Saliva Theophylline Concentrations Research Articles

テオフィリンの唾液試料を用いたＴＤＭの可能性

We investigated whether theophylline concentrations in saliva (Csaliva) are correlated with its serum concentrations (Cserum) to see if they may be used for the therapeutic drug monitoring (TDM) of theophylline when patients refuse blood sampling. Saliva and serum samples were obtained from 6 healthy adult volunteers after administration of single dose of theophylline, and 40 patients of 3 different age groups (infants group aged 0-3 years, n=10 ; childrens group aged 7-12 years, n=9 ; adults group aged 27-81 years, n=21). All patients had been taking theophylline for a time and blood concentrations had reached a steady state. Saliva samples were taken using a sampling pad (OraSure® ; Epitope inc.), and theophylline concentrations in the saliva and serum samples were measured by fluorescence polarization immunoassay (TDx).In the healthy adult volunteers, there was a very good correlation between Csaliva and Cserum (y=0.48 x-0.10, r=0.991, p<0.001), and the ratio of Csaliva to Cserum (Csaliva/Cserum) was 0.46±0.03. The pharmacokinetics parameters Cmax and AUC for saliva were about 0.46 times those for serum and thus their ratios were almost the same as for Csaliva/Cserum. Vd/F for saliva was about 2.2 times that for serum, which was almost the inverse of the ratio for Csaliva/Cserum. There were no significant differences between saliva and serum for Tmax MRT, Ka, Ke, and T1/2.For the patients who had been taking theophylline for a time, there was also a very good correlation between Csaliva and Cserum (y=0.52 x-0.12, r=0.957, p<0.001). Csaliva/Cserum was 0.48±0.10 for the infants group, 0.51±0.07 for the childrens group and 0.50±0.08 for the adults group, so there were no significant differences among the patient groups in this respect.The results of this study show that Cserum can be estimated approximately from Csaliva measurements. Thus in the case of patients from whom it is difficult to obtain blood, it may be possible to check compliance and avoid overdosing using Csaliva. We therefore consider that the use of saliva samples for the TDM of theophylline is an important and convenient method for ensuring that drug therapy is conducted effectively.

Theophylline Concentrations in Serum, Saliva, and Cerebrospinal Fluid in Patients with Essential Tremor

Theophylline concentrations in saliva and serum were compared in 20 patients with essential tremor. There was a strong correlation between the concentrations in saliva and serum (r = 0.9, slope of 0.48). The ratio between unbound and bound theophylline as assessed by ultrafiltration was 0.30. This ratio was similar to that between theophylline concentrations in CSF and serum. The theophylline concentration in serum was not predictable from that obtained in saliva in individual cases. Moreover, the levels in saliva were about 20% higher than the unbound concentrations of theophylline in serum.

Monitoring Theophylline Therapy Using Citric Acid-Stimulated Saliva in Infants and Children With Asthma

Saliva stimulation is required for measurement of drugs in saliva. Chewing on a piece of paraffin, which is the method usually used for saliva stimulation, requires cooperation of the patient and, thus, is inapplicable in infants and young children. To assess the value of determining theophylline concentrations from noninvasively obtained saliva in this age group, we studied the theophylline plasma to saliva concentration ratio in citric acid-stimulated saliva. Theophylline concentration was measured in 137 simultaneously obtained paired specimens of plasma and saliva from 68 patients 2 1/2 months to 14 years of age treated with theophylline for asthma (dosage 20.8 +/- 5.2 mg/kg/d, mean +/- SD). Saliva secretion was stimulated by placing citric acid crystals on the tongue. A strong and highly significant correlation was observed between both determinations (r = .96; P less than .01). The plasma to saliva ratio was 1.78 +/- 0.22 (mean +/- SD), with theophylline concentrations between 3.1 and 32.1 micrograms/mL of plasma. The ratio of estimated to actual plasma theophylline concentrations was 1.02 +/- 0.12 (mean +/- SD). Interindividual coefficient of variation of plasma to saliva theophylline concentrations ratios was 12.4%; mean intraindividual coefficient of variation was 5.3%. The use of citric acid for saliva stimulation is easily applicable to infants and young children. Compared with blood drawing, stimulation of saliva secretion by citric acid is painless and noninvasive, is more readily accepted to patients, is at least as clinically relevant for theophylline determination, and allows frequent measurements of drug levels for individualization of the dosage with samples taken at home.(ABSTRACT TRUNCATED AT 250 WORDS)

Saliva and serum theophylline concentration in management of asthma in children on sustained-release therapy.

