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Selected AbstractsBiodistribution of ultrasmall iron oxide particles in the rat liverJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 4 2001Bernard E. Van Beers MD Abstract Ferumoxtran, an ultrasmall superparamagnetic iron oxide particle, can be located in several tissue compartments in the liver, namely the extracellular space (blood and interstitium), reticuloendothelial cells, and possibly hepatocytes. To better understand the compartmental distribution of ferumoxtran in the liver, we performed a longitudinal study in the rat using microscopy and magnetic resonance imaging. At light microscopy, no substantial cellular uptake of ferumoxtran was observed before one hour after injection. With a dose of 15 ,mol Fe/kg, the number of ferumoxtran particles in the reticuloendothelial cells peaked between one and four hours and with a 150 ,mol Fe/kg dose, it peaked between eight and 24 hours. Within hepatocytes, only sparse particles were observed with electron microscopy, at a dose of 150 ,mol Fe/kg. Imaging performed up until one hour after ferumoxtran injection showed a significant increase in liver signal intensity on T1-weighted images. These results suggest that ferumoxtran mainly acts as an extracellular agent for at least one hour in the rat and that reticuloendothelial accumulation peaks at later time points. Substantial uptake within hepatocytes did not occur. J. Magn. Reson. Imaging 2001;13:594,599. © 2001 Wiley-Liss, Inc. [source] Forearm and leg amino acid metabolism in the basal state and during combined insulin and amino acid stimulation after a 3-day fastACTA PHYSIOLOGICA, Issue 3 2009J. Gjedsted Abstract Aim:, Fasting is characterized by a progressive loss of protein, but data on protein kinetics are unclear and few have studied the effects of re-feeding. The present study was designed to test the hypothesis that a combined infusion of insulin and amino acids after fasting would induce compensatory increases in protein synthesis and reductions in protein breakdown at the whole body level and in muscle. Methods:, We included 10 healthy male volunteers and studied them twice: (1) in the post-absorptive state and (2) after 72 h of fasting. Amino acid kinetics was measured using labelled phenylalanine and tyrosine, whole body energy expenditure was assessed and urea nitrogen synthesis rates were calculated. Results:, After fasting we observed an increase in arterial blood concentration of branched chain amino acids and a decrease in gluconeogenic amino acids (P < 0.05). Isotopically determined whole body, forearm and leg phenylalanine fluxes were unaltered apart from a 30% decrease in phenylalanine-to-tyrosine conversion (2.0 vs. 1.4 ,mol kg,1 h,1, P < 0.01). During infusion of insulin and amino acids, amino acid concentrations increased. Conclusion:, Our data indicate that after a 72-h fast basal and insulin/amino acid-stimulated regional phenylalanine fluxes in leg and forearm muscle are unaltered. During fasting concentrations of gluconeogenic amino acids decrease and hepatic and/or renal phenylalanine-to-tyrosine conversion decreases. Thus, as opposed to glucose and lipid metabolism, fasting does not induce insulin resistance as regards amino acid metabolism. [source] Nutritional supplements combined with dietary counselling diminish whole body protein catabolism in HIV-infected patientsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 1 2000Berneis Background Weight loss and protein malnutrition are frequent complications in HIV-infected patients. The effect of an oral nutritional supplement combined with nutritional counselling on whole body protein metabolism was assessed. Materials and methods HIV-infected individuals with a body mass index < 21 kg m,2 or CD4-T cells < 500 , L,1 in stable clinical condition were randomly allocated to [ 1] receive either oral nutritional supplements (containing 2510 kJ, complete macro- and micronutrients) and dietary counselling (n = 8), or [ 2] identical monitoring but no supplements or specific nutritional advice (controls, n = 7). Whole body leucine kinetics and leucine oxidation rate