Theophylline In Healthy Volunteers Research Articles

Gamma scintigraphic studies on guar gum-based compressed coated tablets for colonic delivery of theophylline in healthy volunteers

The purpose of the present study was the development and in vitro/in vivo evaluation of the guar gum-based colon-specific compression-coated tablet formulation of theophylline, which can be used for the treatment of nocturnal asthma. The core tablets containing 100 mg of theophylline were compression coated with various amounts of guar gum. The physical properties of the tablets were tested and in vitro release studies were performed. Samarium oxide (152-Sm) was added to the core tablet as the tracer. Scintigraphy was used to monitor the tablet's movement and distribution through the GI system of six healthy volunteers. In vivo scintigraphic studies showed that the tablets reached the colon at 5,6 and 8 h in three of the six subjects. Theophylline delivery to the terminal ileum or colon can be achieved and the theophylline-guar gum compression coated tablets may be a promising system for the treatment nocturnal asthma. But, more formulation work may be necessary for the determination of the exact coating thickness and the development of optimum formulation.

MK-0873, a PDE4 inhibitor, does not influence the pharmacokinetics of theophylline in healthy male volunteers

Background MK-0873 is a novel selective phosphodiesterase-4 inhibitor, which has been in development for the treatment of chronic obstructive pulmonary disease (COPD). In this indication, theophylline is still an important treatment, despite its relatively small therapeutic window. In view of this, it is important to investigate whether MK-0873 could affect the pharmacokinetics, safety and tolerability of theophylline, when both drugs are given concomitantly. Aim The objective of this study was to investigate the effect of multiple doses of oral MK-0873, a selective phosphodiesterase-4 inhibitor, on the pharmacokinetics, safety and tolerability profile of orally administered theophylline in healthy volunteers. Methods Eight healthy, non-smoking male subjects participated in this randomized, open-label, 2-period, cross-over study. In one period subjects received an oral dose of 2.5 mg MK-0873 for 6 days co-administered with a single oral dose of 250 mg theophylline on day 5. The other period consisted of a single dose of 250 mg theophylline on day 1. In each period, blood samples were collected at predefined time points to evaluate theophylline pharmacokinetics. Results All subjects completed the study. The study medications were generally well tolerated and no clinically relevant changes were observed in either treatment periods. No significant difference was found in the AUC 0–∞ (77.7 vs. 83.8 h ng/ml; p=0.280) and C max (6.70 vs. 7.77 ng/ml; p=0.125) of theophylline between the MK-0873+theophylline and theophylline only treatment, and bioequivalence was demonstrated for AUC0–∞ (geometric mean ratio with 90% confidence interval: 0.930 (0.826, 1.047)). Conclusion In this study, in a limited number of subjects, co-administration of oral MK-0873 did not affect the pharmacokinetics, safety, and tolerability of oral theophylline in non-smoking healthy male subjects.

Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers

Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia. Danshen extract and theophylline may be prescribed together to treat patients with asthma. In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2. In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product. There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers. Long-term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline. Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract. To examine the potential effect of danshen extract on the pharmacokinetics of theophylline. In a sequential cross-over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h. The 90% confidence interval of C(max), t(1/2) and CL/F of theophylline with 14-day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract. Danshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets.