Relationships between theophylline concentrations in saliva and serum and lung functions were investigated in 27 asthmatic children receiving a sustained-release theophylline. Improvements in lung functions were related to increasing theophylline concentrations. The concentration required to maintain normal lung functions was 10 micrograms/ml in serum and 7 micrograms/ml in saliva. Theophylline concentrations in serum and saliva statistically correlated (r = 0.949). The mean serum - saliva ratio was 1.45 +/- 0.02, with a 13.7% intersubject and a 14.9% intrasubject variation. Predicted serum concentrations were +/- 2 micrograms/ml of measured concentrations in 92 samples (92%). From the results, theophylline concentrations in saliva may be useful in predicting serum values.

Steady-state pharmacokinetics and effects of a new once-daily, slow-release theophylline capsule preparation in asthma.

Plasma and saliva theophylline concentrations were measured in 21 asthmatic subjects receiving chronic oral therapy with a new sustained-release theophylline capsule (K1B Riker) given as a once daily dose, after titration to achieve a before-dose concentration of 8 mg l-1 or greater, or to the maximum dose of 1200 mg of theophylline daily. Plasma concentrations rose from a mean +/- s.d. minimum concentration (Cmin) of 7.9 +/- 2.3 mg l-1 to a mean maximum of 13.6 +/- 3.3 mg l-1 at a median time of 10 h after dosing. Saliva theophylline concentrations were closely related to the plasma theophylline concentration both between and within subjects with a mean saliva to plasma concentration ratio between subjects (S/P ratio) of 0.62 (+/- 0.05) and a mean within subject coefficient of variation of 8.2% (+/- 4.5%). There was a significant but small (10%) change in the mean S/P ratio during the dosing interval. Peak expiratory flow rate (PEFR) changed slightly but significantly during the dosing interval but forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) did not. The drug was well tolerated at the dose used (600-1200 mg once daily).

Relationship between saliva and free and total plasma theophylline concentrations in patients with chronic airflow obstruction.

Total plasma and mixed stimulated saliva theophylline concentrations (by high performance liquid chromatography) and free plasma theophylline concentrations (by equilibrium dialysis) were measured in simultaneously collected samples from 32 outpatients receiving chronic oral theophylline treatment, who had received the drug at least two hours before sampling. There was a close relationship between saliva and total plasma theophylline concentration and between total saliva and free plasma concentration. The mean saliva to total plasma drug concentration ratio was 0.69 (SE 0.09) and the mean difference between paired saliva and free plasma concentration was 0.65 (0.17) microgram/ml. It is concluded that stimulated mixed saliva provides a simple, non-invasive method of assessing total (and free) plasma theophylline concentrations during chronic oral treatment. The therapeutic range for saliva, corresponding to the generally accepted total plasma concentration range (10-20 micrograms/ml), is approximately 7-14 micrograms/ml.

Determination of Salivary Theophylline Concentration by SLFIA Method and Pharmacokinetics in Saliva

Recently, we have reported that theophylline concentrations in plasma as determined by substratelabeled fluorescent immunoassay (SLFIA) well correlated (r= 0.96) with the concentrations by high-pressure liquid chromatography, and that SLFIA procedure had considerable advantages over hitherto available method. Methods for measurin.g theophylline in saliva previously reported were spectrophotometry, gas-liquid and high-pressure liquid chromatographies. Here, we used the SLFIA for the determination of theophylline concentrations in saliva. It was possible to determine salivary theophylline in low concentrations by using salivary altered first dilution rates with SLFIA method. The concentrations of theophylline in the plasma and saliva in 7 normal adults and 3 asthmatic patients who were administered aminophylline were determined by SLFIA method. In normal adults, the time-course of plasma and salivary theophylline levels showed a parallel relationship, and theophylline concentrations in the saliva as determined 2 and 4 hours after administration were about 44% lower than those in the plasma. In asthmatic patients, theophylline concentrations in saliva 2, 4, 6 and 8 hours after administration were also 32% lower than those in the plasma. These results suggested that monitoring patients by means of salivary theophylline level is effective way to predict plasma levels and to help patients avoid pain of bloodletting.

