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AZ45049b_DDW_Miner:AZ45049b 21/5/09 14:15 Page 1 Pharmacokinetics of naproxen and esomeprazole in PN400, a single-tablet, multilayer formulation
of enteric-coated naproxen coupled with immediate-release esomeprazole

Philip Miner, Jr., MD, FACG,1 John Plachetka, PharmD,2 Eric Orlemans, PhD,2 John G. Fort, MD,2 Mark Sostek, MD, AGAF, FACG3
1Oklahoma Foundation for Digestive Disease Research, Oklahoma City, OK, USA; 2POZEN Inc., Chapel Hill, NC, USA; 3AstraZeneca US, Wilmington, DE, USA.
Patients
ᮣ Following AM or PM doses on Day 1 and Day 9, plasma esomeprazole ᮣ Esomeprazole concentrations were higher on Day 9 than Day 1 for each Table 3. Summary of naproxen pharmacokinetic parameters. Values are Mean Abstract
ᮣ Eligible patients were healthy adults aged 18-55 years who tested negative concentrations increased with the esomeprazole dose for all three PN400 for Helicobacter pylori infection and had no history of peptic ulcer disease treatments. On both days, the measurable plasma concentrations of ᮣ Following treatment with naproxen + EC E20, C for esomeprazole plasma esomeprazole were higher following the AM dose than the PM dose for Introduction: PN400 is a single-tablet formulation with an enteric-coated (EC) naproxen core
concentrations were observed at approximately 1.5 hours post-dose (1 hour all three PN400 treatments (Figure 1a and 1b).
surrounded by an immediate-release (IR) esomeprazole mantle designed for initial and rapid Patients with a history of hypersensitivity, allergy, or intolerance to any release of esomeprazole in the stomach followed by release of EC naproxen after esomeprazole NSAID or PPI were excluded from this study.
ᮣ Following naproxen + EC E20 treatment on Day 1 and Day 9, measurable absorption. The aim of this study was to determine levels of exposure of esomeprazole and plasma concentrations of esomeprazole were not available until 0.75-1.5 Naproxen
naproxen when used in combination in PN400 and with EC esomeprazole + naproxen 500 mg.
End points
hours post-dose in the majority of subjects and were measurable for longer ᮣ Pharmacokinetic parameters (C , T , and AUC than concentrations following PN400 administration (Figure 1a and 1b). Methods: This randomized, open-label, 9-day, four-way crossover, single-center study enrolled
esomeprazole and naproxen following the three PN400 treatments, and The plasma esomeprazole profile exhibited was consistent with that of a 28 healthy H. pylori-negative adults without a history of peptic ulcer/acid-related gastrointestinal the naproxen + EC E20 treatment on Day 1 and Day 9.
– measurable plasma concentrations of naproxen were first detected at symptoms. Subjects were randomized to different sequences of the following: A) PN400/E30 approximately 2 hours post-PN400 administration for all three PN400 [EC naproxen 500 mg/IR esomeprazole 30 mg] BID; B) PN400/E20 [EC naproxen 500 mg/IR ᮣ Safety of each treatment group was assessed using clinical adverse events, esomeprazole 20 mg] BID; C) PN400/E10 [EC naproxen 500 mg/IR esomeprazole 10 mg] BID; as well as physical examination, vital signs, and clinical laboratory tests.
Figure 1. Mean plasma esomeprazole concentration vs time curves and D) EC E20 [EC esomeprazole 20 mg] QD + non-EC naproxen 500 mg BID. Blood samples Other end points included pharmacodynamics (primary end point was percent were taken on Days 1 and 9 before dosing and at various times up to 24 hours afterwards for of time on Day 9 in which intra-gastric pH was Ͼ4.0; secondary end point was – pre-AM dose samples showed that naproxen concentrations were pharmacokinetic assessments of esomeprazole and naproxen.
the percent of time on Day 1 in which intra-gastric pH was Ͼ4.0) and safety.
measurable in all subjects and were measurable throughout the entire Results: Esomeprazole was rapidly absorbed from all three doses of PN400 with measurable
(Pharmacodynamics are presented in Poster T1969).