Herb-Drug Interactions

Herbs are often administered in combination with therapeutic drugs, raising the potential of herb-drug interactions. An extensive review of the literature identified reported herb-drug interactions with clinical significance, many of which are from case reports and limited clinical observations. Cases have been published reporting enhanced anticoagulation and bleeding when patients on long-term warfarin therapy also took Salvia miltiorrhiza (danshen). Allium sativum (garlic) decreased the area under the plasma concentration-time curve (AUC) and maximum plasma concentration of saquinavir, but not ritonavir and paracetamol (acetaminophen), in volunteers. A. sativum increased the clotting time and international normalised ratio of warfarin and caused hypoglycaemia when taken with chlorpropamide. Ginkgo biloba (ginkgo) caused bleeding when combined with warfarin or aspirin (acetylsalicylic acid), raised blood pressure when combined with a thiazide diuretic and even caused coma when combined with trazodone in patients. Panax ginseng (ginseng) reduced the blood concentrations of alcohol (ethanol) and warfarin, and induced mania when used concomitantly with phenelzine, but ginseng increased the efficacy of influenza vaccination. Scutellaria baicalensis (huangqin) ameliorated irinotecan-induced gastrointestinal toxicity in cancer patients.Piper methysticum (kava) increased the 'off' periods in patients with parkinsonism taking levodopa and induced a semicomatose state when given concomitantly with alprazolam. Kava enhanced the hypnotic effect of alcohol in mice, but this was not observed in humans. Silybum marianum (milk thistle) decreased the trough concentrations of indinavir in humans. Piperine from black (Piper nigrum Linn) and long (P. longum Linn) peppers increased the AUC of phenytoin, propranolol and theophylline in healthy volunteers and plasma concentrations of rifamipicin (rifampin) in patients with pulmonary tuberculosis. Eleutheroccus senticosus (Siberian ginseng) increased the serum concentration of digoxin, but did not alter the pharmacokinetics of dextromethorphan and alprazolam in humans. Hypericum perforatum (hypericum; St John's wort) decreased the blood concentrations of ciclosporin (cyclosporin), midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline, but did not alter the pharmacokinetics of carbamazepine, pravastatin, mycophenolate mofetil and dextromethorphan. Cases have been reported where decreased ciclosporin concentrations led to organ rejection. Hypericum also caused breakthrough bleeding and unplanned pregnancies when used concomitantly with oral contraceptives. It also caused serotonin syndrome when used in combination with selective serotonin reuptake inhibitors (e.g. sertraline and paroxetine). In conclusion, interactions between herbal medicines and prescribed drugs can occur and may lead to serious clinical consequences. There are other theoretical interactions indicated by preclinical data. Both pharmacokinetic and/or pharmacodynamic mechanisms have been considered to play a role in these interactions, although the underlying mechanisms for the altered drug effects and/or concentrations by concomitant herbal medicines are yet to be determined. The clinical importance of herb-drug interactions depends on many factors associated with the particular herb, drug and patient. Herbs should be appropriately labeled to alert consumers to potential interactions when concomitantly used with drugs, and to recommend a consultation with their general practitioners and other medical carers.

Lack of Effect of Gemifloxacin on the Steady-State Pharmacokinetics of Theophylline in Healthy Volunteers

Gemifloxacin is a novel fluoroquinolone, currently in development for the treatment of respiratory tract infections. This double-blind (with respect to gemifloxacin), randomized, crossover study investigated the possibility of pharmacokinetic interaction between gemifloxacin and theophylline. After a 4–8-day run-in phase to establish the dose of theophylline required to achieve a trough plasma concentration range of 8–15 mg/l, 15 healthy volunteers entered a randomized treatment phase. Volunteers then received oral theophylline, 300–400 mg twice daily, for 22 days. On days 5–11 and 16–22, they also received either placebo or gemifloxacin, 320 mg p.o. once daily, in a crossover fashion. Blood samples were collected up to 12 h after the morning dose of theophylline on days 11 and 22. Theophylline pharmacokinetics were not affected by the co-administration of gemifloxacin. The maximum plasma concentration (C_max) for theophylline ranged from 8.12 to 17.71 mg/l and from 8.79 to 16.35 mg/l during concomitant administration with gemifloxacin and placebo, respectively. The corresponding ranges of the area under the plasma concentration-time curve from time zero to the last quantifiable plasma concentration (AUC_(0–12)) were 84.6–177.5 mg·h/l and 94.8–165.1 mg·h/l during gemifloxacin and placebo administration, respectively. The point estimates (90% confidence intervals) for dose-normalized AUC_(0–12) and C_max (theophylline + gemifloxacin):(theophylline + placebo) were 0.99 (0.93, 1.05) and 1.02 (0.93, 1.11), respectively, which were entirely within the equivalence range (0.80, 1.25). The co-administration of gemifloxacin and theophylline was well tolerated, with no clinically significant changes seen in vital signs, 12-lead electrocardiogram readings or laboratory parameters. Adverse events were generally transient, mild to moderate in nature and similar during the gemifloxacin and placebo treatment periods. In conclusion, theophylline and gemifloxacin may be co-administered without any adjustment in theophylline dose.

