Assessment of combined oral theophylline and inhaled beta‐adrenoceptor agonist bronchodilator therapy.

Abstract

1. The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol, 375 mg oral theophylline and both drugs in combination were compared in a randomized, placebo‐controlled, double‐blind trial in eight patients with chronic, partially reversible airways obstruction. 2. The four treatments were (i) oral theophylline, placebo aerosol (TP); (ii) oral placebo, rimiterol aerosol (PR); (iii) oral theophylline, rimiterol aerosol (TR) and; (iv) oral placebo, placebo aerosol (PP). The aerosol was administered 2 h after the oral treatment. 3. Significant bronchodilatation (% FEV1 change from control) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min, whereas with PR only for 45 min (P less than 0.05). 4. The mean, peak % FEV1 increases from control were 51.8% at 125 min, 31.7% at 125 min, 26.1% at 210 min and 0.9% at 30 min for TR, PR, TP and PP respectively. 5. At 125 min (5 min after aerosol inhalation) the mean % FEV1 change from control with TR (51.8%) Was significantly greater than with PR (31.7%), TP (22.2%) (P less than 0.05) and PP (− 2.4%) (P less than 0.01). 6. The mean, peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively. Theophylline half‐life ranged between 4.3 and 12.5 h (mean +/‐ s.e. mean, 8.0 +/− 0.8 h). 7. Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved.

On the action of combination bronchodilators

“…A higher frequency of side effects was observed qualitatively with use of the combination or terbutaline, as compared to oxtriphylline. Similar results were obtained from a study by MARLIN et al [60] where theophylline was combined with another specific beta2-bronchodilator, rimiterol. These authors demonstrated that oral theophylline interacted with aerosolized rimiterol in an additive fashion to reverse bronchospasm in eight asthmatics.…”

Theophylline‐salbutamol interaction: bronchodilator response to salbutamol at maximally effective plasma theophylline concentrations.

“…Its possible interaction with f2-adrenoceptor agonists has not yet been fully explored either at molecular level (Miech & Lohman, 1975;Trembath & Shaw, 1978) or in patients with airways narrowing. Conventional doses have been shown to have some additive effect when combined in asthmatics (Campbell, Middleton, Mackenzie, Shetter, McHardy & Kay, 1976;Wolfe, Tashkin, Calvarese & Simmons, 1978;Marlin, Hartnett & Berend, 1978) but these studies are incomplete since they ignore both individual differences in response and in theophylline clearance. The majority of patients attending our clinic have severe chronic bronchitis, leading to considerable loss of time from work.…”

Serum level monitoring of a new slow release theophylline formulation in patients with chronic lung disease.

“…Both single dose and steady state pharmacokinetic studies have been performed with these formulations and indicate that approximate peak serum theophylline levels will occur at 2 h with rapid release and 4 to 6 hs with slow release theophylline (Marlin, Hartnett, Berend & Hacket, 1978;McDevitt, Elwood & Russell, 1979;Svedmyr et al, 1979). Although both interpatient and intrapatient variability in the rate of drug absorption will occur, it is considered that these sampling times would provide an estimate of peak serum theophylline for a clinical monitoring survey in a large group of patients when a single sampling time is desirable practice.…”