Comparative steady-state bioavailability of sustained-release theophylline preparations: Theo-Dur, Uni-Dur and Xanthium.

Steady-state bioavailability of sustained-release theophylline (SRT); Theo-Dur, Uni-Dur and Xanthium were compared in 10 healthy males with theophylline clearance ranged from 0.3 - 0.8 ml/min/kg. Each of 400-mg SRT was administered once daily before breakfast for 7 consecutive days, one-week washout period in a crossover fashion. Serial blood samples were collected over 24 hours on days 6 and 7. Serum theophylline concentrations were determined by fluorescence polarized immunoassay. We found that the oral bloavailability relative to Franol (%F [90% CI]) of Theo-Dur, Uni-Dur and Xanthium were 97 (93-106), 85 (79-96) and 77 (72-87), respectively. Average bioequivalence revealed that the Css(min) (microg/ml) of Uni-Dur (5.07) was higher than Theo-Dur (4.29), and Xanthiume (4.18), while the Css(max) and Css(av) (microg/ml) of Theo-Dur (11.02, 7.87) were statistically higher than Uni-Dur (8.51, 6.91) and Xanthium (7.65, 6.27). The extent of absorption assessed by AUCss(0.24) of Theo-Dur was significantly greater than Uni-Dur and Xanthium. However, fluctuation index (% FI) of Theo-Dur (232) was twofold higher than Uni-Dur (137) and Xanthium (113). The median Tss(max) of Uni-Dur was 12 hours which was significantly longer than Xanthium (7 hours) and Theo-Dur (8 hours). There were no statistically significant differences between Uni-Dur and Xanthium regarding bioavailability, Css(max), Css(av) as well as % FI. Moreover, 400 mg OD of Uni-Dur and Xanthium are suitable for subjects with a theophylline clearance of 0.3-0.55 ml/min/kg while 400 mg OD Theo-Dur can be used in subjects with slower clearance rates of 0.3-0.39 ml/min/kg. Subjects with rapid theophylline clearance rates of 0.65-0.8 ml/min/kg required a higher dose of theophylline and twice-daily dosing was more appropriate.

Bioequivalence study of generic atenolol tablets in healthy Thai volunteers.

Two preparations of 50 mg and 100 mg atenolol tablets were evaluated for their bioequivalence in twelve healthy Thai subjects (Prenolol, Berlin Pharmaceutical Industry, as the test formulations vs Tenormin, Zeneca Limited, as the reference formulations). A single oral dose of each preparation was administered in a randomized two-way crossover design, starting from either 50 mg of Prenolol vs Tenormin, thereafter, either 100 mg of Prenolol vs Tenormin. The washout period between each treatment was one week. Atenolol plasma concentrations were determined by the HPLC technique with fluorometric detection. Pharmacokinetic parameters were analyzed by the noncompartmental pharmacokinetic method using TOPFIT. The means and parametric 90 per cent confidence intervals of the ratio [Prenolol/Tenormin] of AUC0-infinity and Cmax were 1.16 (1.05-1.27) and 1.23 (1.07-1.38) for 50 mg preparations and 1.10 (1.00-1.20) and 1.13 (0.95-1.31) for 100 mg preparations, respectively. These values were well within the acceptable bioequivalence ranges. The mean differences of Tmax [Prenolol-Tenormin] were less than 20 per cent for both 50 mg and 100 mg preparations. Hence, Prenolol and Tenormin were bioequivalent with respect to the rate and extent of absorption.

Pharmacokinetics and bioavailability studies of generic ondansetron, and the innovator preparation, in healthy Thai male volunteers.