were determined by [1,13C]-leucine infusions and lean and fat mass were measured before and 12 weeks after intervention. Results Leucine oxidation (protein catabolism) decreased in the group receiving nutritional intervention from 0.33 ± 0.02 to 0.26 ± 0.02 ,mol kg,1 min,1 after 12 weeks (P < 0.05; P < 0.05 vs. control group) but remained unchanged in the control group. Whole body leucine flux showed a tendency to decrease in the intervention group from 1.92 ± 0.19 to 1.73 ± 0.14 ,mol kg,1 min,1 (P = 0.07) and remained unchanged in the control group (2.21 ± 0.16 and 2.27 ± 0.14 ,mol kg,1 min,1, respectively). Lean body mass determined by bioelectrical impedance analysis increased in the nutritional intervention group from 84 ± 2 to 86 ± 2 per cent (P < 0.05) and fat mass decreased from 17 ± 2 to 14 ± 2 per cent (P < 0.05) of total body weight whereas neither mass changed in the control group. Nutritional intervention had no significant effect on lymphocyte CD4 counts, on plasma TNFR 55, TNFR 75 and ILR 2 concentrations and on quality of life. Conclusions The data demonstrate an anticatabolic effect of nutritional supplements combined with dietary counselling in HIV-infected subjects. They suggest that diminished whole body protein catabolism resulted in a change of body composition (increased lean mass, decreased fat mass). [source] Abnormalities of whole body protein turnover, muscle metabolism and levels of metabolic hormones in patients with chronic heart failureJOURNAL OF INTERNAL MEDICINE, Issue 1 2006H. NŘRRELUND Abstract. Objective., It is well known that chronic heart failure (CHF) is associated with insulin resistance and cachexia, but little is known about the underlying substrate metabolism. The present study was undertaken to identify disturbances of basal glucose, lipid and protein metabolism. Design., We studied eight nondiabetic patients with CHF (ejection fraction 30 ± 4%) and eight healthy controls. Protein metabolism (whole body and regional muscle fluxes) and total glucose turnover were isotopically assayed. Substrate oxidation were obtained by indirect calorimetry. The metabolic response to exercise was studied by bicycle ergometry exercise. Results., Our data confirm that CHF patients have a decreased lean body mass. CHF patients are characterised by (i) decreased glucose oxidation [glucose oxidation (mg kg,1 min,1): 1.25 ± 0.09 (patients) vs. 1.55 ± 0.09 (controls), P < 0.01] and muscle glucose uptake [a , v diffglucose (,mol L,1): ,10 ± 25 (patients) vs. 70 ± 22 (controls), P < 0.01], (ii) elevated levels of free fatty acids (FFA) [FFA (mmol L,1): 0.72 ± 0.05 (patients) vs. 0.48 ± 0.03 (controls), P < 0.01] and 3-hydroxybutyrate and signs of elevated fat oxidation and muscle fat utilization [a , v diffFFA (mmol L,1): 0.12 ± 0.02 (patients) vs. 0.05 ± 0.01 (controls), P < 0.05] and (iii) elevated protein turnover and protein breakdown [phenylalanine flux (,mol kg,1 h,1): 36.4 ± 1.5 (patients) vs. 29.6 ± 1.3 (controls), P < 0.01]. Patients had high circulating levels of noradrenaline, glucagon, and adiponectin, and low levels of ghrelin. We failed to observe any differences in metabolic responses between controls and patients during short-term exercise. Conclusions., In the basal fasting state patients with CHF are characterized by several metabolic abnormalities which may contribute to CHF pathophysiology and may provide a basis for targeted intervention. [source] In-vitro and in-vivo evaluation of pH-responsive polymeric micelles in a photodynamic cancer therapy modelJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2001J. Taillefer pH-sensitive polymeric micelles of randomly and terminally alkylated N-isopropylacrylamide copolymers were prepared and characterized. Aluminium chloride phthalocyanine (AlClPc), a second generation sensitizer for the photodynamic therapy of cancer, was incorporated in the micelles by dialysis. Their photodynamic activities were evaluated in-vitro against EMT-6 mouse mammary tumour cells and in-vivo against EMT-6 tumours implanted intradermally on each hind thigh of Balb/c mice. pH-sensitive polymeric micelles were found to exhibit greater