancing or ergogenic properties. The major disadvantages of creatine monohydrate formulations are poor solubility and oral bioavailability. In the present study, creatine transport was examined using Caco-2 monolayers as an in vitro model for intestinal absorption. Confluent monolayers of Caco-2 cells (passage 25,35) were used for the permeability studies. Monolayers were placed in side-by-side diffusion chambers. 14C-Creatine (0.1,0.5 ,Ci/mL) was added to either the apical or basolateral side, and the transport of the creatine across the Caco-2 monolayer was measured over a 90-min period. The apical to basolateral transport of 14C-creatine was small, ranging from 0.2,3% of the original amount appearing on the receiver side in a 90-min period. Interestingly, the basolateral to apical permeability of radiolabeled creatine was substantially greater than that observed in the apical to basolateral direction. Studies with drug efflux transport inhibitors indicate that neither the P-glycoprotein nor multidrug resistance-associated protein is involved in the enhanced basolateral to apical transport of creatine. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1593,1598, 2001 [source] The relationship between cell membrane damage and lipid peroxidation under the condition of hypoxia-reoxygenation: analysis of the mechanism using antioxidants and electron transport inhibitorsCELL BIOCHEMISTRY AND FUNCTION, Issue 6 2009Daisuke Yajima Abstract We consecutively observed lipid peroxidation and cell membrane damage under the condition of hypoxia-reoxygenation (H/R) in cells and analyzed their mechanisms by using electron transport inhibitors and an antioxidant. In H/R experiments, lipid peroxidation and cell membrane damage were observed during the hypoxia phase. In the reoxygenation phase, lipid peroxidation stopped, while cell membrane damage did not. An antioxidant, n-acetylcystein (NAC), and potassium cyanide (KCN) inhibited lipid peroxidation and cell membrane damage, while rotenone did not inhibit either of them. Although antimycin A did not inhibit lipid peroxidation, it inhibited cell membrane damage during the hypoxia phase but not during the reoxygenation phase. These results suggested that lipid peroxidation can affect cell membrane damage as a trigger during the hypoxia phase and the generation of oxidative stress can vary depending on the inhibition locations in the electron transport system. Copyright © 2009 John Wiley & Sons, Ltd. [source] | |||||||||||||