The pharmacokinetics and bioequivalence of two oral formulations of ondansetron were evaluated; Zetron (Biolab Pharmaceutical, Bangkok, Thailand), as the test formulation and Zofran (Glaxo Wellcome Operations, Greenford, UK), as the reference formulation. The two products were administered as a single oral dose of 8 mg according to a randomized two-way crossover design to 12 healthy Thai male volunteers. The washout period between treatment was 1 week. Ondansetron plasma concentrations were measured using HPLC. The oral bioavailability of ondansetron averaged 67 per cent and the elimination half-life after oral administration was 5.6 hours. The means and parametric 90 per cent CI of the ratios of Cmax and AUC 0-alpha [mu Zetron (Test)/mu Zofran (Reference)] were 0.95 (0.84-1.07) and 0.94 (0.80-1.10), respectively. These values were well within the bioequivalence range of 0.8-1.25 as established by the US-FDA. The mean difference of Tmax (Test-Reference) was approximately 20 per cent. Thus, our study demonstrated bioequivalence of the two products (Zetron and Zofran) regarding the rate and extent of absorption.

Comparative studies of quality and bioavailability of methotrexate in Thai patients with rheumatoid arthritis.

The bioavailability of the two generic methotrexate oral preparations (Emtrexate, Pharmachemie Company, Holland and Methotrexate Remedica, Remedica, Cyprus as the test preparations), were compared to the innovator (Methotrexate Lederle, Lederle, U.S.A. as the reference) in 10 patients with rheumatoid arthritis. A single 7.5 mg oral dose of each preparation was given to the subjects in a randomized, double-blind, three-period crossover design with a 1 week washout period. Serum methotrexate concentrations were determined by using Fluorescence Polarization Immunoassay (Abbott TDx). No significant differences in pharmacokinetic parameters (AUC, Cmax, and Tmax) were observed between the test and reference preparations. The mean and 90 per cent CI of the ratio Emtrexate/Methotrexate Lederle and Methotrexate Remedica/Methotrexate Lederle of the Cmax, AUC0-8, and AUC0-alpha were 0.93 (0.87-1.00), 0.9 (0.82-0.98), 0.88 (0.79-0.99) and 0.97 (0.93-1.02), 0.95 (0.90-0.99), 0.94 (0.86-1.02), respectively. These values were well within the acceptable bioequivalence range of 0.8-1.25. The mean and 90 per cent CI of Tmax difference between Emtrexate-Methotrexate Lederle and Methotrexate Remedica-Methotrexate Lederle also overlapped the stipulated bioequivalence range of the Tmax differences of +/- 0.25 hour. Thus, Emtrexate and Methotrexate Remedica were considered bioequivalent to the reference Methotrexate Lederle regarding the rate of absorption and the extent of absorption.

The comparative bioavailability of a generic and the innovator fluconazole preparations in healthy Thai volunteers.

We studied the pharmacokinetics and compared the oral bioavailability of the "generic" (Biozole, Biolab Company, Thailand) and the "innovator" (Diflucan, Pfizer Incorporation, U.S.A.) fluconazole preparations in 12 healthy Thai volunteers. A 200 mg single oral dose of each preparation was given to the subjects in a randomized double-blind 2-period crossover design with 2 weeks washout period. Blood samples were collected just before and at 0.5, 1, 2, 2.5, 3, 4, 24, 48, 56 and 72 hours after drug administration. Serum fluconazole concentrations were determined by using high performance liquid chromatography. Individual concentration-time profiles and the pharmacokinetic parameters were analyzed by the noncompartmental pharmacokinetic method [TOPFIT, a pharmacokinetic data analysis program]. The pharmacokinetic parameters (Tmax, Cmax, Vd, Cl) of fluconazole in Thai healthy volunteers were comparable to those values observed in Caucasian subjects. The relative bioavailability of the generic Biozole was 102.38 +/- 9.79 per cent of Diflucan. The means and 90 per cent confidence intervals (90% CI) of the [Biozole/Diflucan] ratio of AUC0-72, AUC0-inf and Cmax were 1.02 (0.98-1.06), 0.99 (0.95-1.03) and 1.13 (1.03-1.25), respectively. These values were well within the acceptable bioequivalence ranges of 0.8-1.25 proposed by the US FDA. The means and 90 per cent CI of Tmax differences [Biozole-Diflucan] were -0.46 [(-1.03)-(0.12)]. This value was outside the stipulated bioequivalence range of +/- 0.41 h (+/- 20% of the Tmax of the reference formulation). Nevertheless, the Tmax difference was not expected to be related to the differences in safety and efficacy of the drug. Hence, Biozole and Diflucan were bioequivalent with respect to the extent of absorption (AUC), and the Cmax, and could be used interchangeably.

