A bioequivalence study of two brands of glipizide tablets.
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In this open, randomized, two way crossover, bioequivalence study, two 5 mg tablet preparations of glipizide (Glipizyd tabl. 5 mg, Tarchominskie Zaklady Farmaceutyczne POLFA S.A., and Glibenese tabl. 5 mg, Pfizer), were compared in 24 healthy male volunteers. Pharmacokinetic variables (mean maximum plasma concentration, mean time to reach maximum plasma concentration, and the mean area under the plasma concentration-time curve) were not statistically significantly different for the two formulations. It can be concluded that the two tablet preparations of glipizide are likely to be bioequivalent. (+info)
Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A, and intraarticular corticosteroids compared with sulfasalazine alone.
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OBJECTIVE: To determine whether a regimen of methotrexate, cyclosporin A, and corticosteroids introduced at onset in poor-prognosis rheumatoid arthritis (RA) can produce a significant improvement in outcome compared with standard monotherapy with sulfasalazine (SSZ). METHODS: Eighty-two consecutive patients presenting with new, untreated RA of less than 12 months' duration who fulfilled criteria for poor long-term outcome were randomized to receive either combination therapy (n = 40) or SSZ alone (n = 42). The primary outcome measures were remission and American College of Rheumatology (ACR) criteria for 20% improvement at 48 weeks. RESULTS: After 48 weeks, the numbers of patients who met the ACR criteria for 20% improvement were not significantly different between the two groups (combination 58% versus SSZ 45%), and similar numbers of patients had persisting clinical remission (approximately 10% both groups). During the first 3 months, there were significantly greater reductions in parameters of disease activity in the combination group. By 24 weeks, the swollen and tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates had fallen significantly in both groups, with a greater improvement in the swollen and tender joint count in the combination group. At 48 weeks, the radiographic damage score had increased by a median of 1 (range 0-42.5) in the combination group and 1.25 (range 0-72.5) in the SSZ group (P = 0.28; although there were significant differences in the scores for the right hand). There were significantly fewer withdrawals due to lack of efficacy in the combination group than in the SSZ group (1 of 40 versus 10 of 42; P = 0.007). In the combination group, dose reduction was needed in 22.5% because of hypertension and in 22.5% because of elevated creatinine levels. Over 48 weeks, serum creatinine increased in both groups, but particularly in the combination arm. CONCLUSION: In poor-prognosis RA patients, "aggressive" combination therapy led to more rapid disease suppression but did not result in significantly better ACR response or remission rates. This suggests that in poor-prognosis disease, an approach based on identifying patients with poor treatment responses before extra therapy is added ("step-up" approach) may be more appropriate than the use of combination therapy in all patients from the outset. (+info)
Modulation of inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in patients with active rheumatoid arthritis. Findings in a prospective, randomized, double-blind, parallel-design clinical trial in thirty-nine patients at two centers.
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OBJECTIVE: Leflunomide and methotrexate have proven to be efficacious in reducing joint inflammation and slowing destruction in clinical trials of patients with rheumatoid arthritis (RA). This study was conducted to provide more insight into the mechanism of action of these agents in synovial tissue. METHODS: In a 2-center, prospective, randomized, double-blind clinical trial, we compared leflunomide (20 mg/day, after a 3-day 100 mg/day loading dose) and methotrexate (increased stepwise to 15 mg/week) treatment in patients with active RA. Paired synovial tissue biopsy samples were obtained by knee arthroscopy at baseline and after 4 months of treatment. Frozen synovial tissue sections were stained for macrophages (CD68), T cells (CD3), adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], vascular cell adhesion molecule 1 [VCAM-1]), cytokines (tumor necrosis factor alpha, interleukin-1beta [IL-1beta]), matrix metalloproteinase 1 (MMP-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1). RESULTS: Paired synovial tissue sections were available in 35 patients (16 taking leflunomide, 19 taking methotrexate). Both drugs displayed equal clinical efficacy, with 8 leflunomide-treated patients (50%) and 10 methotrexate-treated patients (53%) fulfilling the American College of Rheumatology 20% response criteria. Both compounds showed similar effects on synovial tissue: reduced numbers of macrophages and reduced ICAM-1 and VCAM-1 expression were noted after 4 months of treatment. Both leflunomide- and methotrexate-treated patients exhibited a decreased MMP-1:TIMP-1 ratio in the synovial tissue. In the subset of patients fulfilling the 20% response criteria of the American College of Rheumatology, a more pronounced reduction in the expression of ICAM-1, VCAM-1, IL-1beta, and MMP-1 was found compared with the nonresponders. CONCLUSION: Leflunomide and methotrexate are clinically efficacious drugs that interfere with mechanisms involved in joint inflammation and destruction of joint integrity. (+info)
An area correction method to reduce intrasubject variability in bioequivalence studies.