cytotoxicity in-vitro than control Cremophor EL formulations. In the presence of chloroquine, a weak base that raises the internal pH of acidic organelles, in-vitro experiments demonstrated the importance of endosomal/lysosomal acidity for the pH-sensitive polymeric micelles to be fully effective. Biodistribution was assessed by fluorescence of tissue extracts after intravenous injection of 2 ,mol kg,1 AlClPc. The results revealed accumulation of AlClPc polymeric micelles in the liver, spleen and lungs, with a lower tumour uptake than AlClPc Cremophor EL formulations. However, polymeric micelles exhibited similar activity in-vivo to the control Cremophor EL formulations, demonstrating the higher potency of AlClPc polymeric micelles when localized in tumour tissue. It was concluded that polymeric micelles represent a good alternative to Cremophor EL preparations for the vectorization of hydrophobic drugs. [source] Design, Synthesis and Evaluation of N -Basic Substituted 3-Hydroxypyridin-4-ones: Orally Active Iron Chelators with Lysosomotrophic PotentialJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2000ZU D. LIU To investigate the possibility of targeting chelators into the lysosomal iron pool, nine bidentate 3-hydroxypyridin-4-ones with basic chains have been synthesized. As the turnover of ferritin iron is centred in the lysosome, such strategy is predicted to increase chelator efficacy of bidentate ligands. The pKa values of the ligands together with their distribution coefficients between 1-octanol and 4-morpholinepropane sulphonic acid (MOPS) buffer pH 7.4 have been determined. The in-vivo iron mobilization efficacy of these basic 3-hydroxypyridin-4-ones has been investigated in a 59Fe-ferritin-loaded rat model. No obvious correlation was observed between efficacy and the pKa value of the side chain, although those with pKa > 7.0 tended to be more efficient than those with pKa < 7.0. The imidazole-containing molecules are much less effective than the tertiary amine derivatives. A dose-response study suggested that basic pyridinones are relatively more effective at lower doses when compared with N -alkyl hydroxypyridinones. Optimal effects were observed with the piperidine derivatives 4h and 4i. The derivative 4i at a dose of 150 ,mol kg,1 was more effective than 450 ,mol kg,1 deferiprone, the widely adopted clinical dose. [source] The decline of metallophyte vegetation in floodplain grasslands: Implications for conservation and restorationAPPLIED VEGETATION SCIENCE, Issue 1 2009Esther C.H.E.T. Lucassen Abstract Question: Which biogeochemical processes are responsible for the decline of endemic metallophyte vegetation in floodplain grasslands? Location: Floodplain grasslands along the River Geul (the Netherlands) and metalliferous mine spoils near the River Geul (Belgium). Methods: In order to find factors and soil processes that have caused a decline of metallophytes and an increase of pseudo-metallophytes in floodplain grasslands, a soil study was done at locations currently and formerly dominated by metallophytes. In addition, changes in soil chemistry in recent decades in floodplain grasslands were investigated. Finally, a 2-year plant growth experiment was performed in the field, to test the effects of improving soil conditions by topsoil removal. Results: Metallophytes only occur on acidic floodplain soils (pH-H2O 5.0-5.5) with relatively high Zn availability (total Zn >40 ,mol g,1; Zn/Ca>0.8; Zn-H2O>59 ,mol kg,1) combined with low phosphate availability (Olsen-P,1250 ,mol kg,1). The Olsen-P and total Ca concentrations were relatively high in topsoil (0-20 cm), while total Zn was high throughout the soil profile (0-50 cm). Removal of topsoil led to recovery of P and Zn availability. Under the new soil conditions there was almost no growth and expansion of pseudo-metalliferous grasses in time, wheras metallophytes easily established, maintained and reproduced with significant increases in cover over time. Conclusions: On a global scale, metallophyte vegetation types are increasingly under threat of extinction. Our study shows that factors leading to higher soil alkalinity inhibit Zn