Evaluation of threshold criteria for the nasal histamine challenge test in perennial allergic rhinitis.

Nasal reactivity to histamine was determined in patients with perennial allergic rhinitis and in control subjects. A histamine titration method delivered by a metered dose pump was used. Stuffiness, itching, and the number of sneezes were recorded, nasal secretions measured, and nasal airway resistance was recorded by active anterior rhinomanometry. Increased nasal reactivity to histamine was observed among rhinitic patients and inversely correlated with the severity of nasal symptoms. A 3-fold increase of post-saline nasal airway resistance (NAR) best differentiated the nasal responses to histamine in rhinitic patients from those in control subjects. A histamine dose of < or = 2.5 microg provoked a 3-fold increase in NAR, strongly suggesting moderate or severe symptomatic rhinitis in most cases. Nasal provocation techniques might be a useful tool for objectively assessing disease severity and response to treatment in perennial allergic rhinitis.

A single-dose comparison of three slow-release theophylline oral preparations in healthy Thai volunteers.

The study was done to compare the pharmacokinetic characteristics of three slow-release theophylline (SRT) preparations. Twelve healthy nonsmokers were randomly assigned a single dose of the following treatments at weekly intervals: Theo-Dur, Theo-24 or Xanthium orally, or aminophylline intravenously. Serially collected serum samples were analyzed for theophylline with use of fluorescence polarization immunoassay (FPIA). All three SRT preparations showed reliable absorption characteristics, but Theo-Dur had a shorter Tmax and MRT and a higher Ka. The pharmacokinetic characteristics of Theo-24 and Xanthium were similar except that Xanthium had lower bioavailability. Using single dose data for simulation of steady state pharmacokinetics, we found that a once-a-day dosage regimen with either Theo-24 or Xanthium would maintain serum levels within the therapeutic range for average non-smoking young adults whereas more frequent dosing intervals with Theo-Dur would be more appropriate. Our results argue against open substitution of SRT preparations without, close monitoring of the serum theophylline concentrations when a change is made.

Pharmacokinetics of oral lidocaine and nifedipine in patients with liver cirrhosis.

The pharmacokinetics of oral lidocaine and nifedipine and hemodynamic effects of nifedipine were studied in 10 cirrhotic patients and 10 healthy volunteers. In a randomized two-way crossover design, each subject received 50 mg of lidocaine solution and 10 mg capsule of nifedipine with one-week washout period. After oral lidocaine, cirrhotic patients has a longer time to peak concentration (Tmax) and elimination half-life (t1/2), and a higher area under the curve (AUC). There were no significant differences in peak plasma concentration (Cmax) and elimination rate constant (K(el)) in the two groups. After oral nifedipine, cirrhotic patients had a longer elimination t1/2, lower K(el) and higher AUC. At peak concentration in cirrhotic patients, there was more decrease in the systolic blood pressure and less increase in heart rate. Although large interindividual variability existed in this study, pharmacokinetic parameters were considerably altered in cirrhotic patients.

A comparison of serum magnesium sulfate levels in pregnant women with severe preeclampsia between intravenous and intramuscular magnesium sulfate regimens: a randomized controlled trial.

The frequency of blood samples that achieved therapeutic level was lower in the group of maintenance with intravenous regimen than the intramuscular regimen significantly at 15, 30, 60, 120 and 240 minutes after loading dose. The mean level of serum magnesium sulfate in the intravenous group was significantly lower than intramuscular group. This study supported to choose the maintenance by intramuscular regimen. However, further study is required to analyse the effect of higher level of magnesium sulfate in Thai patients.