Home About us Contact
|
Home About us Contact | ||
|
|
||
Response Study (response + study)
Selected AbstractsAllergenicity evaluation of Bioban CS-1135 in experimental animalsCONTACT DERMATITIS, Issue 6 2004Tetsuo Yamano An industrial preservative, Bioban CS-1135, was evaluated for its contact allergenicity by means of multiple-dose guinea-pig maximization test and non-radioactive murine local lymph node assay. In the guinea-pig test, an induction dose of 0.5% Bioban CS-1135 sensitized all animals of the group. The dose,response study of the elicitation phase determined a minimum elicitation dose of 5% for positive skin reactions. In the murine assay, Bioban CS-1135 at doses of 10% and more exerted significant effects on lymphoid cell proliferation. Although the data clearly designated Bioban CS-1135 as a skin sensitizer, its relative potency was ranked lowest among skin-sensitizing biocides previously evaluated in this laboratory. [source] Insulin release and suppression by tacrolimus, rapamycin and cyclosporin A are through regulation of the ATP-sensitive potassium channelDIABETES OBESITY & METABOLISM, Issue 6 2001D. K. Fuhrer Summary Aim By focusing on the pancreatic , cell response to tacrolimus, cyclosporin A (CsA) and rapamycin we hoped to identify immunophilin, calcineurin and/or novel mechanism involvement and advance the understanding of immunosuppressant regulated insulin control. Methods A glucose responsive , cell model was established in which the glucose response was blocked by immunosuppressant treatment and this model was used to further characterise this effect. Quantification of insulin release to immunosuppressants and specific inhibitors was used to identify the mechanism involved. Results It was found that upon the addition of tacrolimus, rapamycin, or CsA, rapid and significant exocytosis of cellular insulin was seen. A dose response study of this effect revealed optimal concentration windows of 50, 80 nm for tacrolimus, 100,300 nm for rapamycin, and 7,12 mm for CsA in RIN-5F cells. Optimal insulin release for HIT-T15 cells was similar. Additional experiments demonstrate that immunosuppressant pretreatment blocked the subsequent immunosuppressant induced insulin release but not that of a thapsigargin control, suggesting that suppression and release are non-toxic, specific and in the same pathway. Further experiments showed that this insulin release was a calcium dependent process, which was blocked by inhibitors of l -type calcium channels. Continued studies showed that the specific ATP-sensitive potassium channel agonist diazoxide (150 mm) also blocked immunosuppressant-induced insulin release. Conclusions A model that fits this data is a novel calcineurin-independent immunophilin mediated partial closing of the ATP-sensitive potassium channel, which would lead to an initial insulin release but would reduce subsequent responses through this pathway. [source] Enhancement of Ca2+ -regulated exocytosis by indomethacin in guinea-pig antral mucous cells: arachidonic acid accumulationEXPERIMENTAL PHYSIOLOGY, Issue 1 2006Shoko Fujiwara Ca2+ -regulated exocytosis is enhanced by an autocrine mechanism via the PGE2,cAMP pathway in antral mucous cells of guinea-pigs. The inhibition of the PGE2,cAMP pathway by H-89 (an inhibitor of protein kinase A, PKA) or aspirin (ASA, an inhibitor of cyclo-oxygenase, COX) decreased the frequency of ACh-stimulated exocytotic events by 60%. Indomethacin (IDM, an inhibitor of COX), however, decreased the frequency of ACh-stimulated exocytotic events only by 30%. Moreover, IDM increased the frequency of ACh-stimulated exocytotic events by 50% in H-89-treated or ASA-treated cells. IDM inhibits the synthesis of Prostaglandin (PGG/H) and (15R)-15-hydroxy-5,8,11 cis-13-trans-eicosatetraenoic acid (15R-HPETE), while ASA inhibits only the synthesis of PGG/H. Thus, IDM may accumulate arachidonic acid (AA). AACOCF3 or N -(p -amylcinnamoyl) anthranilic acid (ACA; both inhibitors of phospholipase A2, PLA2), which inhibits AA synthesis, decreased the frequency of ACh-stimulated exocytotic events by 60%. IDM, however, did not increase the frequency in AACOCF3 -treated cells. AA increased the frequency of ACh-stimulated exocytotic events in AACOCF3 - or ASA-treated cells, similar to IDM in ASA- and H-89-treated cells. Moreover, in the presence of AA, IDM did not increase the frequency of ACh-stimulated exocytotic events in ASA-treated cells. The PGE2 release from antral mucosa indicates that inhibition of PLA2 by ACA inhibits the