Beneficios clínicos y funcionales de agregar teofilina a la terapia inhalatoria con broncodilatadores de acción corta en pacientes con enfermedad pulmonar obstructiva crónica / Clinical and functional benefits of adding theophylline to a standard treatment with short acting bronchodilators in patients with COPD

Background: Although theophylline is considered a third line bronchodilator drug for the treatment of chronic obstructive pulmonary disease (COPD), it is widely used in Chile, because it is administered orally and has a moderate cost. Aim: To evaluate if theophylline adds clinical and/or functional benefits when associated to standard recommended inhaled bronchodilator therapy. Subjects and methods: Thirty-eight stable COPD patients who accepted to participate in the study approved by the Ethics Committee of our institution were studied. Using a randomized double-blind placebo-controlled study, theophylline (250 mg) or placebo was administered twice a day for 15 days in addition to inhaled salbutamol and ipratropium bromide. Prior to and at the end of the study, patients underwent: a) a spirometry to evaluate changes in dynamic pulmonary hyperinflation using slow vital capacity (SVC) and inspiratory capacity (IC), b) the 6 min walking distance (6 MWD); and c) measurement of maximal inspiratory and expiratory pressures. Dyspnea and quality of life (QoL) were evaluated using appropriate questionnaires. Results: Compared to placebo, patients on theophylline showed significant increases in SVC (p=0.014), IC (p=0.002), and 6 MWD (p=0.005). They also experienced an improvement in dyspnea (p=0.042) and QoL (p=0.011). All patients improved at least one of these parameters with 53% of the patients showing an improvement in 3 or more. Conclusions: Our results indicate that adding theophylline to standard treatment with inhaled bronchodilators provides additional benefits in stable COPD patients by reducing dynamic pulmonary hyperinflation, improving exercise tolerance, dyspnea and QoL.

Paraxanthine/caffeine ratio: as an index for CYP1A2 activity in polycyclic aromatic hydrocarbons exposed subjects.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous in the environment and originate from incomplete combustion process of organic materials. These compounds are bioactivated to reactive metabolites which bind covalently to DNA and subsequently initiate carcinogenesis. PAHs have been well established as an enzyme inducer of cytochrome P450 (CYP) such as CYP1A1 and CYP1A2. Caffeine is primarily metabolized by CYP1A2 to paraxanthine, so it has been used as a specific probe for assessing CYP1A2 activity. The purpose of this study was to compare CYP1A2 activity in female subjects that were automobile exhaust exposed and non-automobile exhaust exposed using serum paraxanthine/caffeine ratio as an index. Each subject took a 180 mg single oral dose of caffeine solution. Blood samples were collected before and 5 hours after caffeine intake. Serum samples were separated by centrifugation and stored at -20 degrees C until analysis by high performance liquid chromatography (HPLC). Carbon monoxide (CO) level in blood was also detected using spectrophotometer. The results showed that serum paraxanthine/caffeine ratio in exposed subjects was significantly higher than non-exposed subjects (mean +/- SE of 0.45 +/- 0.05 and 0.33 +/- 0.03, respectively; p < 0.05). CO level in exposed subjects was also significantly higher than non-exposed subjects (mean +/- SE of 4.03 +/- 0.21 and 3.01 +/- 0.18, respectively; p < 0.05). Conclusion: Paraxanthine/caffeine ratio, as an index for CYP1A2 activity, can be used to determine PAHs exposure. Automobile exhaust exposed subjects demonstrated significantly higher CYP1A2 activity than that of the non-exposed subjects. Exposed subjects have a possibly higher risk of chemical carcinogenesis.

Theophylline blood levels in Sri Lankan asthmatics: comparison of two methods of assay.

