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Clear Reduction (clear + reduction)
Selected AbstractsPre-clinical studies of pramipexole: clinical relevanceEUROPEAN JOURNAL OF NEUROLOGY, Issue 2000J. P. Hubble This paper reviews the preclinical study of the novel dopamine agonist pramipexole and its use in early Parkinson's disease (PD). Emphasis will be given to those properties distinguishing this drug from other dopamine agonists, the relevance of the preclinical data to clinical trial results in early PD, and the putative neuroprotective properties of the compound. The conventional dopamine agonists are ergot-derived compounds that are most widely used as adjunctive therapies in advancing Parkinson's disease (PD). Examples of conventional agonists are bromocriptine and pergolide. Pramipexole is an aminobenzothiazole compound, recently introduced for the treatment of both early and advanced PD. Its nonergot structure may reduce the risk of side-effects, considered unique to ergot drugs, such as membranous fibrosis. Pramipexole is a full dopamine agonist with high selectivity for the D2 dopamine receptor family. This family includes the D2, D3 and D4 receptor subtypes. Pramipexole has a 5- to 7-fold greater affinity for the D3 receptor subtype with lower affinities for the D2 and D4 receptor subtypes. The drug has only minimal ,2 -adrenoceptor activity and virtually no other receptor agonism or antagonism. The optimal dopamine receptor activation for the safe and effective treatment of PD is not known. Findings in animal models and clinical studies indicate that activation of the postsynaptic D2 receptor subtype provides the most robust symptomatic improvement in PD. Given its pharmacological profile, it is not surprising that pramipexole was found to be effective in ameliorating parkinsonian signs in animal models. This therapeutic effect has been confirmed in clinical trials in both early and advanced PD. In early disease, it provides a clear reduction in the chief motor manifestations of PD and improved activities of daily living. Perhaps most striking is the large number of clinical trial patients who have remained on pramipexole monotherapy for many months. The majority of these subjects have been maintained on pramipexole for an excess of 24 months without requiring additional symptomatic treatment with levodopa. This is in contrast to the general clinical experience with older conventional agonists. Pramipexole also has a favourable pharmacokinetic profile. It is rapidly absorbed with peak levels appearing in the bloodstream within 2 h of oral dosing. It has a high absolute bioavailability of > 90% and can be administered without regard to meals. It has no significant effects on other antiparkinson drugs such as levodopa or selegiline. Its excretion is primarily renal and, thus, has little or no impact on hepatic cytochrome P450 enzymes or other related metabolic pathways. Pramipexole has also been theorized to have ,neuroprotectant' properties. Oxyradical generation is posited as a cause or accelerant of brain nigral cell death in PD. Pramipexole stimulates brain dopamine autoreceptors and reduces dopamine synthesis and turnover which may minimize oxidative stress due to dopamine metabolism. Furthermore, the compound has a low oxidation potential that may serve as an oxyradical scavenger in the PD brain. In summary, pramipexole is a new antiparkinson medication found to have unique dopamine agonist characteristics and putative neuroprotective properties. [source] pH-dependent antitumor activity of proton pump inhibitors against human melanoma is mediated by inhibition of tumor acidityINTERNATIONAL JOURNAL OF CANCER, Issue 1 2010Angelo De Milito Abstract Metastatic melanoma is associated with poor prognosis and still limited therapeutic options. An innovative treatment approach for this disease is represented by targeting acidosis, a feature characterizing tumor microenvironment and playing an important role in cancer malignancy. Proton pump inhibitors (PPI), such as esomeprazole (ESOM) are prodrugs functionally activated by acidic environment, fostering pH neutralization by inhibiting proton extrusion. We used human melanoma cell lines and xeno-transplated SCID mice to provide preclinical evidence of ESOM antineoplastic activity. Human melanoma cell lines, characterized by different mutation and signaling profiles, were treated with ESOM in different pH conditions and evaluated for proliferation, viability and cell death. SCID mice engrafted with human melanoma were used to study ESOM