plasma concentrations as early as 10 minutes after the AM dose and at 20-30 minutes after Statistical analysis
ᮣ The mean plasma profiles of naproxen were comparable following the three and AUCs for esomeprazole from PN400 were generally dose- PN400 treatments, particularly on Day 9 (Figure 2a and 2b), demonstrating ᮣ The primary analysis was performed using Analysis of Variance (ANOVA) to for EC naproxen was delayed in relation to the T delayed-release characteristics consistent with the formulation design of determine the point estimate and 90% CI of the Day 9 to Day 1 ratios for esomeprazole. Steady-state AUCs for naproxen monocomponent were comparable to all PN400. The higher mean naproxen plasma concentrations observed at the with non-EC naproxen occurred considerably earlier than with the EC end of a 24-hour daily interval resulted from the delayed absorption of naproxen component of the PN400 formulations. Esomeprazole and naproxen pharmacokinetic ᮣ Adverse events were coded using the Medical Dictionary for Regulatory naproxen from PN400 (Figure 2a and 2b).
parameters for the AM dose on Day 9 of BID dosing for PN400 are provided in the Table.
Activities (MedDRA, version 8.0) for system organ class and preferred term.
ᮣ The safety analysis was based on the safety population.
Figure 2. Mean plasma naproxen concentration vs time curves 3. Results
Patient disposition
Twenty-eight subjects were randomized to treatment and were included in the safety, pharmacokinetics, and intent-to-treat (ITT) populations.
The study was completed by 27 subjects and 25 subjects were included in the per-protocol (PP) population; the three patients excluded from the Values are mean (% coefficient of variation) for C – one who withdrew because of personal reasons Table 4. Clinical adverse events reported by Ͼ1 subject (greater than 4%) on Conclusion: PN400 produced dose-dependent increases in plasma esomeprazole
– one with invalid intra-gastric pH data.
concentrations and similar naproxen concentrations to dosing with EC E20 + naproxen. The pharmacokinetics of esomeprazole administered as the PN400 formulation were consistent Patient demographics
for esomeprazole preceded that for EC naproxen. Baseline characteristics of enrolled subjects are outlined in Table 1. Table 1. Baseline demographics (ITT population) The pharmacokinetic parameters of esomeprazole for all PN400 treatments following administration of the AM and PM doses on Day 1 and Day 9 are 1. Introduction
ᮣ The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated Table 2. Summary of esomeprazole pharmacokinetic parameters. Values are with a substantial risk of upper gastrointestinal (GI) adverse events ranging from endoscopic erosions and ulcers to serious ulcer complications such as perforation, obstruction, and bleeding.1 The efficacy of proton pump inhibitors (PPIs) (eg, esomeprazole) for the prevention of NSAID-associated endoscopic injury and upper GI symptoms ᮣ Mean plasma concentrations of naproxen were much higher on Day 9 Enteric-coated (EC) esomeprazole 20 mg QD has demonstrated clinical efficacy in the prevention of gastroduodenal ulcers in at-risk patients using NSAIDs.4 4. Conclusions
PN400 is a single-tablet, fixed-dose formulation of an EC naproxen 500 mg Following naproxen + EC E20 treatment on Day 1, plasma naproxen core surrounded by an immediate-release (IR) esomeprazole mantle, concentrations were measurable in all subjects at the 10-minute post-dose Esomeprazole was rapidly absorbed following administration of the
designed to provide sequential delivery of gastroprotective esomeprazole sample time and for up to 24 hours, consistent with a non-EC naproxen three PN400 treatments—plasma concentrations were measurable
as early as 10 minutes after dose, consistent with an immediate-
release formulation; elimination of esomeprazole from plasma
This study evaluated the pharmacodynamics, pharmacokinetics, and ᮣ Following AM and PM doses on Day 1 and Day 9, mean plasma naproxen occurred between 6-8 hours post dose.
safety of three different dose formulations of PN400. Here we present the concentrations were higher and occurred earlier following naproxen + EC pharmacokinetic and safety findings of the study (the pharmacodynamic E20 treatment than with any of the PN400 treatments (Figure 2a and 2b).
