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Richard Pollard, MD
UC Davis Medical Center
4150 V St, Suite G500 PSSB
Sacramento, CA 95817
Phone: 916-734-3742
Fax: 916-734-7766
Stavudine Extended/Prolonged Release (XR/PRC*) vs Stavudine Immediate Release
(IR) in Combination with Lamivudine and Efavirenz: 48 Week Efficacy and Safety
JG Baril1, RB Pollard*2, F Raffi3, M Whelden4, V Rutkiewicz4, H Brett-Smith4.
1Clinique du Quartier Latin, Montreal, Canada; 2Univ of CA, Davis Med Ctr. Sacramento, CA; 3Hopital de L'Hotel Dieu, Nantes, France; 4Pharmaceutical Research Institute, Bristol-Myers Squibb, Wallingford, CT ABSTRACT
RESULTS (continued)
Background: A multinational, randomized, double-blind, placebo-controlled
Table 2. Patient Disposition From Randomization to Week 48
study evaluated the antiviral activity, safety and tolerability of once-daily d4T extended/prolonged release capsules (XR/PRC) compared to the current twice-daily formulation of d4T immediate release (IR), when used in a HAART regimen in treatment-naïve HIV-infected subjects. Methods: Adult subjects
with CD4 ≥100 cells/µL (≥ 75 cells/µL if no prior AIDS event) and HIV RNA ≥ 2,000 copies/mL (c/mL) were randomized to either d4T XR/PRC or d4T IR, each in combination with 3TC + EFV (standard doses). The study had 90% power to demonstrate non-inferiority based on the primary outcome of proportion with HIV RNA < 400 c/mL at 48 weeks (wks). Results: Of 797
randomized subjects, 783 began treatment. Median baseline HIV RNA and CD4 were 4.8 log10 c/mL and 277 cells/µL, respectively. All subjects had 48 wks of follow-up (median 56 wks). Two virologic response (VR) analyses for LOQ <400 c/mL demonstrate similarity: VR-Treated (VR-T, an ITT analysis for all treated subjects), XR/PRC 80% vs IR 75% ([XR/PRC-IR], 4.4, 95%CI -1.5, 10.3); VR-Completers (VR-C; an On-Treatment analysis), 91% XR/PRC vs 89% IR. Analyses for LOQ <50 c/mL also support similarity: VR-T, XR/PRC 59% vs *Other includes noncompliance, administration decision, and protocol violation.
IR 57%; VR-C, XR/PRC 67% vs IR 67%. Mean increases in CD4 were: XR/PRC †Refers to the % of total patients randomized, not % female patients randomized.
+202 vs IR +182 c/mL. At 48 wks, 4% of subjects discontinued therapy in each ‡One additional IR death (metastatic breast cancer) was not a reason for study discontinuation; group due to an adverse event (AE). Grade 3/4 clinical AEs occurred in 43 therefore does not appear in this table.
(11%) of XR/PRC and 41 (10%) of IR subjects. Events of hepatotoxicity,pancreatitis, or symptomatic hyperlactacidemia/lactic acidosis syndromeoccurred in a total of 3 (<1%) XR/PRC vs 7 (1.5%) IR subjects. Grade 2-4 23 patients (16 XR/PRC; 7 IR) switched the EFV component of the regimen to NFV peripheral neurologic symptoms related to treatment occurred in 3% of
XR/PRC and 5% of IR subjects. Conclusion: d4T XR/PRC is well tolerated
Figure 2. Proportion of Patients With HIV-1 RNA < LOQ at Week 48
and exhibits an antiviral and immunologic profile similar to that of d4T IR whenused in a HAART regimen for treatment-naïve patients. d4T XR/PRC is anoption when designing once daily regimens.