OBJECTIVES: To assay theophylline blood levels in a sample of Sri Lankan chronic asthmatics taking oral theophylline, and to evaluate a simple and cost effective ultraviolet spectrophotometric assay for theophylline levels in blood. SETTING: Chronic asthmatics taking oral theophylline attending medical clinics at the National Hospital of Sri Lanka (NHSL) were recruited for the study. Blood samples were collected from recruited patients on their subsequent clinic visit. DESIGN AND METHODS: A cross-sectional study of theophylline blood levels. Blood samples were assayed for trough theophylline levels using two methods: an automated homogeneous enzyme immunoassay (EMIT), and a low cost ultraviolet spectrophotometric method. RESULTS: Only 2 patients of the 24 had theophylline blood levels in the accepted therapeutic range (10 to 20 micrograms/ml) (3.4); 19 patients had levels under 5 micrograms/ml. A correlation coefficient of 0.99 was obtained in the statistical comparison of the two methods, indicating that the spectrophotometric method has similar accuracy as the reference EMIT assay. CONCLUSIONS: The results signal a need for monitoring of theophylline in asthmatics when accepted clinical indications are present. The ultraviolet spectrophotometric method is ideal to initiate therapeutic drug monitoring (TDM) in the country because of its low cost (about Rs. 55 per assay), requiring only a UV recording spectrophotometer.

Monitorización de los niveles séricos de teofilina durante el tratamiento con teofilina del niño asmático / Monitoring of theophyline serum levels during the treatment of asmatic children with theophyline

Se estudiaron 30 niños con diagnóstico de asma bronquial, a los cuales se les realizó mediciones sanguíneas de teofilina aplicando el método de monitorización de Ritshell y Thompson de un punto. Se analizaron diferentes variables como fueron: la edad, hábitos tóxicos, dosis administrada, vías e intervalo de dosificación. Además se tuvieron en cuenta diferentes fármacos que pueden aumentar o disminuir los niveles séricos de teofilina, así, como las reacciones adversas que se manifestaron durante el tratamiento. Se detectaron errores en cuanto a la dosis diaria de teofilina, intervalo entre las dosis y vía de administración. En la mayoría de los niños (86,7%) no se lograron niveles de teofilina en suero dentro del margen terapéutico entre 10 y 20 mg/ ml.

Comparative steady-state bioavailability of sustained-release theophylline preparations: Theo-Dur, Uni-Dur and Xanthium.

Steady-state bioavailability of sustained-release theophylline (SRT); Theo-Dur, Uni-Dur and Xanthium were compared in 10 healthy males with theophylline clearance ranged from 0.3 - 0.8 ml/min/kg. Each of 400-mg SRT was administered once daily before breakfast for 7 consecutive days, one-week washout period in a crossover fashion. Serial blood samples were collected over 24 hours on days 6 and 7. Serum theophylline concentrations were determined by fluorescence polarized immunoassay. We found that the oral bloavailability relative to Franol (%F [90% CI]) of Theo-Dur, Uni-Dur and Xanthium were 97 (93-106), 85 (79-96) and 77 (72-87), respectively. Average bioequivalence revealed that the Css(min) (microg/ml) of Uni-Dur (5.07) was higher than Theo-Dur (4.29), and Xanthiume (4.18), while the Css(max) and Css(av) (microg/ml) of Theo-Dur (11.02, 7.87) were statistically higher than Uni-Dur (8.51, 6.91) and Xanthium (7.65, 6.27). The extent of absorption assessed by AUCss(0.24) of Theo-Dur was significantly greater than Uni-Dur and Xanthium. However, fluctuation index (% FI) of Theo-Dur (232) was twofold higher than Uni-Dur (137) and Xanthium (113). The median Tss(max) of Uni-Dur was 12 hours which was significantly longer than Xanthium (7 hours) and Theo-Dur (8 hours). There were no statistically significant differences between Uni-Dur and Xanthium regarding bioavailability, Css(max), Css(av) as well as % FI. Moreover, 400 mg OD of Uni-Dur and Xanthium are suitable for subjects with a theophylline clearance of 0.3-0.55 ml/min/kg while 400 mg OD Theo-Dur can be used in subjects with slower clearance rates of 0.3-0.39 ml/min/kg. Subjects with rapid theophylline clearance rates of 0.65-0.8 ml/min/kg required a higher dose of theophylline and twice-daily dosing was more appropriate.