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PURPOSE: This paper investigates the use of a corrected area (AUC*K) to compensate for intrasubject variability in bioequivalence studies. METHODS: Using computer simulation, this technique was applied to bioequivalence studies for two drugs. Both drugs exhibit first-order absorption and linear one-compartment disposition kinetics and total elimination by the liver. Drug I has a low intrinsic clearance (Cl(int)) and is not bound to blood components, while Drug II has a high Cl(int) and is highly bound. Two-way crossover trials, each including 24 subjects, were simulated using a spreadsheet program, which also performs ANOVA and provides 90% confidence intervals for C(max), AUC and AUC*K. The intrasubject CV for the parameter of interest was 30%. For all other pharmacokinetic parameters, the intrasubject CVs were 10%. RESULTS: Drug I: With high variability in Cl(int), AUC's were concluded to be bioequivalent in 335, 303, 222, 102 and 32 of 500 trials for mean difference in % absorbed (DeltaA = [A(test) -A(ref)]x100/A(ref)), -5%, -10%, -15% and -20% respectively. The corresponding numbers of trials that passed for AUC*K were 500, 500, 500, 382 and 23. Drug II: With high variability in Cl(int), 273, 281, 190, 106 and 29 of 500 trials passed for AUC at DeltaA of 0%, -5%, -10%, -15% and -20% respectively. The corresponding numbers that passed for AUC*K were 378, 351, 239, 113 and 38 trials. For both drugs, when high variability was assigned to V, area correction reduced the number of trials passing for AUC. When the same intrasubject %CV was assigned to both Cl and V, area correction resulted in no change (Drug I) or a decrease (Drug II) in the number of passing trials. Assigning high intrasubject %CV to DeltaA did not appear to alter the outcome of the simulation. CONCLUSION: Area correction appears to be helpful only when high intrasubject variability exists in clearance and not in the other parameters. It may be more helpful for drugs with low, compared to high Cl(int) since in the latter case variability in Cl(int) is reflected in both systemic clearance and bioavailability. It is recommended that area correction be attempted in bioequivalence studies of drugs where high intrasubject variability in clearance is known or suspected. It should be avoided where there appears to be a difference in K between treatments. The value of this approach in regulatory decision making remains to be determined. (+info)
Are the current bioequivalence standards sufficient for the acceptance of narrow therapeutic index drugs? Utilization of a computer simulated warfarin bioequivalence model.
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PURPOSE: The purpose of this computer simulation was to determine the likelihood of two bioequivalent (vs. reference) generic warfarin formulations (with varying bioavailability) passing current bioequivalence criteria against each other at varying bioavailability. Methods. A bioequivalence simulation program generated 100 warfarin bioequivalence (BE) studies with 24 patients/study. The reference formulation (R) was assigned a bioavailability of 90%. In these simulations the first generic (G(1)) had a bioavailability that was incrementally decreased from 90%. The second generic (G(2)) had a bioavailability that was incrementally increased from 90%. The bioequivalence testing was performed initially as G(1 )vs. R, then G(2) vs. R, and finally G(2) vs. G(1). The tests were performed according to current criteria for therapeutic index drugs. RESULTS: 5400 BE studies with a total of 129,600 subjects and 2,462,400 sampling times were simulated. When G(1) vs. R was compared, fewer than 80% of studies passed when the relative AUC(0-t )ratios were 88% or less. When G(2) vs. R were compared, fewer than 80% of studies passed when the relative AUC(0-t )ratios were 113% or greater. When Generic 2 and Generic 1 were compared fewer than 80% of studies passed when the relative AUC(0-t) ratios deviated from the reference by 7% or more. DISCUSSION Despite limitations this simulation indicates that two bioequivalent (vs. reference) generic warfarin products may not be bioequivalent to each other. Alternative methods of assessing bioequivalence are needed when more than one generic of narrow therapeutic index drug exists on the market. (+info)
Bioavailability of four ursodeoxycholic acid preparations.
