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High Dosage (high + dosage)
Selected AbstractsCD-sens: a biological measure of immunological changes stimulated by ASITALLERGY, Issue 5 2009A. Nopp Background:, Allergen-specific immunotherapy (ASIT) in allergic rhinitis and asthma is the only treatment that effects the long-term development of these diseases. Basophil allergen threshold sensitivity, CD-sens, which is a valuable complement to resource-demanding clinical challenge tests, was used to monitor the initiation of ASIT induced allergen ,blocking activity'. Methods:, Patients IgE-sensitized to timothy (n = 14) or birch (n = 19) pollen were started on conventional (8,16 weeks) or ultra rush ASIT, respectively, and followed by measurements of CD-sens, allergen binding activity (ABA) and serum IgG4- and IgE-antibody concentrations. Results:, CD-sens decreased during the early phase of ASIT-treatment. In parallel, ABA increased and correlated significantly with the increasing levels of IgG4 antibody concentrations. High dosages of allergen were more effective while mode of dosing up did not seem to matter. No change was seen in basophil reactivity. Conclusion:, CD-sens and ABA, in contrast to basophil reactivity, seem to be promising tools to monitor protective immune responses initiated by ASIT. [source] Effects and serum levels of glibenclamide and its active metabolites in patients with type 2 diabetesDIABETES OBESITY & METABOLISM, Issue 6 2001A. Jönsson SUMMARY Objective To study the effects and serum levels of glibenclamide (Gb) and its active metabolites in patients on chronic Gb medication on different daily doses. Material and methods Fifty patients with type 2 diabetes on regular Gb therapy (1.75,14.0 mg daily). Blood samples were taken immediately before and 90 min after regular Gb intake. A standardized breakfast was served 30 min after drug intake. Serum insulin and proinsulin levels were determined by ELISA methods without cross-reactivities. Serum drug levels were determined by HPLC. Fischer's R to Z -test (correlation coefficients) and paired Student t -tests were used when comparing values within the entire group and unpaired non-parametric Mann,Whitney tests were used when comparing high and low dose levels. A p-value <,0.05 was considered significant. Results There were significant correlations between daily Gb dose, on the one hand, and, on the other, HbAlc (r = 0.55), ,-insulin (r = , 0.59) and ,-proinsulin (r = , 0.52) levels. Significant correlations between Gb therapy duration and insulin (r = , 0.40) and proinsulin (r = , 0.34) secretion and between Gb dose and ratio proinsulin/insulin (RPI) at both time points (r = 0.32 and 0.30) were also found. The RPI was lower after Gb intake. In patients on , 10.5 mg steady state serum metabolite levels (Ml and Ml + M2) were higher (29(0,120) and 33 (0,120) ng/ml) than those of Gb itself (18(0,64) ng/ml). A great inter-subject variability in Gb levels at both time points was seen. Conclusions Our results indicate that, in patients on chronic medication, Gb is capable of stimulating both insulin and proinsulin secretion; the effect on insulin release is relatively greater. The effect was more pronounced in patients on a low Gb dose, either because of less impaired ,-cells in those receiving low doses, or due to reduced sulphonylurea sensitivity in those on high dosage (down-regulation). In patients on a daily dose of 10.5 mg or more, serum metabolite levels of clinical relevance were demonstrated; the metabolites may contribute to hypoglycaemic events. [source] Chronic toxicity and responses of several important enzymes in Daphnia magna on exposure to sublethal microcystin-LRENVIRONMENTAL TOXICOLOGY, Issue 3 2005Wei Chen Abstract In the current study, the toxicological mechanisms of microcystin-LR and its disadvantageous effects on Daphnia magna were examined. Survival rate, number of newborn, activity of several important enzymes [glutathione S-transferase (GST), lactate dehydrogenase (LDH), phosphatases, and glutathione], accumulated microcystins, and ultrastructural changes in different organs of Daphnia were monitored over the course of 21-day chronic tests. The results indicated that low concentrations of dissolved microcystin had no harmful effect on Daphnia. On the contrary, stimulatory effects were detected. In the presence of toxin at high dosage and for long-term exposure, GST and glutathione levels decreased significantly. The decreased enzyme activity in the antioxidant system probably was caused by detoxification reactions with toxins. And these processes of