Stavudine (d4T) is currently approved as an immediate release formulation (d4T IR), dosed 40 mg BID for patients ≥60 kg and 30 mg BID for those <60 kg body weight. An extended-release encapsulated bead formulation of d4T (d4TXR/PRC*) that can be dosed once-daily was developed to simplify HIVtreatment and improve patient adherence to therapy. The 100 mg QD dose Figure 3. Proportion of Patients With HIV RNA <LOQ at Week 48 (ITT)
was selected based on modeling and simulations that predicted comparabledaily exposure (AUC) to the 40 mg IR BID. The difference in total daily dose is due to lower absorption of d4T from the colon; IR releases all drug in the upper GI tract whereas XR/PRC releases drug continuously throughout the entire GItract. Data from Phase I PK studies have confirmed the dose-equivalencebetween XR/PRC 100 mg QD and IR 40 mg BID and that XR/PRC can be taken without regard to food intake (see poster TuPeB4555; additional PK data is presented in poster TuPeB4554). Previously presented data from the final analysis of a 48-week Phase II/III clinical trial comparing d4T XR/PRC and d4T IR when used in combination with lamivudine (3TC) and efavirenz (EFV) have shown similar virologic and immunologic responses as well as comparable safety and tolerability (BMS 096)1. This study, BMS 099, is a similarly designed Phase III trial to evaluate the antiviral activity, safety, and tolerability of d4T XR/PRC compared to d4T IR when used in combination with 3TC and EFV in antiretroviral naive adults. Data presented here are from the 48-week analysis. OBJECTIVES
The difference estimates (XR/PRC-IR) for the 2 analyses at both LOQ=400 andLOQ=50 all met the prescribed criteria (lower limit greater than -12%) Compare the following outcomes between d4T XR/PRC and d4T IR treatment demonstrating similarity between XR/PRC and IR regimens Figure 4. HIV RNA: Mean Change From Baseline to Week 48
Proportion of patients with HIV RNA <400 copies/mL @ week 48 Proportion of patients with HIV RNA <50 copies/mL @ week 48 Magnitude and durability of HIV RNA and CD4+ cell changes from baseline Phase III multinational, prospective, randomized, double-blind, double-dummy study CD4+ ≥100 cells/mm3 (≥75 if no prior AIDS-defining event) Figure 5. CD4 Count: Mean Change From Baseline to Week 48
Antiretroviral-naive (≤30 days of any NRTI, NNRTI, or PI) Patients with primary (acute) HIV infection or a newly diagnosed HIV-related opportunistic infection or condition were excluded This study was designed to provide at least 90% power to demonstrate similar antiviral activity (proportion of patients with HIV RNA <400 copies/mL at 48 weeks) between the d4T XR/PRC and d4T IR-containing regimens Treatment regimens were considered similar if the lower limit of the 95% confidence interval (CI) of the difference in proportions (XR/PRC-IR) wasgreater than -12% Figure 1. Study Design
Enrollment (stratified: HIV RNA <30,000 or ≥30,000) Table 3. Clinical Adverse Events and Laboratory Abnormalities
(median time on study = 56 weeks)
Clinical Adverse Events Related to Study Regimen, All Treated Patients (Grade 2-4 events occurring in at least 3% of patients) Patients 60 kg
Patients <60 kg
All patients received 3TC 150 mg BID + EFV 600 mg QD EFV ➔ NFV allowed in cases of EFV intolerance Laboratory Abnormalities (Grade 3-4), All Patients With Laboratory Values Available Data Analysis
The VRT/ITT analysis is an ITT analysis for all treated patients; it includes patients who received at least one dose of study drug and excludes those who were randomized but who never initiated treatment (7 in XR/PRC; 7 in IR).
Failures were defined as patients with HIV RNA >/= LOQ (limit of quantitation of the HIV RNA assay) or those who discontinued for any reason The OT (on-treatment) analysis includes all patients on treatment at time of analysis. Responders were patients with HIV RNA < LOQ at week 48. Failures were defined as patients with HIV RNA >/= LOQ at week 48 Over a median follow-up of 56 weeks the following safety observations were made: Pancreatitis occurred in 0 XR/PRC subjects and in 3 IR subjects Lactic acidosis syndrome (LAS) or symptomatic hyperlactemia (SHL) occurred in 2 XR/PRC subjects and 6 IR subjects Lipodystrophy was reported in only 3% of XR/PRC subjects and 4% of IR subjects 797 patients were randomized; 783 initiated therapy at 71 sites worldwide The baseline characteristics were well matched between the two treatment DISCUSSION/CONCLUSIONS
Stavudine XR/PRC 100 mg dosed once daily (75 mg QD for those <60 kg) Table 1. Baseline Characteristics
provides comparable daily drug exposure (AUC) to 40 mg IR dosed twice daily (30 mg BID for those <60 kg). This AUC equivalence translates into similar clinical efficacy and comparable safety as measured by: Proportion of patients achieving HIV RNA <400 or <50 copies/mL Overall rates of clinical adverse events and laboratory abnormalities Stavudine was well tolerated through week 48, with only 4% of patients in each Although not achieving statistical significance, medically important events of peripheral neurologic symptoms, pancreatitis, and LAS/SHL occurred in fewer XR/PRC subjects Stavudine XR/PRC may be used to construct fully once-daily regimens that may improve patient adherence and may thereby result in better long-term clinical outcomes.
1Montaner, 8th Eur. Conf. Clin. Aspects Treat. HIV Infect. Abstract LB/O4, 2001.
The investigators would like to thank all the sites, staff and patients who participated in this study. *Refers to stavudine extended release capsules/prolonged release capsule.


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