Correlation of serum and saliva theophylline concentration after administration of a sustained release preparation.

The correlation between serum and saliva levels of theophylline was investigated in seven healthy volunteers after multiple dose administration of a low dose (300 mg/day) and a high dose (900 mg/day) of a sustained release theophylline preparation (Theo-Dur). Tablets were taken for five days, at 8 a. m. and 8 p. m. and a last dose was taken on Day 6 at 8 a. m. Fourteen serum and saliva samples were collected simultaneously during the dosing period and for up to 32 h after the last dose. On the 300 mg/day regimen the level in saliva was 55.3% of the serum level, with an overall variability of 6.7% and an intrasubject variability of 10.5%. After 900 mg/day, the saliva concentration was 55.5% of the serum concentration, with an overall variability of 7.6% and an intrasubject variability of 12.7%. A good correlation was found between both determinations (r = 0.99), which suggests that saliva levels could be used to monitor theophylline after administration of a sustained release tablet.

Salivary theophylline estimation in the management of asthma in children.

Simultaneous sampling was performed to determine whether saliva could replace plasma in the monitoring of theophylline dosages. Forty-eight children with moderate to severe asthma received oral theophylline preparation (usually sustained release) on a daily basis. They provided simultaneous saliva and plasma samples at routine out-patient visits. Saliva and plasma theophylline concentrations showed a wide variation between individuals, and their ratios also differed. Saliva theophylline concentrations below 7 micrograms/ml reflect plasma concentrations below 10 micrograms/ml, i.e. sub-therapeutic, while saliva concentrations above 7 micrograms/ml are consistent with therapeutic dosage. Estimation of saliva theophylline concentration on routine visits avoids the discomfort of blood sampling. It reflects whether daily oral theophylline dosage in childhood asthma is below or within the therapeutic range. The need for changes in dosage and the degree of patient-compliance with therapy can be usefully indicated.

Monitoring of serum or saliva theophylline concentrations by a new radioimmunoassay

The new radioimmunoassay RIA-mat Theophylline appeared to be highly specific, as none of the drugs structurally related to theophylline or other substances tested showed a noticeable cross reaction. Precision and accuracy are better than comparable assays, the sensitivity of detection is much better than e.g. if using an enzyme immunoassay.

Indirect Plasma-Theophylline Monitoring in Asthmatic Children by Determination of Theophylline Concentration in Saliva

The concentration of theophylline in mixed saliva and in plasma of 16 asthmatic children on regular theophylline therapy was obtained two and four hours after a maintenance dose. There is a strong and highly statistically significant correlation between the theophylline concentration in saliva and plasma. This correlation is not affected by the pH or flow rate of saliva. The concentration of theophylline in plasma could be predicted from the concentration in saliva within ± 10% in 20, and within ± 20% in all of the 32 samples. Determination of theophylline concentrations in saliva is an effective, convenient, noninvasive, and painless method for routine indirect monitoring of plasma-theophylline concentrations in asthmatic children on regular theophylline therapy.

Relationship between theophylline concentration in plasma and saliva of man.

The concentration of theophylline in the plasma and saliva of 7 normal adults receiving single oral doses of 200 mg theophylline per square meter of body surface area (BSA) was determined spectrophotometrically over 8 hours. There was an excellent linear relationship between theophylline concentrations in plasma and saliva, over a plasma concentration range of 4 to 14 µg per milliliter. Theophylline concentrations in the saliva were about 48% lower than in the plasma and are similar to the concentration of free (not protein‐bound) drug in the plasma. There is very little intersubiect and intrasubiect variation of theophylline blank values in plasma and saliva, in the recovery of theophylline from plasma and saliva, and in the proportionality factor that relates saliva to plasma concentrations of the drug. These observations suggest that theophylline determination in saliva may be a convenient, painless, and noninvasive method for routine monitoring of theophylline levels.