detoxification at the beginning of chronic tests may enable phosphatases in Daphnia magna to withstand inhibition by the toxins. At the same time, we also found that the LDH activity in test animals increased with exposure to microcystin-LR, indicating that adverse effects occurred in Daphnia. With microcystin given at a higher dosage or for a longer exposure, the effect on Daphnia magna was fatal. In the meantime, microcystin began to accumulate in Daphnia magna, and phosphatase activity started to be inhibited. From the ultrastructure results of cells in D. magna, we obtained new information: the alimentary canal may be the target organ affected by exposure of microcystins to D. magna. The results of the current study also suggested that the oxidative damage and PPI (protein phosphatase inhibition) mechanisms of vertebrates also are adapted to Daphnia. © 2005 Wiley Periodicals, Inc. Environ Toxicol 20: 323,330, 2005. [source] A randomized 4-arm multicenter study of interferon alfa,2b plus ribavirin in the treatment of patients with chronic hepatitis C not responding to interferon aloneHEPATOLOGY, Issue 1 2001Giorgio Saracco To determine whether a higher dosage of interferon (IFN) associated with ribavirin and/or prolonged time of administration may improve therapeutic efficacy, we conducted a 4-arm randomized trial on patients with chronic hepatitis C not responding to one or more previous treatment courses with IFN monotherapy. Group 1 (n = 139) received 3 million units (MU) IFN-,2b 3 times a week (t.i.w.) plus ribavirin 1,000 mg/d for 12 months; group 2 (n = 162) received 5 MU t.i.w. plus ribavirin for 12 months; group 3 (n = 142) received 3 MU t.i.w. plus ribavirin for 6 months; and group 4 (n = 151) received 5 MU t.i.w. plus ribavirin for 6 months. The primary end point was hepatitis C virus (HCV)-RNA clearance at the end of 6-month follow-up. HCV-RNA was negative in 15% of group 1, 23% of group 2, 11% of group 3, 16% of group 4 (group 2 vs. group 3, P = .04). Among patients with genotypes 1 and 4, sustained response was significantly higher in group 2 vs. group 3 (18% vs. 7%, P = .03; group 1 = 9%, group 4 = 12%, P = not significant [NS]). In patients with genotypes 2 and 3, sustained virologic response was not affected by the different regimens (group 1 = 32%, group 2 = 30%, group 3 = 30%, group 4 = 35%, P = NS). In conclusion, about 23% of nonresponders to IFN monotherapy may achieve a sustained response if re-treated by 5 MU t.i.w. IFN plus ribavirin 1,000 mg/d for 1 year. Patients with genotype 1 should receive a high dosage of IFN plus ribavirin for 12 months, whereas therapy for patients with genotype 2 or 3 should be less aggressive. [source] Inhibition of Listeria monocytogenes in chicken cold cuts by addition of sakacin P and sakacin P-producing Lactobacillus sakeiJOURNAL OF APPLIED MICROBIOLOGY, Issue 2 2002T. Katla Aims: To evaluate the potential of sakacin P and sakacin P-producing Lactobacillus sakei for the inhibition of growth of Listeria monocytogenes in chicken cold cuts, by answering the following questions. (i) Is sakacin P actually produced in food? (ii) Is sakacin P produced in situ responsible for the inhibiting effect? (iii) How stable is sakacin P in food? Methods and Results:Listeria monocytogenes, a Lact. sakei strain and/or the bacteriocin sakacin P were added to chicken cold cuts, vacuum packed and incubated at 4 or 10°C for 4 weeks. Each of two isogenic Lact. sakei strains, one producing sakacin P and the other not, had an inhibiting effect on the growth of L. monocytogenes. The effect of these two isogenic strains on the growth of L. monocytogenes was indistinguishable, even though sakacin P was produced in the product by one of the two Lact. sakei strains. The addition of purified sakacin P had an inhibiting effect on the growth of L. monocytogenes. A high dosage of sakacin P (3·5 ,g g,1) had a bacteriostatic effect throughout the storage period of 4 weeks, while a low dosage (12 ng g,1) permitted initial growth, but at a slow rate. After 4 weeks of storage, the number of L. monocytogenes in the samples with a low dosage of sakacin P was 2 logs below that in the untreated control. When using a high dosage of sakacin P, the bacteriocin was detected in samples stored for up to 6 weeks. Conclusions: (i) Sakacin P is produced by a Lact. sakei strain when growing on vacuum-packed chicken cold cuts. (ii) Inhibiting effects of Lact. sakei, other than sakacin P, are active in inhibiting the growth of L. monocytogenes growing on chicken cold cuts. (iii) Sakacin P is stable on chicken cold cuts over a period of 