AA accumulation in unstimulated and ACh-stimulated antral mucosa. The dose,response study of AA and IDM demonstrated that the concentration of intracellular AA accumulated by IDM is less than 100 nm. In conclusion, IDM modulates the ACh-stimulated exocytosis via AA accumulation in antral mucous cells. [source] Nonlinear response of N2O flux to incremental fertilizer addition in a continuous maize (Zea mays L.) cropping systemGLOBAL CHANGE BIOLOGY, Issue 10 2005Claire P. McSwiney Abstract The relationship between nitrous oxide (N2O) flux and N availability in agricultural ecosystems is usually assumed to be linear, with the same proportion of nitrogen lost as N2O regardless of input level. We conducted a 3-year, high-resolution N fertilizer response study in southwest Michigan USA to test the hypothesis that N2O fluxes increase mainly in response to N additions that exceed crop N needs. We added urea ammonium nitrate or granular urea at nine levels (0,292 kg N ha,1) to four replicate plots of continuous maize. We measured N2O fluxes and available soil N biweekly following fertilization and grain yields at the end of the growing season. From 2001 to 2003 N2O fluxes were moderately low (ca. 20 g N2O-N ha,1 day,1) at levels of N addition to 101 kg N ha,1, where grain yields were maximized, after which fluxes more than doubled (to >50 g N2O-N ha,1 day,1). This threshold N2O response to N fertilization suggests that agricultural N2O fluxes could be reduced with no or little yield penalty by reducing N fertilizer inputs to levels that just satisfy crop needs. [source] Acceleromyography and mechanomyography for establishing potency of neuromuscular blocking agents: a randomized-controlled trialACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2009C. CLAUDIUS Background: Acceleromyography (AMG) is increasingly being used in neuromuscular research, including in studies establishing the potency of neuromuscular blocking and reversal agents. However, AMG is insufficiently validated for use interchangeably with the gold standard, mechanomyography (MMG) for this purpose. The aim of this study was to compare AMG and MMG for establishing dose,response relationship and potency, using rocuronium as an example. Methods: We included 40 adult patients in this randomized-controlled single-dose response study. Anaesthesia was induced and maintained with propofol and opioid. Neuromuscular blockade was induced with rocuronium 100, 150, 200 or 250 ,g/kg. Neuromuscular monitoring was performed with AMG (TOF-Watch® SX) with pre-load (Hand Adapter) at one arm and MMG (modified TOF-Watch® SX) on the other, using 0.1 Hz single twitch stimulation. Dose,response relationships were determined for both recording methods using log (dose) against probit (maximum block). The obtained slopes of the regression lines, ED50, ED95 and the maximum block were compared. Results: The ED50 and ED95 [95% confidence interval (CI)] for AMG were 185 ,g/kg (167,205 ,g/kg) and 368 ,g/kg (288,470 ,g/kg), compared with 174 ,g/kg (159,191 ,g/kg) and 338 ,g/kg (273,418 ,g/kg) for MMG. There were no statistically significant biases in maximum block, ED50, ED95 or slopes obtained with the two methods. Conclusion: Our results indicate that any possible difference between AMG and MMG is so small that it justifies AMG to be used for establishing the potency of neuromuscular blocking agents. However, the wide CIs show that we cannot rule out a 13% higher ED50 and a 26% higher ED95 for AMG. [source] Low sensitivity of retina to AMPA-induced calcificationJOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2003Noemí Andrés Abstract Glutamate is involved in most CNS neurodegenerative diseases. In particular, retinal diseases such as retinal ischemia, retinitis pigmentosa, and diabetic retinopathy are associated with an excessive synaptic concentration of this neurotransmitter. To gain more insight into retinal excitotoxicity, we carried out a dose,response study in adult rats using ,-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), a glutamate analogue. AMPA intraocular injections (between 0.27 and 10.8 nmol) caused no morphologic modification, but a 10.8 + 21 nmol double injection in a 10-day interval produced a lesion characterized by discrete neuronal loss, astroglial and microglial reactions, and calcium precipitation. Abundant calcium deposits similar to those present in rat and human brain excitotoxicity or hypoxia-ischemia neurodegeneration were detected by alizarin red staining within the retinal surface and