Performance of a Modified Starch Hydrophilic Matrix for the Sustained Release of Theophylline in Healthy Volunteers

Two experimental formulations of theophylline with a hydrophilic starch matrix were evaluated for their sustained-release characteristics after single administration in healthy human volunteers. Theo-dur was chosen as a reference sustained-release formulation. In a first study, the extent of absorption was similar for a syrup, for Theo-dur, and for the experimental formulation of theophylline with 70% drum-dried corn starch as the sustained-release agent (DDCS-70). The maximal plasma concentration (Cmax was significantly lower, and the time to reach Cmax as well as the time span during which the plasma concentration was at least 75% of the Cmax were significantly higher for Theo-dur than for the DDCS-70 formulation. A sustained-release profile, as for Theo-dur, was not reached for DDCS-70. In a second study the influence of the starch:drug ratio on the bioavailability was investigated. The decrease in starch content from 70 to 50% of the formulation did not improve the plasma concentration-time profile towards a sustained-release profile.

Effect of piperine on bioavailability and pharmacokinetics of propranolol and theophylline in healthy volunteers

The effect of piperine on the bioavailability and pharmacokinetics of propranolol and theophylline has been examined in a crossover study. Six subjects in each group received a single oral dose of propranolol 40 mg or theophylline (150 mg) alone or in combination with piperine 20 mg daily for 7 days. An earlier tmax and a higher Cmax and AUC were observed in the subjects who received piperine and propranolol. It produced a higher Cmax, longer elimination half-life and a higher AUC with theophylline. In clinical practice, the enhanced systemic availability of oral propranolol and theophylline could be exploited to achieve better therapeutic control and improved patient compliance.

Influence of Mexiletine on the Pharmacokinetics of Theophylline in Healthy Volunteers

Preliminary reports suggest an interaction exists between theophylline and mexiletine. We conducted a two-way crossover study in 15 healthy male subjects to assess the magnitude of the pharmacokinetic interaction between mexiletine and theophylline. Twelve subjects completed 5 days of therapy on sustained-release theophylline 200 mg every 12 hours alone and 5 days of therapy with theophylline and mexiletine 150 mg every 8 hours. The two treatment periods were separated by a minimum of 7 days. On the morning of day 5 of each treatment period, blood samples for theophylline to be assayed by fluorescence immunoassay were collected over 24 hours. Mexiletine significantly increased the mean AUC, Cmax, t1/2 beta, and Cl of theophylline. Mexiletine did not affect tmax or Vd. Side effects occurred in 4 subjects during treatment with theophylline alone all of which were judged to be mild in intensity. During concomitant theophylline-mexiletine therapy, 10 subjects reported side effects of which 4 were judged to be severe, 1 moderate, and 5 mild. The magnitude of the increase in theophylline plasma concentrations induced by mexiletine as measured by AUC (0-24) was 58%, which is similar to other preliminary reports of this interaction. The authors conclude that the magnitude of the pharmacokinetic interaction between theophylline and mexiletine may be clinically significant in patients in light of the increased incidence of side effects in our healthy subjects. Theophylline dosage adjustments will be required in patients who receive concomitant mexiletine therapy.

The influence of ofloxacin and enoxacin on the metabolic pathways of theophylline in healthy volunteers. A pilot study.

The pharmacokinetic parameters of theophylline and its major metabolites were measured in two healthy volunteers, after the administration of theophylline alone and during co-medication with ofloxacin, 200 mg twice daily, or enoxacin, 200 mg twice daily. During enoxacin co-medication, elimination half-lives of theophylline increased from 8.7 h to 17.4 h and from 6.1 to 12.3 h, respectively. As the renal clearance of theophylline did not change, the decreased elimination of theophylline during enoxacin co-medication must result from a reduced metabolic clearance. Enoxacin co-medication caused a clearly decreased formation of the metabolites 1-methyluric acid and 3-methylxanthine, formed by N-demethylation, whereas the C-8 oxidation of theophylline was less influenced compared to the blank. Enoxacin's interference with the theophylline disposition is predominantly based on the inhibition of the microsomal N-demethylation. Ofloxacin co-medication did not induce a change in the plasma parameters or renal excretion of theophylline and its metabolites.