4 weeks. Significance and Impact of the Study: Both sakacin P and Lact. sakei were found to have potential for use in the control of L. monocytogenes in chicken cold cuts. [source] Evodia rutaecarpa protects against circulation failure and organ dysfunction in endotoxaemic rats through modulating nitric oxide releaseJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 10 2002Wen Fei Chiou Using a rat model of septic shock we studied the effects of Evodia rutaecarpa, a Chinese herbal medicine with antimicrobial and anti-inflammatory activity, on haemodynamic parameters, biochemical markers of organ function and nitric oxide (NO) production. Anaesthetized rats challenged with a high dosage of endotoxin (Escherichia coli lipopolysaccharide; LPS; 50 mg kg,1, i.v.) for 6 h showed a severe decrease in mean arterial pressure. This was accompanied by delayed bradycardia, vascular hyporeactivity to phenylephrine and increase in plasma levels of lactate dehydrogenase, aspartate aminotransferase, bilirubin and creatinine, as well as NOx (NO,2 plus NO,3). Pretreatment with ethanol extract of E. rutaecarpa (25,50 and 100 mg kg,1, i.v.), 1 h before LPS, dose-dependently prevented the circulation failure, vascular hyporeactivity to phenylephrine, prevented liver dysfunction and reduced the NOx over-production in plasma in endotoxaemic rats. A selective inducible NO-synthase (iNOS) inhibitor, aminoguanidine (15 mg kg,1, i.v.), also effectively ameliorated the above pathophysiological phenomenon associated with endotoxaemia so that the normal condition was approached. Endotoxaemia for 6 h resulted in a significant increase in iNOS activity in the liver homogenate, which was attenuated significantly by E. rutaecarpa pretreatment. In summary, E. rutaecarpa, at the dosages used, exerted these beneficial effects probably through inhibition of iNOS activity and subsequent modulation of the release of NO. These significant results may offer E. rutaecarpa as a candidate for the treatment of this model of endotoxaemia. [source] Physiological and growth responses of the montane bryophyte Racomitrium lanuginosum to atmospheric nitrogen depositionNEW PHYTOLOGIST, Issue 1 2003I. S. K. Pearce Summary ,,The effects of nitrogen (N) deposition on the moss Racomitrium lanuginosum within montane heath in Scotland were investigated over 5 yr. ,,Permanent field plots were sprayed with KNO3 or NH4Cl solutions, at doses equivalent to 10 and 40 kg N ha,1 yr,1, in 3,6 applications each summer. ,,Racomitrium growth and cover were severely reduced by N addition, whilst the proportion of dead shoots greatly increased. N dose decreased inducibility of shoot nitrate reductase activity (NRA), suggesting that N saturation of Racomitrium occurred, and caused an increase in potassium leakage. At high dosage, effects of NH4+ were more detrimental than NO3,. ,,Physiological responses to N indicate that the habitat's critical load (CL) is exceeded by addition of 10 kg N ha,1 yr,1. The differential toxicity of the two forms of N suggests that predominant ion type in deposition should be taken into consideration when CLs are set. In contrast to tissue N, NRA correlated well with shoot growth, and may thus be a useful biological indicator of moss condition. [source] NO signalling in cytokinin-induced programmed cell deathPLANT CELL & ENVIRONMENT, Issue 9 2005FRANCESCO CARIMI ABSTRACT Cell death can be induced by cytokinin 6-benzylaminopurine (BA) at high dosage in suspension-cultured Arabidopsis cells. Herein, we provide evidence that BA induces nitric oxide (NO) synthesis in a dose-dependent manner. A reduction in cell death can be observed when the cytokinin is supplemented with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) or the nitric oxide synthase (NOS) inhibitors: 2-aminoethyl-isothiourea (AET) and NG. -monomethyl- l -arginine ( l -NMMA), which suggests that NO is produced via a NOS and is a signalling component of this form of programmed cell death. In BA-treated cells, mitochondrial functionality is altered via inhibition of respiration. This inhibition can be prevented by addition of either cPTIO or AET implying that NO acts at the mitochondrial level. [source] Effect of sublingual medication of sildenafil citrate/ apomorphine on sexual behaviour of male ratsANDROLOGIA, Issue 2 2009X. Huang Summary The study investigated the combined effect of sublingually administered sildenafil (SN) and apomorphine (APO SL) on the sexual behaviour of male rats. Male Sprague,Dawley rats (50) were divided into five groups (10 rats per each group): blank control, sildenafil group and SN plus