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Maximal Effects (maximal + effects)
Selected AbstractsShort-term dietary restriction and fasting precondition against ischemia reperfusion injury in miceAGING CELL, Issue 1 2010James R. Mitchell Summary Dietary restriction (DR) extends lifespan and increases resistance to multiple forms of stress, including ischemia reperfusion injury to the brain and heart in rodents. While maximal effects on lifespan require long-term restriction, the kinetics of onset of benefits against acute stress is not known. Here, we show that 2,4 weeks of 30% DR improved survival and kidney function following renal ischemia reperfusion injury in mice. Brief periods of water-only fasting were similarly effective at protecting against ischemic damage. Significant protection occurred within 1 day, persisted for several days beyond the fasting period and extended to another organ, the liver. Protection by both short-term DR and fasting correlated with improved insulin sensitivity, increased expression of markers of antioxidant defense and reduced expression of markers of inflammation and insulin/insulin-like growth factor-1 signaling. Unbiased transcriptional profiling of kidneys from mice subject to short-term DR or fasting revealed a significant enrichment of signature genes of long-term DR. These data demonstrate that brief periods of reduced food intake, including short-term daily restriction and fasting, can increase resistance to ischemia reperfusion injury in rodents and suggest a rapid onset of benefits of DR in mammals. [source] N,N -dimethyl-thioamphetamine and methyl-thioamphetamine, two non-neurotoxic substrates of 5-HT transporters, have scant in vitro efficacy for the induction of transporter-mediated 5-HT release and currentsJOURNAL OF NEUROCHEMISTRY, Issue 5 2008Marco Gobbi Abstract We studied two non-neurotoxic amphetamine derivatives (methyl-thioamphetamine, MTA and N,N- dimethylMTA, DMMTA) interacting with serotonin (5-HT) transporters (SERTs) with affinities comparable to that of p- Cl-amphetamine (pCA). The rank order for their maximal effects in inducing both [3H]5-HT release from rat brain synaptosomes or hSERT-expressing HEK-293 cells, and currents in hSERT-expressing oocytes, was pCA » MTA , DMMTA. A correlation between drug-induced release and currents is also strengthened by the similar bell shape of the dose,response curves. Release experiments indicated that MTA and DMMTA are SERT substrates although MTA is taken up by HEK-293 cells with a Vmax 40% lower than pCA. The weak effects of MTA and DMMTA in vitro might therefore be due to their properties as ,partial substrates' on the mechanisms, other than translocation, responsible for currents and/or release. After either local or systemic in vivo administration, MTA and DMMTA release 5-HT in a manner comparable to pCA. These findings confirm that the neurotoxic properties of some amphetamine derivatives are independent of their 5-HT-releasing activity in vivo. It is worth noting that only those amphetamine derivatives with high efficiency in inducing 5-HT release and currents in vitro have neurotoxic properties. [source] Systemic vitamin C and vitamin E do not prevent photoprovocation test reactions in polymorphous light eruptionPHOTODERMATOLOGY, PHOTOIMMUNOLOGY & PHOTOMEDICINE, Issue 2 2000B. Eberlein-König The possible influence of oxidative stress is discussed in the pathogenesis of polymorphous light eruption (PLE). A double-blind, placebo-controlled study of prophylactic treatment with systemic administration of vitamin C (3 g/d) and E (1500 IU/d) for 8 days was undertaken in 9 patients with PLE (verum, n=4; placebo, n=5). Evaluation of the maximal effects after photoprovocation before and after intake of the antioxidants revealed a reduction of most skin reactions (overall skin reaction, papules/vesicles) in both groups with marked differences in the placebo group. The antioxidants in the doses given and over the time period used did not influence the development of PLE, but might interfere with immunosuppressive effects of repeated photoprovocation tests. [source] Mycophenolate mofetil for severe childhood atopic dermatitis: experience in 14 patientsBRITISH JOURNAL OF DERMATOLOGY, Issue 1 2007M. Heller Summary Background, Reports of successful treatment of atopic dermatitis (AD) with mycophenolate mofetil (MMF) have thus far been limited to adults. Considering that the condition typically develops during childhood and is most active during this period, MMF would represent a valuable addition to the therapeutic armamentarium for paediatric AD. Objectives, To evaluate the safety and efficacy of MMF in the treatment of severe childhood AD. Methods, A retrospective analysis was performed of all children treated with MMF as systemic monotherapy for severe, recalcitrant AD between August 2003 and August 2006 at New York University Medical Center. Fourteen patients meeting these criteria were identified. Results, Four patients (29%) achieved complete clearance, four (29%) had > 90% improvement (almost complete), five (35%) had 60,90% improvement and one (7%) failed to respond. Initial responses occurred within 8 weeks (mean 4 weeks), and maximal effects were attained after 8,12 weeks (mean 9 weeks) at MMF doses of 40,50 mg kg,1 daily in younger children and 30,40 mg kg,1 daily in adolescents. The medication was well tolerated in all patients, with no infectious complications or development of leucopenia, anaemia, thrombocytopenia or elevated aminotransferases. Conclusions, This retrospective case series demonstrates that MMF can be a safe and effective treatment for severe, refractory AD in children. MMF represents a promising therapeutic alternative to traditional systemic immunosuppressive agents with less favourable side-effect profiles, and prospective controlled studies are warranted, further to assess its benefits in paediatric AD. [source] In vitro and in vivo pharmacological characterization of