administration effects on tumor growth and tumor pH by magnetic resonance spectroscopy (MRS). ESOM inhibited proliferation of melanoma cells in vitro and induced a cytotoxicity strongly boosted by low pH culture conditions. ESOM-induced tumor cell death occurred via rapid intracellular acidification and activation of several caspases. Inhibition of caspases activity by pan-caspase inhibitor z-vad-fmk completely abrogated the ESOM-induced cell death. ESOM administration (2.5 mg kg,1) to SCID mice engrafted with human melanoma reduced tumor growth, consistent with decrease of proliferating cells and clear reduction of pH gradients in tumor tissue. Moreover, systemic ESOM administration dramatically increased survival of human melanoma-bearing animals, in absence of any relevant toxicity. These data show preclinical evidence supporting the use of PPI as novel therapeutic strategy for melanoma, providing the proof of concept that PPI target human melanoma modifying tumor pH gradients. [source] Efficacy and safety of a new single-dose terbinafine 1% formulation in patients with tinea pedis (athlete's foot): a randomized, double-blind, placebo-controlled studyJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 10 2006JP Ortonne Abstract Background, Tinea pedis is a common dermatophyte infection with frequent recurrences. Terbinafine (presently used as a 1-week topical treatment of tinea pedis) is now available in a novel topical solution (film-forming solution , FFS), developed to allow single application. Objectives, To demonstrate the efficacy and safety of terbinafine 1% FFS in a randomized, double-blind, placebo-controlled, phase III trial, and to determine relapse or re-infection rate of tinea pedis at 12 weeks. Patients/methods, Fifty-four centres (27 in France; 27 in Germany) enrolled 273 evaluable patients (2 : 1 randomization). Patients applied terbinafine 1% FFS or placebo only once between, under and over the toes, soles and sides of both feet. Efficacy assessments included direct microscopy, mycological culture, and clinical signs and symptoms at baseline, and at weeks 1, 6 and 12 after the single drug application. Results, Effective treatment (negative mycology plus absent/minimal symptoms) at week 6 in the terbinafine 1% FFS group was 63%; vehicle was 17% (P 0.0001). Mycological cure was 72% in the terbinafine group and 21% in the placebo (P 0.0001) at week 6. Clinical signs/symptoms decreased significantly in the active group compared to the placebo. The self-assessment of itching and burning sensation by the patient showed a clear reduction in symptoms starting 15 min after treatment application (this could be attributed to the cooling effect of the FFS). Recurrence (positive culture at 3 months) occurred in 12.5% of the effectively treated patients at week 6 in the terbinafine group. FFS was well tolerated. Conclusion, Terbinafine 1% FFS, single dose application is an effective, safe and convenient treatment for tinea pedis. The relapse/re-infection rate 3 months after the end of single-dose therapy is similar to that previously demonstrated in a study using terbinafine 1% cream for 7 days. [source] Replacement of Fish Meal with Soybean Meal in the Production Diets of Juvenile Red Snapper, Lutjanus campechanusJOURNAL OF THE WORLD AQUACULTURE SOCIETY, Issue 1 2005D. Allen Davis The replacement of fish meal with soybean meal in fish diets has met with varying degrees of success. Quite often, poor responses to high soybean meal diets are either due to shifts in the nutrient profile or a reduced palatability of the diet when fish meal is removed. The present research was designed to evaluate the replacement of menhaden fish meal with solvent-extracted soybean meal in practical diets containing 10% poultry by-product meal and formulated to contain 40% protein, 8% lipid, and a total sulfur amino acid content of > 3.0% of the protein. The response of red snapper (mean initial weight 10.9 g) to diets containing graded levels of fish meal (30,20, 10, 0%) as well as the response to a low fish meal diet (10%) without poultry by-product meal were evaluated over a 6-wk growth period. Significant (P± 0.05) differences in final mean weight, percent weight gain, and feed conversion were observed. Final weights (percent gain) ranged from 30.9 g (185.5%) for fish offered diets with 30% fish meal to 12.6 g (16.3%) for fish offered diets with 0% fish meal. Corresponding feed conversion efficiencies ranged from 60.1% to 7.7%. No significant differences were observed for survival between treatment means. Although there