APO SL high dosage, medium dosage and low dosage group. After sublingual administration of the agents (control and SN plus APO SL) and a sole dosage of sildenafil (stomach irrigation), the rats were mated with female counterparts in pairs, and the latent period of chasing, the frequency of chasing in 60 min, the latent period of mounting and the frequency of mounting in 60 min were recorded. The lower dosage of SN plus APO SL exerted a stronger influence on the sexual activities in male rats than did the higher sole dosage of sildenafil. Identification of common neurochemical and neuroanatomical substrates of sexual responding between animals and humans suggests that the evolution of sexual behaviour has been highly conserved and indicates that animal models of human sexual response can be used successfully as pre-clinical tools. So sublingual medication of SN combined with APO SL may be at least a support inference about male sexual libido. [source] Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure optionsEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2004Y. Balash The treatment of both generalized and focal dystonia is symptomatic. There is no evidence-based information about the efficacy of the different methods of the pharmacological therapeutic options currently being applied in dystonia. The specific questions addressed by this study were which treatments for dystonia have proven efficacy and which of them have unproven results. Following evidence-based principles, a literature review based on MEDLINE and the Cochrane Library, augmented by manual search of the most important journals was performed to identify the relevant publications issued between 1973 and 2003. All articles appearing in the professional English literature, including case reports, were considered. In the presence of comparable studies the meta-analysis was performed to obtain pooled information and make a reasonable inference. Based on this review, we conclude: (i) botulinum toxin has obvious benefit (level A, class I,II evidence) for the treatment of cervical dystonia and blepharospasm; (ii) trihexyphenidyl in high dosages is effective for the treatment of segmental and generalized dystonia in young patients (level A, class I,II evidence); (iii) all other methods of pharmacological intervention for generalized or focal dystonia, including botulinum toxin injections, have not been confirmed as being effective according to accepted evidence-based criteria (level U, class IV studies). [source] Effect of vitamin E and selenium on the tissue inhibitor of metalloproteinase-1 mRNA expression in hepatic stellate cellsJOURNAL OF DIGESTIVE DISEASES, Issue 3 2001Xuanhai Li OBJECTIVE: To investigate the effects of vitamin E and different doses of selenium on the expression of the tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA in the hepatic stellate cells (HSC) of CCl4 -induced hepato-fibrotic rats. The mechanism of these therapeutic actions is investigated at a molecular level. METHODS: Hepatic fibroses were induced by intraperitoneal injection of 40% CCl4 in olive oil and treated by dietary supplementation with vitamin E and different doses of selenium. Liver tissue sections were stained with routine hematoxylin and eosin staining and Masson trichrome staining for collagen. With ,-actin as an internal control, the reverse transcriptase,polymerase chain reaction (RT-PCR) method was applied to quantify the change of TIMP-1 mRNA in HSC. RESULTS: The expression level of TIMP-1 mRNA in HSC was significantly downregulated and collagenous fiber proliferation in the liver was also significantly reduced in the groups of rats treated with vitamin E (250 mg/kg) and low dosages of selenium (0.2 mg/kg). However, the expression of TIMP-1 mRNA was upregulated, but not significantly, in the group treated with high dosages of selenium (1.0 mg/kg). CONCLUSIONS: The expression level of TIMP-1 mRNA in HSC was significantly downregulated and collagenous fiber proliferation in the liver was significantly reduced in the groups of rats treated with vitamin E and appropriate dosages of selenium. This did not occur in groups with high dosages of selenium. [source] Teriparatide (Biosynthetic Human Parathyroid Hormone 1,34): A New Paradigm in the Treatment of OsteoporosisBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 6 2004Kim T. Brixen Biosynthetic human parathyroid hormone 1,34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2,3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 ,g/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged. [source] | |||||||||||||