the novel UT receptor ligand [Pen5,DTrp7,Dab8]urotensin II(4,11) (UFP-803)BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2006Valeria Camarda The novel urotensin-II (U-II) receptor (UT) ligand, [Pen5,DTrp7,Dab8]U-II(4,11) (UFP-803), was pharmacologically evaluated and compared with urantide in in vitro and in vivo assays. In the rat isolated aorta, UFP-803 was inactive alone but, concentration dependently, displaced the contractile response to U-II to the right, revealing a competitive type of antagonism and a pA2 value of 7.46. In the FLIPR [Ca2+]i assay, performed at room temperature in HEK293hUT and HEK293rUT cells, U-II increased [Ca2+]i with pEC50 values of 8.11 and 8.48. Urantide and UFP-803 were inactive as agonists, but antagonized the actions of U-II by reducing, in a concentration-dependent manner, the agonist maximal effects with apparent pKB values in the range of 8.45,9.05. In a separate series of experiments performed at 37°C using a cuvette-based [Ca2+]i assay and CHOhUT cells, urantide mimicked the [Ca2+]i stimulatory effect of U-II with an intrinsic activity (,) of 0.80, while UFP-803 displayed a small (,=0.21) but consistent residual agonist activity. When the same experiments were repeated at 22°C (a temperature similar to that in FLIPR experiments), urantide displayed a very small intrinsic activity (,=0.11) and UFP-803 was completely inactive as an agonist. In vivo in mice, UFP-803 (10 nmol kg,1) antagonized U-II (1 nmol kg,1)-induced increase in plasma extravasation in various vascular beds, while being inactive alone. In conclusion, UFP-803 is a potent UT receptor ligand which displays competitive/noncompetitive antagonist behavior depending on the assay. While UFP-803 is less potent than urantide, it displayed reduced residual agonist activity and as such may be a useful pharmacological tool. British Journal of Pharmacology (2006) 147, 92,100. doi:10.1038/sj.bjp.0706438 [source] THE NOVEL SELECTIVE TOLL-LIKE RECEPTOR 4 SIGNAL TRANSDUCTION INHIBITOR TAK-242 PREVENTS ENDOTOXAEMIA IN CONSCIOUS GUINEA-PIGSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 5-6 2009Masamune Kuno SUMMARY 1TAK-242 is a novel compound that suppresses nitric oxide and cytokine production by selectively inhibiting intracellular signals from toll-like receptor (TLR)-4. In the present study, we investigated the effectiveness of TAK-242 against sepsis using an endotoxaemia model in conscious and unrestricted guinea-pigs. Measures examined included muscle tension paralysis of the intestine, blood pressure, high morbidity group box (HMGB)-1 levels and survival rate. 2Tension of the longitudinal muscle of the colon was monitored continuously by telemetry. Arterial blood pressure was monitored via a carotid artery catheter. TAK-242 was administered intravenously through a jugular vein catheter. Guinea-pigs were divided into a control group, given vehicle (placebo emulsion), and the experimental group, administered 3 or 10 mg/kg TAK-242, 1 h before administration of 10 mg/kg lipopolysaccharide (LPS). 3In the control group, the tension of the longitudinal muscle of the colon decreased in a time-dependent manner and blood pressure was reduced, with maximal effects observed 1,3 h after administration of LPS. In the TAK-242-treated group, LPS-induced relaxation of the intestine and hypotension were significantly inhibited. In the control group, HMGB-1 levels were increased after LPS administration and this reaction was significantly blocked in the TAK-242-treated group. Importantly, survival rate was increased after TAK-242 treatment. 4In conlusion, the results of the present study show that TAK-242 inhibited the symptoms associated with endotoxaemia in a guinea-pig model of sepsis and that it may, therefore, be an effective treatment for sepsis. [source] CHARACTERIZATION OF THE ACUTE CARDIOVASCULAR EFFECTS OF INTRAVENOUSLY ADMINISTERED INSULIN-LIKE GROWTH FACTOR-I IN CONSCIOUS SPRAGUE-DAWLEY RATSCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 12 2006Nga Cao SUMMARY 1Insulin-like growth factor (IGF)-I has acute effects on cardiovascular function, including a well-characterized vasodilator response in isolated arteries. In addition to increasing the release of nitric oxide, IGF-I also has effects on a variety of other signalling pathways that affect vascular tone, in particular interactions with the sympathetic nervous system and the renin,angiotensin,aldosterone system. We sought to characterize the effects of intravenous IGF-I on blood pressure and on responses to noradrenaline (NA), angiotensin II, acetylcholine and dobutamine. 2Administration of IGF-I administration caused small decreases in mean arterial pressure (5.4 ± 1.5%) and responsiveness to the prazosin-sensitive vasoconstrictor effects of NA (a 2.1 ± 0.6-fold increase in ED50; n = 40; P < 0.01) and both effects were maximal at 200 µg/kg IGF-I. In addition, IGF-I significantly increased pulse pressure increases induced by low doses of dobutamine (from an increase in pulse pressure of 9.9 ± 1.2 to 13.4 ± 1.9 mmHg; n = 39; P < 0.05). Administration of IGF-I had no significant effect on responses to AngII or ACh. 3Intravenous administration of IGF-I receptor antisense oligonucleotides (400 µg/kg) abolished the effects of IGF-I on NA-induced vasoconstriction (n = 11; P < 0.05), whereas administration of a mismatch oligonucleotide did not. 4These data indicate that the maximal effects of exogenously administered IGF-I include modest direct vasodilation and inhibition of constrictor responses to NA and an increase in the effect of dobutamine on pulse pressure. The magnitude of these effects was less than what previous in vitro studies and those performed in anaesthetized animals may have indicated likely. 5The modest magnitude of the dilator effects of IGF-I observed in conscious rats in vivo in the present study suggests that IGF-I is unlikely to be a major player in regulating vascular tone in normotensive animals. [source] | |||||||||||||||||||||||||