availability at the expense of the metallophyte vegetation. Factors leading to a higher Olsen-P concentration stimulate the growth of more competitive pseudo-metallophyte grasses. Both eutrophication and alkalinisation have contributed to the decline of metallophyte vegetation in floodplains of the River Geul. Removal of the alkaline- and phosphate-enriched soil top layer restores the original soil chemistry and enables re-colonisation by the metallophyte vegetation. The results can be applied in conservation and restoration strategies for such sites. [source] Antinociceptive effect of a ruthenium complex in miceAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 4 2008M. P. Cristiano Summary 1,The ruthenium complexes are important tools in inorganic chemistry. Different biological properties are found in the presence of distinct coordinate ligands, which offer a variety of potential clinical and pharmacological uses. 2,The aim of this work was to evaluate the antinociceptive and behavioural effects of the ruthenium complex, trans -[RuCl2(i-dinic)4]Cl, in mice. 3,The potential analgesic activity was tested using the formalin and hot plate tests and the behavioural effect was evaluated using the rotarod and spontaneous locomotor tests. The complex was administered at concentrations of 1.3, 4.5 and 18.0 ,mol kg,1 i.p. Morphine (6.0 mg kg,1, i.p.) and diclofenac sodium (20.0 mg kg,1, i.p.) were used as reference drugs. 4,The compound had no sedative activity on motor ataxia in the behavioural and analgesic tests. No significant effect was observed in the first phase of the formalin test, however, an effect was observed in the second phase. 5,The complex studied was probably more powerful than the reference drugs as an antinociceptive agent, as this mechanism also involved the nitric oxide (NO) pathway. From this perspective, further experimental studies will be useful to understand the effect of these compounds on NO and the relationship between prostaglandin and NO biosynthesis. [source] Mechanisms underlying the anti-inflammatory activity and gastric safety of acemetacinBRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2007A E Chávez-Pińa Background and purpose: Acemetacin is regarded as a pro-drug of indomethacin and induces significantly less gastric damage but the reasons for this greater gastric safety of acemetacin are unclear. The anti-inflammatory effects of acemetacin have been attributed, at least in part, to its hepatic biotransformation to indomethacin. The aim of this study was to determine the effects of acemetacin and indomethacin in an in vivo model of acute inflammation and to examine the importance of biotransformation of acemetacin (to indomethacin) to its anti-inflammatory actions. Experimental approach: The zymosan airpouch model was used in rats. Indomethacin or acemetacin (2.7,83.8 ,mol kg,1) were administered orally or directly into the pouch. Leukocyte infiltration, prostaglandin (PG) E2 and leukotriene (LT) B4 levels in exudates, and whole blood thromboxane (TX) B2 synthesis were measured. Key results: Acemetacin was rapidly converted to indomethacin after its administration. Both acemetacin and indomethacin elicited comparable, dose-dependent reductions of leukocyte infiltration and of PGE2 and TXB2 synthesis. However, indomethacin induced more gastric damage than acemetacin and elevated LTB4 production in the airpouch. Conclusions and implications: The similar effects of acemetacin and indomethacin on leukocyte infiltration and PG synthesis are consistent with rapid biotransformation of acemetacin to indomethacin. Some of this biotransformation may occur extra-hepatically, for instance in inflammatory exudates. Acemetacin probably exerts actions independent of conversion to indomethacin, given the different effects of these two drugs on LTB4 production. Such differences may contribute to the relative gastric safety of acemetacin compared to indomethacin. British Journal of Pharmacology (2007) 152, 930,938; doi:10.1038/sj.bjp.0707451; published online 17 September 2007 [source] A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injuryBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2004Wei-Ping