S. H. D. Jackson

The relationship between theophylline clearance and age in adult life.

SummaryFifty three subjects (31 normal volunteers and 22 patients with asthma) between the ages of 20 and 87 years had their theophylline clearance measured. Volume of distribution (V) and terminal elimination half-life (t1/2) were also calculated in the volunteers who received i.v. theophylline.Although patients tended to have higher clearance values than volunteers, in both groups the oldest third had the lowest clearances. For the combined group (corrected for the patient effect) the oldest third (mean age 70 years) had a mean clearance of 0.53 versus 0.72 for the middle third (mean age 47 years) and 0.73 ml/min/kg CBW for the youngest third (mean age 26 years). There was no statistically significant age related change in V/kg CBW but t1/2 did rise with increasing age.Thus, although clearance does not fall with increasing age during younger adult life, there is a fall during late adult life becoming apparent in the seventh, eighth and ninth decades.

A comparison of the haemodynamic effects of nifedipine, nisoldipine and nitrendipine in man

SummaryNifedipine (10 mg), nisoldipine (10 mg) and nitrendipine (20 mg) were given orally to 8 normal volunteers in a placebo controlled, double blind, crossover study.Blood pressure (BP), pulse (P) and systolic time intervals (STI) were recorded at time 0, 30, 60, 90, 120 min after drug administration. Adverse effects were also recorded.There was a fall in BP, pre-ejection time (PEP), PEP/LVET (left ventricular ejection time) and electro-mechanical systole index (QS2 index), and a rise in LVET index in response to the three active drugs compared with placebo.All active drugs, but not placebo, were associated with adverse effects.

Indomethacin does not attenuate the effects of hydralazine in normal subjects

SummaryIndomethacin 100 mg/day or matching placebo was given for 2.5 days to 9 healthy volunteers in a double-blind cross-over study, followed by an intravenous injection of 0.2 mg/kg of hydralazine. Compared to placebo, indomethacin produced no statistically significant change in pulse rate or blood pressure in both standing and supine positions. Hydralazine injection was followed by a statistically significant fall in lying and standing diastolic pressure and a rise in lying and standing pulse after both indomethacin and placebo pretreatments. There were no significant differences in these effects following indomethacin compared to placebo pretreatment. These results do not support the hypothesis that endogenous prostaglandins are involved in the mechanism of action of hydralazine.

The relationship between clearance of theophylline and age within the adult age range

SummaryTwenty volunteers aged between 20 and 57 years were given 197 mg of theophylline (as lysine theophylline) by iv infusion over 5 minutes to test the hypothesis that within the adult age range theophylline clearance declines with age. Samples were assayed for theophylline using the EMIT assay and clearance was determined by standard methods. Clearance values were 0.73 ml/min/kg below age 38 years and 0.75 ml/min/kg at and above age 38 years. Multiple regression analysis using age as a continuous variable showed no relationship between age and clearance.

Methods of comparing pharmacokinetics of slow release preparations: a comparison of “Theo-Dur” and “Phyllocontin” in patients with asthma

SummaryThe pharmacokinetics of two slow release theophylline preparations “Theo-Dur” (T) containing theophylline only and “Phyllocontin” (P) containing aminophylline have been compared in 12 patients with asthma. Each patient received both treatments in random order. The dose of treatment administered 12 hourly was increased or decreased to produce plasma theophylline concentrations of 10–20 mg/l at clinic visits normally 7 to 8 h after dosing. Pharmacokinetic studies were carried out after at least one weeks treatment with this dose. After the first study day patients were crossed over to the second treatment at a dosage providing a similar amount of theophylline. They returned for a second study day after at least one week. Comparison of the dose corrected AUC, time to peak concentrations, within patient coefficients of variation (CV), number of concentration time points falling within 25% of Cmax and percentage fluctuations in plasma concentration showed no significant differences between the two preparations.

Comparison of Effects of Lysine Aspirin, Soluble Aspirin and Conventional Aspirin on Buccal Potential Difference in Healthy Volunteer Subjects

The effects of aspirin, soluble aspirin and lysine aspirin on buccal mucosal potential difference (p.d.) were compared in a double-blind trial. Placebo and three doses of each preparation containing 150, 300 and 600 mg of aspirin were allocated according to a latin square design. Six volunteer subjects were studied; each received a total of 10 treatments at least 24 h apart. All doses of each preparation considered, a significant treatment effect was seen [F (d.f. = 2,306) = 6.2, P<0.003]. Lysine aspirin showed the least effect of the active treatments on buccal p.d. with a change from baseline of +8.5 mV compared with +13.3 for soluble aspirin +14.4 for conventional aspirin and —5.2 mV for placebo.

The disposition of inhaled lysine theophylline in volunteers.

SummarySix healthy volunteers received an iv infusion of 317 mg lysine theophylline (equivalent to 197 mg anhydrous theophylline) in order to calculate theophylline clearance by standard methods. They subsequently received a 20 minute inhalation of nebulised lysine theophylline. Serum and salivary theophylline concentrations were measured and all saliva was collected for the first hour. From these concentrations estimates were made of the distribution of theophylline into the blood and saliva with 40% to 94% identified in the blood. Very high salivary concentrations were reached during the inhalation phase with saliva: serum concentration ratios of between 60 and 1600.