the optic nerve. Glial reactivity, associated normally with astrocytes in the nerve fiber, was assessed in Müller cells. GABA immunoreactivity was detected not only in neuronal elements but also in Müller cells. In contrast to the high vulnerability of the brain to excitotoxin microinjection, AMPA-induced retinal neurodegeneration may provide a useful model of low central nervous system sensitivity to excitotoxicity. © 2003 Wiley-Liss, Inc. [source] Clinical trial: a dose,response study of fospropofol disodium for moderate sedation during colonoscopyALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 7 2008L. B. COHEN Summary Background, An effective agent is needed that provides rapid onset of sedation and quick recovery for patients undergoing colonoscopy. Aim, To assess the efficacy and safety of fospropofol disodium in providing sedation in patients undergoing colonoscopy. Methods, A randomized, double-blind, multicentre trial evaluated 127 adult patients who received fospropofol (2, 5, 6.5 or 8 mg/kg) or midazolam 0.02 mg/kg following pre-treatment with fentanyl. Supplemental doses of study medication were allowed to reach a Modified Observer's Assessment of Alertness/Sedation scale score ,4. Efficacy end points included sedation success, measures of clinical benefit, sedation, and recovery as well as patient- and doctor-rated satisfaction. Results, Fospropofol produced a significant dose-dependent increase in sedation success from 24% (2 mg/kg), 35% (5 mg/kg) and 69% (6.5 mg/kg) to 96% (8 mg/kg; P < 0.001). There were also dose-dependent trends for time to sedation, requirements for alternative sedative medication, supplemental doses of sedative and fentanyl, time to ready for discharge and doctor-rated satisfaction scores. Fospropofol was well tolerated, with most adverse events mild-to-moderate in severity. Conclusion, The 6.5 mg/kg dose of fospropofol provides the ideal balance of efficacy and safety for patients undergoing colonoscopy and has been selected for phase 3 clinical development. [source] Usefulness of specific immunotherapy in patients with atopic dermatitis and allergic sensitization to house dust mites: a multi-centre, randomized, dose,response studyALLERGY, Issue 2 2006T. Werfel Background:, The effect of specific immunotherapy (SIT) on eczema in atopic dermatitis is not known. Therefore, a multi-centre, randomized dose,response trial, double-blind with respect to the efficacy of a biologically standardized depot house dust mite preparation was performed. Methods:, Eighty-nine adults with a chronic course of atopic dermatitis, SCORAD ,40 and allergic sensitization to house dust mites [CAP-FEIA ,3] were included, of whom 51 completed the study. Subcutaneous SIT with a house dust mite preparation (Dermatophagoides pteronyssinus/D. farinae) applying maintenance doses of 20, 2000 and 20 000 SQ-U in weekly intervals for 1 year. The main outcome measures addressed the change of the SCORAD as average of the values after 9 and 12 months of SIT in comparison with the value at baseline. Results:, The SCORAD declined in the three dose groups in a dose-dependent manner (P = 0.0368, Jonckheere,Terpstra test) and was significantly lower in the two high-dose groups (2000, 20000 SQ-U) compared with the low-dose group of 20 SQ-U (P = 0.0379, U -test) after 1 year of SIT. The use of topical corticosteroids was significantly reduced with higher doses (P = 0.0007, Mantel,Haenszel chi-square test). Conclusions:, Allergen-SIT for 1 year with a house dust mite preparation is able to improve the eczema in patients with atopic dermatitis who are sensitized to house dust mite allergens and reduces the need for topical corticosteroids. SIT may be valuable in the treatment of this chronic skin disease. [source] Impact of certain flavonoids on lipid profiles,potential action of Garcinia cambogia flavonoidsPHYTOTHERAPY RESEARCH, Issue 5 2001Asha Sarah Koshy Abstract Flavonoids from Cocos nucifera, Myristica fragrance, Saraka asoka and Garcinia cambogia exerted hypolipidaemic activity in rats. Lipid lowering activity was maximum in rats administered flavonoids (10,mg/kg BW/day) from Garcinia cambogia. A dose response study revealed biphasic activity. Higher doses were less effective in reducing lipid levels in serum and tissues, although devoid of toxic effects. Copyright © 2001 John Wiley & Sons, Ltd. [source] Optimal remifentanil dosage for providing excellent intubating conditions when co-administered with a single standard dose of propofolANAESTHESIA, Issue 7 