Plasmatic levels of theophylline in asthmatic patients: comparative evaluations of two different methods

Background. There are several criteria to choose an analytical method for drug monitoring. Such methods have to comply with standard values and quality control as well as other subjective features such as cost and the time consumed to obtain quantification (TOCQ). The purpose of this work was to compare two methods used to quantify plasmatic levels of theophylline in asthmatic patients as support to choose the best method. Methods. We analyzed plasma samples from 30 asthmatic pediatric patients at the pediatric service of the Hospital General de Mexico, who were under treatment with theophylline and whose were monitoring of drug levels was indicated. Plasma samples were analyzed by liquid chromatography (HPLC) and by enzyme immunoassay (EMIT), and were then compared with respect realibility, as well as cost and TCOQ. Results. The difference of the plasmatic levels of theophylline quantified by both methods was not significant (p>0.05); both showed a good correlation index (r=0.995), and both were realible based on other validity parameters. However, TCOQ for HPLC was 20.0 ñ 5.5 min (mean ñ SD) for each sample analyzed, and 2.3 ñ 0.5 for EMIT. With respect to the cost of each analysis, HPLC required 2.3ñ 0.5 USD (mena ñ SD) and EMIT 4.5 ñ 0.3 USD. Conclusions. Analytical methods used to quantify plasmatic levels of theophylline based on HPLC and EMIT proved to be suitable, because they fulfilled the criteria and standard values regarding quality control, although laboratorits have to select subjectively the best method according to cost and TCOQ, since HPLC was less expensive, and EMIT was more rapid

Estimation of saliva theophylline concentration in the management of asthmatic patients

Plasma and saliva concentrations of theophylline were studied in 91 patients receiving sustained release theophylline preparation. Co-efficient of correlation between saliva and plasma found to be nearly perfect with P-0.906, suggesting that measurement of plasma concentration can be determined by saliva concentration to an extent of about 84%

Theophylline-ranitidine interaction in elderly COPD patients

Most controlled studies in humans indicate that ranitidine does not alter theophylline metabolism, even at high doses. However, there have been several case reports published recently which demostrate the development of theophylline toxicity mostly in older patients receiving stable oral doses of this drug when ranitidine was administered simultaneously. We studied eleven elderly (mean age, 69,0 + or - 6.2 years) patients with chronic obstructive pulmonary disease (COPD). During one week the patients took slow-release theophylline, 200 mg every 12 h, followed by one week intake of the same dose of theophylline plus ranitidine tables, 150 mg every 12h. At the end of each period, blood samples were obtained 0,1,2,3,4,6,7,8 and 12h after the morning dose for the determination of serum theophylline levels. the peak theophylline concentration was achieved after 4.1 + or - 0.9 h while the patients were taking theophylline, and after 2.9 + or - 1.4 h with the combined regimen. This difference was statistically significant. These results suggest that the reported increases in serum theophylline levels in older patients receiving theophylline and ranitidine cannot be ascribed to slower theophylline metabolism in the geriatric patient with COPD who is also given ranitidine.

Arrhythmogenic effects of combined orally administered theophylline and albuterol in patients with chronic obstructive pulmonary disease

1. Studies in asthmatic subjects have reported conflicting results about the arrhythmogenic effects of beta agonist and theophylline. The purpose of the present study was to evaluate the effects of the combination of these drugs in patients with chronic obstructive pulmonary disease (COPD). 2. Twelve COPD patients (FEV1 = 1.2 + or - 0.3 L; PaO2 = 65.7 + or - 9.0 mmHg) we evaluated by 24-h Holter monitoring on three different days. The first evaluation was done after the patient had been without any treatment for at least 24 h, the second after sustained-release theophylline for one week and the third after oral beta agonist (albuterol) and theophylline for one week. 3. Mean serum level of theophylline was 1.9, 15.6 an 17.7 µg/ml, and mean heart rate was 78.3, 82.0 and 84.5 beats/min for the first, second and third period, respectively. Four patients showed more than 10 premature atrial contractions/h in the baseline Holter, and this rate did not increase after either treatment. Three patients had more than 10 premature ventricular contractions/h (PVC) at baseline, with no increase while receiving theophylline or the combination of theophylline and albuterol. However, one patient did have worsening of the arrhythmia while taking both drugs. There were 5 single PVCs/h at baseline and 150 single and 9 coupled PVCs/h plus 1 episode of non-sustained ventricular tachycardia during combined therapy. 4. We conclude that the combination of theophylline and a beta agonist (albuterol) may increase the premature ventricular contraction rate and the complexity of ectopic activity in COPD patients

