Comparative studies on the tolerance of bioequivalent doses of intravenous methylxanthine preparations in healthy subjects

: In a comparative tolerance study with two different intravenous methylxanthine preparations, a theophylline-ethylendiamine preparation (TE-reference preparation) was tested against a combination of theophylline, proxyphylline (7-(2-hydroxypropyl)-theophylline) and diprophylline (7-(2,3-dihydroxypropyl)-theophylline) (Neobiphyllin; TPD = test preparation) in 10 healthy volunteers by a single blind cross-over design. Both preparations were infused under continuous control of vital parameters (blood pressure, pulse, respiration frequency, heart rhythm) as infusions (1 ampoule with 800 mg TPD or 1 short-infusion with 480 mg of TE for 20 min, each) up to the individual tolerance limit or the pre-defined limit of 3 ampoules/short infusions, respectively. The maximum tolerated infusion time and the serum levels at which the first side-effects appeared, were compared. These maximum doses could be administered to 6 volunteers under TPD, but only to two under medication with the reference preparation. Side-effects under TPD occurred in 5, after infusion of the reference preparation in 9 volunteers. Serum levels of theophylline at the end of the infusion period reached (14.6 +/- 4.21 (TPD) and 23.01 +/- 6.02 mg/l (TE), respectively. The average infusion time for the test preparation was 54.8, for the reference preparation 46.2 min. The average serum theophylline levels of the 5 volunteers with side-effects under TPD reached--when these side-effects occurred --11.26 +/- 4.52 mg/l; the same volunteers showed after administration of TE levels of 14.94 +/- 7.49 mg/l. Our results showed an approx. additive effect of the side-effects together with an--according to literature--over-additive pharmacological effect of the single components of TPD.(ABSTRACT TRUNCATED AT 250 WORDS)