Wu Nitric oxide (NO) participates, at least in part, to the establishment and maintenance of pain after nerve injury. Therefore, drugs that target the NO/cGMP signaling pathway are of interest for the treatment of human neuropathic pain. Various compounds endowed with NO-releasing properties modulate the expression and function of inducible nitric oxide synthase (iNOS), the key enzyme responsible for sustained NO production under pathological conditions including neuropathic pain. With this background, we synthesized a new chemical entity, [1-(aminomethyl)cyclohexane acetic acid 3-(nitroxymethyl)phenyl ester] NCX8001, which has a NO-releasing moiety bound to gabapentin, a drug currently used for the clinical management of neuropathic pain. We examined the pharmacological profile of this drug with respect to its NO-releasing properties in vitro as well as to its efficacy in treating neuropathic pain conditions (allodynia) consequent to experimental sciatic nerve or spinal cord injuries. NCX8001 (1,30 ,M) released physiologically relevant concentrations of NO as it induced a concentration-dependent activation of soluble guanylyl cyclase (EC50=5.6 ,M) and produced consistent vasorelaxant effects in noradrenaline-precontracted rabbit aortic rings (IC50=1.4 ,M). NCX8001, but not gabapentin, counteracted in a concentration-dependent fashion lipopolysaccharide-induced overexpression and function of iNOS in RAW264.7 macrophages cell line. Furthermore, NCX8001 also inhibited the release of tumor necrosis factor alpha (TNF,) from stimulated RAW264.7 cells. NCX8001 (28,280 ,mol kg,1, i.p.) reduced the allodynic responses of spinal cord injured rats in a dose-dependent fashion while lacking sedative or motor effects. In contrast, gabapentin (170,580 ,mol kg,1, i.p.) resulted less effective and elicited marked side effects. NCX8001 alleviated the allodynia-like responses of rats to innocuous mechanical or cold stimulation following lesion of the sciatic nerve. This effect was not shared by equimolar doses of gabapentin. Potentially due to the slow releasing kinetics of NO, NCX8001 alleviated pain-like behaviors in two rat models of neuropathic pain in a fashion that is superior to its parent counterpart gabapentin. This new gabapentin derivative, whose mechanism deserves to be explored further, offers new hopes to the treatment of human neuropathic pain. British Journal of Pharmacology (2004) 141, 65,74. doi:10.1038/sj.bjp.0705596 [source] Proarrhythmic potential of halofantrine, terfenadine and clofilium in a modified in vivo model of torsade de pointesBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2002Andrew J Batey This study was designed to compare the proarrhythmic activity of the antimalarial drug, halofantrine and the antihistamine, terfenadine, with that of clofilium a K+ channel blocking drug that can induce torsade de pointes. Experiments were performed in pentobarbitone-anaesthetized, open-chest rabbits. Each rabbit received intermittent, rising dose i.v. infusions of the ,-adrenoceptor agonist phenylephrine. During these infusions rabbits also received increasing i.v. doses of clofilium (20, 60 and 200 nmol kg,1 min,1), terfenadine (75, 250 and 750 nmol kg,1 min,1), halofantrine (6, 20 and 60 ,mol kg,1) or vehicle. Clofilium and halofantrine caused dose-dependent increases in the rate-corrected QT interval (QTc), whereas terfenadine prolonged PR and QRS intervals rather than prolonging cardiac repolarization. Progressive bradycardia occurred in all groups. After administration of the highest dose of each drug halofantrine caused a modest decrease in blood pressure, but terfenadine had profound hypotensive effects resulting in death of most rabbits. The total number of ventricular premature beats was highest in the clofilium group. Torsade de pointes occurred in 6 out of 8 clofilium-treated rabbits and 4 out of 6 of those which received halofantrine, but was not seen in any of the seven terfenadine-treated rabbits. These results show that, like clofilium, halofantrine can cause torsade de pointes in a modified anaesthetized rabbit model whereas the primary adverse