Assessment of azapropazone-theophylline interaction in the rat

The effect of the non-steroidal anti inflammatory drug, azapropazone [AZP], on the pharmacokinetics of coadministered theophylline was studied in the rat. Animals were pretreated for one week with a daily does of AZP [50 mg kg-1, p.o] prior to coadministration with theophylline [25 mg kg-1]. Plasma the rophylline concentrations were measured serially over a period of 12 hr from dosing, by hplc and the relevant pharmacokinetic parameters [Cmax, Tmax,t1/2 and AUC0-00] subsequently estimated. The mean values for these parameters were generally higher in the coadminstration schedule but the differences from baseline levels were not statistically significant, indicating the little or no interaction exists between theophylline and AZP at least in the present animal model. Further studies in appropriate subjects will however be needed to verify the apparent safety of the drug combination as indicated by these results

Prophylactic theophylline infusion for prevention of apnea of prematurity.

To assess if there was any advantage in the prophylactic use of theophylline to prevent apnea in preterms, we treated 56 preterms (Group A) < 34 weeks gestation with theophylline infusion and compared these with 25 age and weight matched preterms (Group B) who received no therapy. Aminophylline (25 mg/ml) was infused from admission in all neonates (group A) at rates ranging 0.2 to 0.38 mg/kg/h and blood levels estimated on an Abbots TDX analyser by Fluorescence Polarization Immunoassay, after 5 days infusion. All neonates (Groups A + B) were monitored on a Corometric 505 neonatal monitor. In Group A, 1/48 developed primary apnea while in Group B, 4-21 had primary apnea (p < 0.05). Serum theophylline ranged from 2.3 to 39.5 micrograms/ml with a mean of 12.7 micrograms/ml. The mean serum level of theophylline in 4 cases who exhibited clinical evidences of toxicity was 30.1 micrograms/ml. A statistically significant difference (p < 0.05) was noted in birth weight and serum level inspite of similar infusion rates of theophylline. A linear correlation r = 0.65 was noted between serum level and infusion rate. Multivariate regression analysis, between birth weight and gestational age to serum level, showed a linear correlationship only between birth weight and serum level (r = 0.45).

Aplicación de un programa de computación para ajuste de dosis de teofilina en pacientes asmáticos / Application of a computer programme for regulate the theophylline dose in asthmatics patients

El monitoreo terapéutico de teofilina con niveles séricos ha contribuido en gran parte a la eficiencia clínica de este fármaco. El objetivo de la presente comunicación ha sido el de mostrar la aplicación de un programa de computación para su monitoreo terapéutico en pacientes asmáticos. El método que el programa aplica para el ajuste de dosis de teofilina consiste en: 1.-Administrar una dosis inicial, calculada en base a parámetros farmacocinéticos poblacionales, y corregidos de acuerdo con la posible presencia de factores que modifiquen la absorción, distribución y eliminación de este fármaco. 2.-Una vez obtenidos los niveles séricos, se recalculan los parámetros individuales, y la dosis requeridos para que los mismos permanezcan en rango terapéutico. La utilización de este programa permite un ajuste rápido y seguro de las dosis de teofilina, así como el evaluar como cada paciente absorbe, distribuye y elimina dicho fármaco. La gráfica de niveles séricos que brinda el programa permite que el médico clínico se familiarice con los principios de la farmacocinética y mejore el empleo clínico de este fármaco

