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Dosage Levels (dosage + level)
Selected AbstractsDisposition of perfluorinated acid isomers in sprague-dawley rats; Part 2: Subchronic doseENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 3 2009Amila O. De Silva Abstract Two major industrial synthetic pathways have been used to produce perfluorinated acids (PFAs) or their precursors: Telomerization and electrochemical fluorination (ECF). Products of telomer and ECF origin can be distinguished by structural isomer profiles. A mixture of linear and branched perfluoroalkyl isomers is associated with ECF. Telomer products characteristically consist of a single perfluoroalkyl geometry, typically linear. In biota, it is unclear if the isomer profile is conserved relative to the exposure medium and hence whether PFA isomer profiles in organisms are useful for distinguishing environmental PFA sources. A companion study suggested isomer-specific disposition following a single oral gavage exposure to rats. To confirm these findings under a more realistic subchronic feeding scenario, male and female rats were administered PFA isomers by diet for 12 weeks, followed by a 12-week depuration period. The diet contained 500 ng/g each of ECF perfluorooctanoate (PFOA, ,80% n -PFOA), ECF perfluorooctane sulfonate (PFOS, ,70% n -PFOS), and linear and isopropyl perfluorononanoate (n - and iso -PFNA). Blood sampling during the exposure phase revealed preferential accumulation of n -PFOA and n -PFNA compared to most branched isomers. Female rats depurated all isomers faster than males. Both sexes eliminated most branched perfluorocarboxylate isomers more rapidly than the n -isomer. Elimination rates of the major branched PFOS isomers were not statistically different from n -PFOS. Two minor isomers of ECF PFOA and one branched PFOS isomer had longer elimination half-lives than the n-isomers. Although extrapolation of these pharmacokinetics trends in rats to humans and wildlife requires careful consideration of dosage level and species-specific physiology, cumulative evidence suggests that perfluorocarboxylate isomer profiles in biota may not be suitable for quantifying the relative contributions of telomer and ECF sources. [source] Kava in Arnhem Land: a review of consumption and its social correlatesDRUG AND ALCOHOL REVIEW, Issue 3 2000Alan R. Clough Abstract The debate about the effects and public health importance of the way Aboriginal people drink kava has been confounded by claims, based on anecdote, of imputed health effects. Anecdote and comment have promoted the perception that dosage levels among Aboriginal people are much greater than in Pacific island societies. In this paper we review published data about kava consumption, and evaluate it with respect to information collected from observation of one Aboriginal community in Arnhem Land (Northern Territory) where people tend to consume kavaat a steady tempo; 37g of kava powder containing around 3800mg of kava lactones in 670ml of water in an hour. The highest levels of consumption in Arnhem Land have been reported to be up to 900g/week of kava powder with heavy consumers drinking at least 610g/week, levels comparable to estimates for Pacific-island societies. The significance of a steady drinking tempo means that an individual's weekly kava consumption relates directly to the amount of time spent drinking which, in turn, is correlated with categories of social setting of drinking (p < 0.0002). Lone drinkers appear to be the heaviest users while lowest consumption takes place in private domestic situations, where people enjoy kava as part of family group activities. Surrogates of consumption levels may be found in local socio-economic circumstances. This approach may be useful when more direct measurement of consumption is difficult or impossible. [source] A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemiaJOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2010Masahiko Sato Abstract Vitamin D3 analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC50,=,7.1,±,1.6,nM) and induced osteocalcin promoter activity (EC50,=,1.9,±,1.6,nM). VDRM2 was less potent in inducing Ca2+ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC50,=,37,±,12,nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08,µg/kg per day. Hypercalcemia was observed at a dose of 4.6,µg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35,91]. 1,,25-dihydroxyvitamin D3 [1,,25(OH)2D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046,µg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23,µg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1,13, 3.2,7.7, and 3.5,6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal bone-formation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. © 2010 American Society for Bone and Mineral Research [source] A structure/function study of polyaminoamide dendrimers as silica scale growth inhibitorsJOURNAL OF CHEMICAL TECHNOLOGY & BIOTECHNOLOGY, Issue 6 2005Konstantinos D Demadis Abstract Dendrimers have attracted immense attention during the last decade due to their interesting properties both from a basic and an applied research viewpoint. Encapsulation of metal nanoparticles for catalysis, drug delivery and light harvesting are only some applications of dendrimers that are breaking new ground. A novel application of dendrimer technology is described in the present paper that relates to industrial water treatment. Industrial water systems often suffer from undesirable inorganic deposits. These can form either in the bulk or on metallic surfaces, such as heat exchangers or pipelines. Silica (SiO2) scale formation and deposition is a major problem in high-silica-containing cooling waters. Scale prevention rather than removal is highly desired. In this paper, benchtop screening tests on various silica inhibition chemistries are