• 5
    Mar
  • Theophylline and Antiparasitic Drug Interactions: METHODS

Six nonsmoking, adult, male volunteers participated in the study. Each subject was judged to be in good health on the basis of a physical examination, clinical laboratory testing, and ECC. These data can be found in lable 1. The study was an open label, randomized, crossover design. All subjects signed an informed consent approved by the institutional review committee.

Aminophylline (25 mg/ml for injection), thiabendazole (500-mg chewable tablets, Mintezol) and mebendazole (100-mg tablets, Vermox) were used.

Phase 1

Subjects abstained from alcohol and methylxanthine-containing food and beverages for 48 h prior to the aminophylline infusion. Utilizing an IMED infusion pump (IMED Corp, San Diego, CA) a 6 mg/kg intravenous dose of aminophylline was administered over 30 min in all subjects.

Blood samples were collected prior to the aminophylline infusion and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24 and 30 h after completion of the infusion.

Phases 2 and 3

Following a one-week washout period, subjects were randomized to receive either thiabendazole or mebendazole. Thiabendazole, 1.5 g, or mebendazole, 100 mg, was taken orally (every 12 h) for six doses. The aminophylline infusion and sampling period were repeated 1 h after the fourth dose of thiabendazole or mebendazole, as described in the baseline phase. After this phase, the subjects were then crossed over to receive the other therapy. Blood sampling and aminophylline infusion were repeated as described in phase 1.
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Table 1—Subject Demographics

Subject

Age (yr)

Weight (kg)

Height (cm)

1

28

71.4

177.8

2

24

66.4

172.7

3

29

69.5

168.9

4

27

74.0

179.1

5

26

66.8

180.3

6

34

69.5

172.7

Mean±SD

28±3

69.6 ±2.8

175.2 ±4.5

Sample Analysis

Plasma samples were analyzed for theophylline by a modified reverse phase, HPLC technique. A Waters C-18 column and Waters model 440 UV absorbance detector (wavelength 280 nm) were utilized (Waters Corp, Milford, MA). Column elution was carried out with a flow rate of 1 ml/min prepared in pooled human serum ranging in concentration from 1.4 to 112 jimol/L (0.25 to 20 mg/L). The standard curve was linear and reproducible within this range. Unknown concentrations were determined by a peak-height ratio technique. The sensitivity limit was 1.4 |imol/L (0.25 ^g/ml). Reproducibility measurements yielded inter-day variability of 3 to 6 percent.

Pharmacokinetic Analysis

The decline in the theophylline postdistributive plasma concentrations for all subjects was monoexponential, characterized by a one-compartmental model. The independent pharmacokinetic parameters of clearance and volume of distribution were modeled using an iterative least-squares program.

Table 2—Effect of Thiabendazole and Mebendazole on Mean (SD) Pharmacokinetic Barometers cf Theophylline after Intravenous Administration

Baseline

Thiabendazole

Mebendazole

Parameter

(n = 6)

(n = 3)

(n = 6)

p Value

Cl (L/h/kg)

0.067 (0.016)

0.023 (0.006)*

0.060 (0.024)

0.0032

Vd (L/kg)

0.63 (0.042)

0.59 (0.083)

0.67 (0.035)

0.0468

K(h”‘)

0.11 (0.027)

0.039 (0.010)*

0.090 (0.032)

0.0028

tl/2 (h)

6.72 (1.47)

18.60 (5.63)*

8.43 (2.57)

0.0016

С max (mg/L)

9.36 (0.52)

10.27 (1.49)

8.80 (0.52)

0.0270

Statistical Analysis

Statistical analysis of the resultant kinetic parameters was performed utilizing a univariate two-way ANOVA accounting for subject and treatment effects (Table 2). An alpha level of less than 0.05 was considered significant. When a significant difference was detected, Tukey s multiple range test was used for comparisons among means. Cialis Jelly

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