Influencia da associacao teofilina e beta-2-agonista por via oral, na funcao pulmonar de pacientes portadores de doenca pulmonar obstrutiva cronica / Influence of the combination of theophylline and beta 2 agonists by oral route on pulmonary function of patients with chronic obstructive lung disease

A eficacia da associacao de teofilina e agentes beta-adrenergicos na terapeutica da obstrucao bronquica e tema controverso na literatura. Com este objetivo, foram estudados nove pacientes portadores de DPOC, com idades entre 51 e 69 (media de 60,6 ñ 6,6) anos, nos quais foi comparada a funcao pulmonar com o uso de teofilina isolada ou combinada ao salbutamol, por via oral. Apos a suspensao de qualquer medicacao broncodilatadora por 24 horas foram determinados os valores basais da capacidade vital forcada (CVF) e do volume expiratorio forcado no primeiro segundo "(VEF IND. 1)". Teofilina de acao prolongada (600mg/dia) foi, entao, administrada por via oral por sete dias, seguidos de sete dias de ingestao oral na mesma dose de teofilina associada a 16mg/dia de salbutamol. Os parametros espirometricos foram analisados ao final de cada semana. A CVF basal foi de 0,85 e 2,57 (media 1,78 ñ 0,64) litros, o "VEF IND. 1" 0,70 a 164 (medida 1,15 ñ 0,30) litros e a teofinemia 0,1 a 3,1 (media 1,81 ñ 1,01) ug/ml. Ao final da primeira semana, a CVF foi de 1,38 a 3,26 (media 2,03 ñ 0,65) litros, o "VEF IND. 1" 0,85 a 1,73 (media 1,40 ñ 0,29) litros e os niveis sericos de teofilina 8,1 a 21,0 (media 13,40 ñ 4,18) ug/ml. Com a associacao teofilina e salbutamol a CVF encontra-se entre 1,24 e 2,57 (media 1,90 ñ 0,50) litros e o "VEF IND. 1" entre 0,96 e 1,90 ...

Efeitos dos agonistas beta-2-adrenergicos por via oral, sobre os niveis sericos de teofilina / Effects of adrenergic beta 2 agonists by oral route on theophylline blood levels

Diversas drogas interferem com a farmacocinetica da teofilina, acarretando variacoes de seus niveis sericos. Com o objetivo de caracterizar possiveis influencias dos beta-2-adrenergicos por via oral, na teofilinemia de pacientes em uso desta droga, analisamos dez portadores de obstrucao bronquica, com idades entre 51 a 69 (media de 59,90 ñ 6,67) anos. O estudo consistiu na analise da concentracao serica de teofilina 24 horas apos a suspensao de toda medicacao, depois de um periodo de administracao diaria isolada de 600 mg de teofilina de acao prolongada, e apos sete dias de associacao da mesma dose de teofilina com 16 mg diarios de salbutamol por via oral. As amostras sanguineas foram colhidas 4 horas apos a ingestao da dose matinal de teofilina. Os resultados obtidos foram respectivamente 2,08 ñ 1,20 ug/ml, 15,18 ñ 6,87 ug/ml e 11,45 ñ 5,15 ug/ml. Os valores da fase (teofilina isolada) foram significativamente maiores aos obtidos apos a combinacao de teofilina e salbutamol. Estes resultados permitem concluir que esta associacao por via oral interfere na farmacocinetica da teofilina. Sugerimos que nos individuos em uso destas drogas, os niveis de teofilina sejam monitorizados, para eventual correcao da dose administrada.

A study on the chronopharmacokinetics of theophylline in rabbits.

The Chronopharmacokinetics of a single oral dose of theophylline was studied in rabbits. It was observed that morning (06.00 hr) dosing was characterized by significantly low rate of absorption (t 1/2a and Tmax) but higher extent of absorption (AUC0-alpha) compared to that after nocturnal dosing (22.00 hr). The plasma half life (t1/2el) was significantly less at night compared to that in daytime. The data may have considerable clinical relevance.