2009L. Bouvet Summary This dose,response study aimed to determine the dose of remifentanil combined with propofol 2.5 mg.kg,1 which provided excellent intubation conditions in 95% of patients. Ninety premedicated female ASA 1 and 2 patients were randomly allocated to five remifentanil dose groups (1, 2, 3, 4 or 5 ,g.kg,1). Induction of anaesthesia was performed with a blinded dose of remifentanil infused over 60 s simultaneously co-administered with propofol 2.5 mg.kg,1 infused over 45 s. Tracheal intubation was attempted 150 s after the beginning of induction. Intubating conditions were assessed with the Copenhagen score. A probit analysis was performed to calculate the intubating efficient doses (IED) of remifentanil in 95% of patients (IED95). Our data revealed that the IED95 of remifentanil was 4.0 (95% CI: 3.4,5.6) ,g.kg,1, which was associated with a maximum decrease in heart rate and mean arterial pressure of < 30%, a finding which also applied to the other groups. [source] Inhibition of allergen-induced wheal and flare reactions by levocetirizine and desloratadineBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2008Nelly Frossard What is already known about this subject ,,The reproducible and standardized histamine-induced wheal and flare model helps identify the objective effectiveness of antihistamines in humans, as well as their differences in onset and duration of action. ,,Some of the newest antihistamines have already been compared in a head-to-head setting using this model. However, their objective action at inhibiting the allergen-induced wheal and flare response has not been reported yet. What this study adds ,,The time,response study presented here shows the objective activity of two of the newest generation of antihistamines, levocetirizine and desloratadine, at inhibiting the allergen-induced wheal and flare response in a randomized, cross over, placebo-controlled trial. ,,This model is interesting to the clinical setting since allergic subjects are recruited, and the response to allergen involves mast cell degranulation and release of numerous vasoactive and pro-inflammatory mediators additionally to histamine. ,,In addition, this study reports receptor occupancy for both antihistamines at therapeutic dosage, leading to analysis of potential differences in activity. ,,This study clearly shows the potential anti-inflammatory properties of desloratadine and levocetirizine in their skin activity when allergen is the challenging agent as occurs in the clinical situation. Aims To evaluate the inhibitory activity of the new-generation antihistamines levocetirizine and desloratadine at their therapeutic doses on the allergen-induced wheal and flare reaction at 1.5 h, 4 h, 7 h, 12 h and 24 h postdose, and to measure their plasma and skin concentrations. Methods A double-blind, randomized, cross-over, placebo-controlled study in 18 allergic subjects was carried out. The time,response of the wheal and flare reaction areas under the curve (AUC) were compared by anova. Results Both antihistamines significantly (P < 0.001) inhibited the allergen-induced wheal and flare reactions compared with placebo. Levocetirizine was significantly more potent than desloratadine. Mean ± SEM wheal AUC(0,24 h) was 506.4 ± 81.0 with levocetirizine and 995.5 ± 81.0 mm2 h with desloratadine as compared with placebo (1318.5 ± 361.0 mm2 h). Flare AUC(0,24 h) was 5927.3 ± 1686.5 and 15838.2 ± 1686.5 mm2 h, respectively [P < 0.001 for both compared with placebo (22508.2 ± 7437.1 mm2 h)]. Levocetirizine showed significant inhibition of wheal and flare already at 1.5 h postdose compared with placebo (P , 0.001); desloratadine achieved a significant effect only after 4 h. The mean total plasma concentration at 12 h and 24 h after intake was higher for levocetirizine (58.1 ± 13.4 and 20.0 ± 8.1 ng ml,1, respectively) as compared with desloratadine (0.82 ± 0.24 and 0.45 ± 0.16 ng ml,1). Similarly, higher mean unbound skin concentrations were observed for levocetirizine 24 h after intake (1.80 ng g,1) than for desloratadine (0.07 ng g,1). This was associated with greater receptor occupancy for levocetirizine (54%) than desloratadine (34%) at 24 h. Conclusions Levocetirizine suppressed the cutaneous allergic reactions with a higher potency than desloratadine, which correlated with its high receptor occupancy. Receptor occupancy rather than drug affinity or plasma half-life is more representative of antihistamine potency. [source] Liver dysfunction in Turner's syndrome: prevalence, natural