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BACKGROUND: Ursodeoxycholic acid (UDCA) is the drug of choice for treating primary biliary cirrhosis and dissolving cholesterol gallstones. OBJECTIVES: The objective of this study was to compare the bioavailability of four commercially available ursodeoxycholic acid formulations in standardized doses. METHODS: Twenty-four healthy subjects were studied in groups of four, and received each of the different UDCA preparations in random order, with a 1-week washout or more in-between. Serum UDCA levels were determined for a 6-h period. The mean area under the curve (AUC), Cmax and Tmax were determined for each drug formulation, and the results compared. Dose proportionality was determined using the Canadian Ursofalk tablet using either 250 mg, 500 mg or 750 mg dosing. The intraparticipant variability was assessed by asking each participant to repeat the last drug that they took the second time, 1 week later. RESULTS: The mean AUC was 68.99 micromol/1.6 h-1 for the USA UDCA tablet, 59.34 micromol/1.6 h-1 for the Canadian UDCA tablet, 55.55 micromol/1.6 h-1 for Ursolvan capsules, and 46.66 micromol/1.6 h-1 for Actigall capsules. The mean Cmax values were 24.29, 17.85, 16.63 and 413.32 nmol/mL, respectively. The mean Tmax was 1.82, 2.3, 2.79 and 3.39 h, respectively. Linear aggression analysis assessing the direct proportionality of AUC on the dose for the Canadian UDCA tablet gave an estimate of 0.063 + 0.0164 (standard error, P-value=0.0117), e.g. if the dose increases from 250 mg to 500 mg, the serum ursodeoxycholic acid increases by 250 x 0.063=15.75. There was excellent reproducibility for the AUC for the North American tablets (0.97, 0.88) compared to the two capsules (0.32, 0.15). CONCLUSIONS: The significantly higher AUC and Cmax and shorter Tmax for the Canadian Ursofalk tablets compared to the UDCA capsule preparations supports better bioavailability. (+info)
Clinical and therapeutic profile of patients presenting with acute coronary syndromes who do not have significant coronary artery disease.The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators.
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BACKGROUND: A proportion of patients who present with suspected acute coronary syndrome (ACS) are found to have insignificant coronary artery disease (CAD) during coronary angiography, but these patients have not been well characterized. METHODS AND RESULTS: Of the 5767 patients with non-ST-segment elevation ACS who were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin (Eptifibatide) Therapy (PURSUIT) trial and who underwent in-hospital angiography, 88% had significant CAD (any stenosis >50%), 6% had mild CAD (any stenosis >0% to +info)
Clinical pharmacology of gatifloxacin, a new fluoroquinolone.
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Gatifloxacin is an advanced-generation, 8-methoxy fluoroquinolone that is active against a broad spectrum of pathogens, including antibiotic-resistant Streptococcus pneumoniae. The drug has high oral bioavailability (96%), and, therefore, oral and intravenous formulations are bioequivalent and interchangeable. Gatifloxacin has a large volume of distribution ( approximately 1.8 L/kg), low protein binding ( approximately 20%), and broad tissue distribution and is primarily excreted unchanged in the urine (>80%). Gatifloxacin can be administered without dose modification in patients with hepatic impairment, in women, and in the elderly. In vitro experiments and clinical studies indicate that gatifloxacin does not interact with drugs metabolized by the cytochrome P450 enzyme family. At therapeutically relevant doses, gatifloxacin's pharmacodynamically linked parameters (the ratio of maximum serum concentration to minimum inhibitory concentration and the ratio of the area under the curve to minimum inhibitory concentration) are similar to or better than those of other fluoroquinolones. Clinical studies show that gatifloxacin has limited potential to prolong the QT interval on the electrocardiogram and lacks the potential to cause photosensitivity reactions, to alter oral glucose tolerance, or to cause crystalluria. (+info)