reported, with emphasis on materials with a dendrimeric structure. Specifically, the inhibition properties of commercially available STARBURST® polyaminoamide (PAMAM) dendrimers generations 0.5, 1, 1.5, 2, and 2.5 are investigated in detail together with other commonly-used scale inhibitors. Experimental results show that inhibition efficiency largely depends on structural features of PAMAM dendrimers such as generation number and nature of the end groups. PAMAM dendrimers are effective inhibitors of silica scale growth at 40 ppm dosage levels. PAMAM dendrimers also act as silica nucleators, forming SiO2,PAMAM composites. This occurs because the SiO2 formed by incomplete inhibition interacts with cationic PAMAM-1 and -2. The general scope of silica formation and inhibition in industrial waters is also discussed. Copyright © 2005 Society of Chemical Industry [source] The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo,,ARTHRITIS & RHEUMATISM, Issue 7 2009Joel M. Kremer Objective To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. Methods Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks after treatment. The primary efficacy end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at 6 weeks. Results By week 6, the ACR20 response rates were 70.5%, 81.2%, and 76.8% in the 5 mg, 15 mg, and 30 mg twice daily groups, respectively, compared with 29.2% in the placebo group (P < 0.001). Improvements in disease activity in CP-690,550,treated patients compared with placebo were seen in all treatment groups as early as week 1. ACR50 and ACR70 response rates significantly improved in all treatment groups by week 4. The most common adverse events reported were headache and nausea. The infection rate in both the 15 mg twice daily group and the 30 mg twice daily group was 30.4% (versus 26.2% in the placebo group). No opportunistic infections or deaths occurred. Increases in mean low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels, and increases in mean serum creatinine level (0.04,0.06 mg/dl) were seen in all CP-690,550 treatment arms. Conclusion Our findings indicate that CP-690,550 is efficacious in the treatment of RA, resulting in rapid, statistically significant, and clinically meaningful reductions in the signs and symptoms of RA. Further studies of CP-690,550 in RA are warranted. [source] Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol,conjugated uricase) in patients with treatment-failure gout: Results of a phase II randomized study,ARTHRITIS & RHEUMATISM, Issue 9 2008John S. Sundy Objective To assess the efficacy of pegloticase in achieving and maintaining plasma urate levels of <6 mg/dl in gout patients in whom other treatments have failed, and to assess the pharmacokinetics and safety of pegloticase. Methods Forty-one patients were randomized to undergo 12,14 weeks of treatment with pegloticase at 1 of 4 dosage levels: 4 mg every 2 weeks, 8 mg every 2 weeks, 8 mg every 4 weeks, or 12 mg every 4 weeks. Plasma uricase activity, plasma urate, and antipegloticase antibodies were measured, pharmacokinetic parameters were assessed, and adverse events were recorded. Results The mean plasma urate level was reduced to ,6 mg/dl within 6 hours in all dosage groups, and this was sustained throughout the treatment period in the 8 mg and 12 mg dosage groups. The most effective dosage was 8 mg every 2 weeks. Twenty-six patients received all protocol doses. The percentage of the patients in whom the primary efficacy end point (plasma urate <6 mg/dl for 80% of the study period) was achieved ranged from 50% to 88%. Gout flares occurred in 88% of the patients. The majority of adverse events (excluding gout flare) were unrelated to treatment and were mild or moderate in severity. Infusion-day adverse events were the most common reason for study withdrawal (12 of 15 withdrawals). There were no anaphylactic reactions. Antipegloticase antibody, present in 31 of 41 patients, was associated with reduced circulating half-life of pegloticase in some patients. Conclusion Pegloticase, administered in multiple doses, was effective in rapidly reducing and maintaining plasma urate levels at ,6 mg/dl in most patients in whom conventional therapy had been unsuccessful due to lack of response, intolerability, or contraindication. [source] Pharmacokinetics of lovastatin extended-release dosage form (Lovastatin XL) in healthy volunteersBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 4 2002Michael Lamson Abstract The purpose of this study was to evaluate pharmacokinetics and dose proportionality of lovastatin extended-release dosage form (ER-lovastatin) in the dosage levels of 10, 20 and 40 mg in 9 healthy male subjects. Each subject was randomized to receive a single oral dose of ER-lovastatin either 10, 20 or 40 mg in a three-way crossover design with a washout period of 7 days between the treatments. Subjects were served dinner at approximately 5:30 PM followed by dosing at approximately 10:00 PM in each study period. Serial plasma samples were collected up to 48 h after dosing and assayed for lovastatin and its active metabolite lovastatin acid using an LC/MS/MS method. The plasma concentration,time profiles of lovastatin and its active metabolite lovastatin acid exhibited delayed- and extended-release characteristics at each dose. Mean (±) values for the Cmax of lovastatin were 1.04±0.43, 2.03±0.65 and 4.03±3.02 ng/ml for the 10, 20 and 40 mg dosage, respectively. The corresponding values for the AUC0,48 h of lovastatin were 14.6±7.8, 34.1 ±13.7, and 53.9±35.6 ng h/ml. The same tendency was also found for Cmax and AUC0,48 h values of lovastatin acid. Results from this study demonstrated as the dose of ER-lovastatin increased from 10 to 40 mg, the Cmax and AUC0,48 h values of lovastatin as well as lovastatin acid appeared to increase linearly. Copyright © 2002 John Wiley & Sons, Ltd. [source] | ||||||||||