history and effect of exogenous oestrogenCLINICAL ENDOCRINOLOGY, Issue 2 2008Olympia Koulouri Summary Objectives, Raised liver enzymes are a common feature of Turner's syndrome (TS), but the cause remains unclear. We studied the hepatic function in a large cohort of women with TS and tested the effect of increasing doses of hormone replacement therapy (HRT) on liver function tests (LFTs). Design and patients, LFTs were assessed in three studies. A cross-sectional review of liver function of 125 women (median age: 31 years), a longitudinal study of 30 women (mean follow-up period: 8 years) and a dose,response study of 14 women with TS and 11 controls with hypogonadism, who received oral 17-,-oestradiol (E2) 1, 2 and 4 mg daily in a cyclical formulation for 12 weeks each. Measurements, Clinical features, oestrogen use and metabolic parameters were compared to liver enzymes (,-glutamyl transferase (GGT), alanine aminotransferase (ALT) and alkaline phosphatase (ALP)), albumin and bilirubin. LFTs were also measured during each treatment interval of the dose,response study. Hepatic autoimmunity was sought in the cross-sectional study. Results, When compared to the control population, as opposed to reference ranges, 91% of women with TS demonstrated liver enzyme elevation, with a yearly incidence of 2·1%. LFTs correlated positively with cholesterol (P < 0·001), BMI (P = 0·004) and type of oestrogen therapy (P = 0·04). Increasing doses of HRT resulted in a significant decrease in GGT, ALT, bilirubin and albumin. No evidence of excessive hepatic autoimmunity was found. Conclusion, The prevalence of raised liver enzymes in TS may have been underestimated by the use of reference ranges rather than matched controls. Obesity and hyperlipidaemia are associated with raised LFTs, as well as the use of HRT compared to the oral contraceptive pill (OCP). Exogenous oestrogen both as OCP and HRT improves liver function. Liver dysfunction in TS is likely to be a form of hepatic steatosis and intervention trials are now indicated. [source] A dose,response study of salivary cortisol after dexamethasone suppression test in Cushing's disease and its potential use in the differential diagnosis of Cushing's syndromeCLINICAL ENDOCRINOLOGY, Issue 6 2003Margaret Castro Summary objective, A dose,response study with different doses of dexamethasone (dex) to assess the corticotrophic resistance in Cushing's disease (CD) using salivary cortisol as an end point has not yet been evaluated. We also reported our experience with salivary cortisol compared to plasma cortisol determination during dex suppression test (DST) and after ovine corticotrophin release hormone (oCRH) test in the differential diagnosis of Cushing's syndrome (CS). design, We studied 46 patients with CS, including 28 patients with CD, 16 with adrenal disease and two with occult ectopic adrenocorticotropic hormone (ACTH) tumours. Salivary cortisol was compared to plasma cortisol and ACTH during a DST 2 mg for 2 days, 8 mg for 2 days and 24 mg for 1 day, and after oCRH test. results, We observed a dose-dependent suppression of salivary cortisol, plasma cortisol and ACTH in CD patients. Salivary cortisol presented a higher percentage of suppression than plasma cortisol: 42%vs. 15% (P < 0·002), 82%vs. 67% (P < 0·002) and 90%vs. 83% (P < 0·03) after 2, 8 and 24 mg/day dex, respectively. The lowest percentage of suppression was observed for plasma ACTH. The parallelism of these lines identified that the criterion of 65% suppression of salivary cortisol corresponding to 50% suppression of plasma cortisol after 8 mg/day for 2 days is consistent with CD. The sensitivity and specificity using 50% suppression for plasma cortisol were 81% and 83%, respectively, for 8 mg DST. Using the criterion of 65% suppression of salivary cortisol, the sensitivity and specificity were 86% and 100%, respectively, for 8 mg DST. After oCRH test the sensitivity and specificity were 86% and 91%, respectively, for ACTH, 100% and 64%, respectively, for plasma cortisol and 93% and 91%, respectively, (20% of increment) or 86% and 100%, respectively, (35% increment) for salivary cortisol. conclusion, In conclusion, salivary cortisol presents more profound suppression than plasma cortisol or ACTH in a dose,response pattern after different doses of dex in patients with CD. In addition, our data suggest that measurement of salivary cortisol might improve the DST as compared to plasma cortisol in the differential diagnosis of CS. [source] | ||||||||||||||||||||||