was a clear reduction in performance as the fish meal was replaced with soybean meal, the use of 10% poultry by-product meal or 10% fish meal resulted in similar performance of the fish. This is a good indication that poultry by-product meal does not have palatability problems and could be used as a substitute. The present findings suggest that replacing fish meal with high levels of soybean meal appears to reduce the palatability of the diet. While the cost reducing benefit, with respect to the replacement of fish meal, has been shown with other species, before high levels of inclusion can be efficiently utilized further research is needed to address the palatability problems observed with red snapper. [source] Quality of life in hepatitis CLIVER INTERNATIONAL, Issue 7 2006Edna Strauss Abstract: A number of different studies have shown a clear reduction in the quality of life of hepatitis C virus (HCV)-related liver-disease patients. Quality of life can be assessed by means of both generic and specific instruments, depending on the aim of the study and the population being studied. The application of a specific instrument to patients with liver diseases provides a broader assessment of different parameters related to hepatic disorders. In hepatitis C, alterations such as the stigma of liver disease, concerns about the disease and symptoms of the disease could be demonstrated with this type of instrument. The impact of the diagnosis of hepatitis C, a potentially serious disease, and the presence of comorbidities such as alcohol and drugs may lead to lower quality of life. Longitudinal studies have proved that, following diagnosis, the stigma of liver disease becomes more apparent over time. Women report worse quality of life than men, supporting that gender differences in hepatitis are also important when assessing quality of life. Alterations in the quality of life of patients submitted to treatment are mainly related to the somatic side effects of Interferon and Ribavirin and are most noticeable in the first weeks of therapy. Early improvement in the quality of life of patients who become HCV-RNA negative suggests that the virus itself plays a biological role. There is no doubt that liver transplantation leads to an improvement in quality of life. Nevertheless, a major concern is the relapse of HCV, with the associated lower quality of life. [source] Urinary CD4+ effector memory T cells reflect renal disease activity in antineutrophil cytoplasmic antibody,associated vasculitisARTHRITIS & RHEUMATISM, Issue 9 2009Wayel H. Abdulahad Objective Numbers of circulating CD4+ effector memory T cells are proportionally increased in patients with proteinase 3 antineutrophil cytoplasmic antibody,associated vasculitis (AAV) whose disease is in remission and are decreased during active disease, which presumably reflects their migration toward sites of inflammation. Since renal infiltrating cells may appear in urine, we investigated the presence of CD4+ effector memory T cells in urinary sediment as a reflection of renal disease activity in AAV. Methods CD4+ effector memory (CD45RO+CCR7,CD3+CD4+) T cells were quantitated in the urine and peripheral blood of patients with AAV with renal involvement (n = 33), patients with AAV without renal involvement (n = 18), patients with AAV whose disease was in remission (n = 29), and patients with active disease (n = 22), using 4-color flow cytometric analysis. Numbers and percentages of urine CD4+ effector memory T cells in 12 patients with AAV with active renal disease were obtained over several weeks of followup during remission induction. Results A notable increase in urine CD4+ effector memory T cell numbers was observed in patients with active renal AAV compared with patients whose disease was in remission and patients with active disease without renal involvement. The increase in these cells in the urine of patients with active renal AAV was accompanied by a reciprocal decrease in these cells in peripheral blood. Results from followup analysis showed a clear reduction in urine CD4+ effector memory T cells following treatment. Moreover, a negative correlation was observed between percentages of circulating and urine CD4+ effector memory T cells, consistent with their migration toward sites of inflammation. Conclusion Our findings indicate that the presence of CD4+ effector memory T cells in urine reflects renal involvement in AAV. Flow cytometric analysis of these cells in urine may contribute to assessing renal disease activity in patients with AAV. [source] | ||||||||||