Esomeprazole C
and AUC following administration of PN400
were dose-dependent; esomeprazole concentrations were higher
ᮣ The aim of this study was to determine levels of exposure of esomeprazole ᮣ The pharmacokinetic parameters of naproxen for all PN400 treatments on Day 9 than on Day 1 for each of the PN400 treatments.
and naproxen, and time to exposure to these drugs, when used in combination following administration of the AM and PM doses on Day 1 and Day 9 in PN400 and with naproxen 500 mg + EC esomeprazole (20 mg).
The naproxen plasma concentration vs time profiles were
comparable across all three PN400 treatments; higher
ᮣ C for naproxen plasma concentration occurred approximately 3-4 hours concentrations were observed at the end of a 24-hour
Esomeprazole
post-AM dose, and between 10-14 hours post-PM dose on Day 1 and daily interval, consistent with delayed-release characteristics.
Day 9 for all three PN400 treatments. The delay in naproxen absorption 2. Methods
was consistent with the EC naproxen in the PN400 formulations.
Esomeprazole T for all three PN400 treatments occurred
approximately 1 hour earlier than that observed for naproxen + EC E20.
Study design
ᮣ Naproxen C and AUCs post- AM and PM doses on Day 1 and Day 9 – measurable plasma concentrations of esomeprazole were obtained were comparable among all three PN400 treatments, consistent with ᮣ PN400 was well tolerated with no serious adverse events.
ᮣ This was a prospective, randomized, Phase I, open-label, single-center, rapidly with all three PN400 treatments—at 10 minutes after the AM the same dose of naproxen in each formulation.
cross-over study comprising four treatment periods.
dose and at 20-30 minutes after administration of the PM dose.
These finding support the ongoing evaluation of PN400 in
ᮣ Following treatment with EC E20 + naproxen, naproxen was quickly – esomeprazole was rapidly eliminated from plasma in the majority of patients at risk for developing NSAID-associated ulcers.
On Day 1 of the first treatment period, patients were randomized into one subjects by 6-8 hours post-dose (AM and PM) for all three PN400 absorbed, with peak plasma concentrations observed at 1.5 hours of four treatment sequences to receive each of the following treatments for 9 days in a cross-over fashion, with a washout period of у14 daysbetween treatments: Safety
References
– PN400/E30 (EC naproxen 500 mg/IR esomeprazole 30 mg) BID – pre-AM dose samples showed that esomeprazole concentrations were ᮣ Adverse events are summarized in Table 4.
1. Laine L. Gastroenterology 2001; 120: 594-606.
– PN400/E20 (EC naproxen 500 mg/IR esomeprazole 20 mg) BID measurable in 19 subjects receiving PN400/E30 treatment, 13 receivingPN400/E20 treatment, and 6 receiving PN400/E10 treatment.
ᮣ C for esomeprazole plasma concentration occurred approximately 0.5 hours 2. Scheiman JM. Curr Treat Options Gastroenterol 2008; 11: 125-134.
ᮣ No serious adverse events were reported and no patients withdrew from – PN400/E10 (EC naproxen 500 mg/IR esomeprazole 10 mg) BID post-AM dose, and between 1.0-1.5 hours post-PM dose on Day 1 and Day 9 3. Hawkey CJ et al. N Engl J Med 1998; 338: 727-734.
– post- AM and PM dose samples showed that, in the PN400 treatments – Naproxen + EC E20 (non-EC naproxen 500 mg BID and EC containing higher esomeprazole doses (PN400/E30 and PN400/E20), 4. Scheiman JM et al. Am J Gastroenterol 2006; 101: 701-710.
ᮣ Most laboratory abnormalities were small deviations from the normal range.
plasma concentrations of esomeprazole were measurable at earlier ᮣ Esomeprazole C and AUCs were higher following the AM dose than the Acknowledgements
ᮣ Study medication was administered 60 minutes before meals in the post-dose time points in a large number of subjects and for a longer PM dose on Day 1 and Day 9 for all three PN400 treatments and were ᮣ Vital sign measurements and physical examination findings were similar Editorial support was provided by Complete Medical Communications and was funded by AstraZeneca.
Poster presented at Digestive Disease Week, Chicago, Illinois, 30 May – 4 June 2009

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