[Comparative studies on the tolerance of bioequivalent doses of intravenous methylxanthine preparations in healthy subjects]. / Vergleichende Untersuchungen zur Verträglichkeit bioäquivalenter Dosen intravenöser Methylxanthin-Zubereitungen bei gesunden Probanden.

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)

Dyphylline versus theophylline: a double-blind comparative evaluation.

This study was a randomized double-blind evaluation of three doses of dyphylline, theophylline, and placebo for blocking exercise-induced bronchospasm (EIB). Twenty patients aged 12 to 17 years took one of the following on five separate days prior to an exercise challenge: 10, 15, or 20 mg/kg dyphylline; 6 mg/kg anhydrous theophylline; or placebo. Linear relationships were found between the log of dyphylline doses and per cent changes from baseline for PEFR, FEV1 and FEF25-75%. The 15 and 20 mg/kg doses differed significantly from placebo in preventing declines in PEFR, FEV1, and FEF25-75%. While significant, these changes were one half to one third those found with 6 mg/kg theophylline. Tremor was twice as common with theophylline. While dyphylline has therapeutic effectiveness compared to placebo for blocking EIB, its benefit is small. Further evaluations are needed to elucidate optimal dosaging for maximal effectiveness.

Effect of probenecid on dyphylline elimination.

Dyphylline is a methylxanthine bronchodilator with such a short a biologic t 1/2 that development of practical dosing regimens has been difficult. Because its rapid renal elimination suggests active secretion, the effect of 1 gm probenecid on single-dose elimination kinetics of dyphylline was determined. Twelve subjects (six male, six female) participated in a crossover design. Subjects were their own controls and received dyphylline, 20 mg/kg orally, alone and after probenecid. The dyphylline t 1/2 increased from 2.57 +/- 0.45 to 4.88 +/- 1.2 hr, whereas the elimination rate constant decreased from 0.276 +/- 0.056 to 0.150 +/- 0.037 hr-1 after probenecid. There was no significant change in the dyphylline apparent volume of distribution. Dyphylline total body clearance fell from 173 +/- 20 to 95 +/- 12 ml/kg . hr. The combined use of these drugs may lead to a practical dyphylline dosage schedule in aminophylline-hypersensitive patients or those incapacitated by theophylline gastrointestinal side effects.

Dyphylline aerosol can induce bronchospasm in human asthmatics.

Dihydroxypropyl theophylline (dyphylline) was administered by aerosol in a single dose of 250 mg aerosolized over five minutes to two asthmatic volunteers and in a single dose of 375 mg aerosolized over ten minutes to two other asthmatic volunteers. Serial spirometry was then performed. Marked bronchospasm occurred within ten minutes in two of the subjects, and developed more slowly in another. One subject demonstrated no significant change. Aerosolized dyphylline solution was not an effective bronchodilator, using the methods described in this study.