effect of terfenadine was cardiac contractile failure. British Journal of Pharmacology (2002) 135, 1003,1012; doi:10.1038/sj.bjp.0704550 [source] Bradyzide, a potent non-peptide B2 bradykinin receptor antagonist with long-lasting oral activity in animal models of inflammatory hyperalgesiaBRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2000Gillian M Burgess Bradyzide is from a novel class of rodent-selective non-peptide B2 bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). Bradyzide has high affinity for the rodent B2 receptor, displacing [3H]-bradykinin binding in NG108-15 cells and in Cos-7 cells expressing the rat receptor with KI values of 0.51±0.18 nM (n=3) and 0.89±0.27 nM (n=3), respectively. Bradyzide is a competitive antagonist, inhibiting B2 receptor-induced 45Ca efflux from NG108-15 cells with a pKB of 8.0±0.16 (n=5) and a Schild slope of 1.05. In the rat spinal cord and tail preparation, bradyzide inhibits bradykinin-induced ventral root depolarizations (IC50 value; 1.6±0.05 nM (n=3)). Bradyzide is much less potent at the human than at the rodent B2 receptor, displacing [3H]-bradykinin binding in human fibroblasts and in Cos-7 cells expressing the human B2 receptor with KI values of 393±90 nM (n=3) and 772±144 nM (n=3), respectively. Bradyzide inhibits bradykinin-induced [3H]-inositol trisphosphate (IP3) formation with IC50 values of 11.6±1.4 nM (n=3) at the rat and 2.4±0.3 ,M (n=3) at the human receptor. Bradyzide does not interact with a range of other receptors, including human and rat B1 bradykinin receptors. Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. Bradyzide shows long-lasting oral activity in rodent models of inflammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED50, 0.84 ,mol kg,1; duration of action >4 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal effect exceeding that of the non-steroidal anti-inflammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. In summary, bradyzide is a potent, orally active, antagonist of the B2 bradykinin receptor, with selectivity for the rodent over the human receptor. British Journal of Pharmacology (2000) 129, 77,86; doi:10.1038/sj.bjp.0703012 [source] Lipophilicity Plays a Major Role in Modulating the Inhibition of Monoamine Oxidase B by 7-Substituted CoumarinsCHEMISTRY & BIODIVERSITY, Issue 2 2006Angelo Carotti Abstract A series of coumarin derivatives (1,22), bearing at the 7-position ether, ketone, ester, carbamate, or amide functions of varying size and lipophilicity, were synthesized and investigated for their in vitro monoamine oxidase-A and -B (MAO-A and -B) inhibitory activities. Most of the compounds acted preferentially as MAO-B inhibitors, with IC50 values in the micromolar to low-nanomolar range. A structure,activity-relationship (SAR) study highlighted lipophilicity as an important property modulating the MAO-B inhibition potency of 7-substituted coumarins, as shown by a linear correlation (n=20, r2=0.72) between pIC50 and calculated log P values. The stability of ester-containing coumarin derivatives in rat plasma provided information on factors that either favor (lipophilicity) or decrease (steric hindrance) esterase-catalyzed hydrolysis. Two compounds (14 and 22) were selected to investigate how lipophilicity and enzymatic stability may affect in vivo MAO activities, as assayed ex vivo in rat. The most-potent and -selective MAO-B inhibitor 22 (=7-[(3,4-difluorobenzyl)oxy]-3,4-dimethyl-1-benzopyran-2(2H)-one) within the examined series significantly inhibited (>60%) ex vivo rat-liver and striatal MAO-B activities 1,h after intraperitoneal administration of high doses (100 and 300,,mol kg,1), revealing its ability to cross the blood,brain barrier. At the same doses, liver and striatum MAO-A was less inhibited in vivo, somehow reflecting MAO-B selectivity, as assessed in vitro. In contrast, the metabolically less stable derivative 14, bearing an isopropyl ester in the lateral chain, had a weak effect on hepatic MAO-B activity in vivo, and none on striatal MAO-B, but, surprisingly, displayed inhibitory effects on MAO-A in both peripheral and brain tissues. [source] | ||||||||||||||||||||||