Evaluation and clinical application of a bracketing calibration-based isotope dilution liquid chromatography-tandem mass spectrometry candidate reference measurement procedure for serum theophylline.

A candidate reference measurement procedure (RMP) for serum theophylline via isotope dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed. With a single-step precipitation pretreatment and a 6-min gradient elution, the method achieved baseline separation of theophylline and its analogs on a C18-packed column. A bracketing calibration method was used to ensure repeatable signal intensity and high measurement precision. The intra-assay and inter-assay imprecisions were 1.06%, 0.84%, 0.72% and 0.47%, 0.41%, 0.25% at concentrations of 4.22 µg/mL (23.40 µmol/L), 8.45 µg/mL (46.90 µmol/L), and 15.21 µg/mL (84.43 µmol/L), respectively. Recoveries ranged from 99.35 to 102.34%. The limit of detection (LoD) was 2 ng/mL, and the lowest limit of quantification (LLoQ) was 5 ng/mL. The linearity range extended from 0.47 to 60 µg/mL (2.61-333.04 µmol/L). No ion suppression and carry-over (< 0.68%) were observed. The relative bias for this candidate RMP that participated in 2023 External Quality Control for Reference Laboratories (RELA) conducted by the International Federation of Clinical Chemistry (IFCC) was within a range of 0.17 to 0.93%. Furthermore, two clinical immunoassay systems were compared with this candidate RMP, demonstrating good correlations. The results of the Trueness Verification Plan indicate significant differences among routine systems, highlighting the need for standardization efforts. The developed candidate RMP for serum theophylline serves as a precise reference baseline for standardizing clinical systems and assigning values to reference materials.

Effect of theophylline on serum and milk pharmacokinetics of tylosin following intramuscular administration in lactating goats.

AIM OF THE WORK: The study was conducted to evaluate the influence of theophylline pre-treatment on serum pharmacokinetics and milk elimination of tylosin following single intramuscular (IM) administrations in lactating goats. METHODS AND RESULTS: In a cross-over study, tylosin was injected via intramuscular (IM) at a single dose of 15 mg/kg b.wt. After a one-month washout period goats received theophylline at a daily IM dose of 2 mg/kg b.wt. for seven consecutive days then tylosin was injected IM dose of 15 mg/kg b.wt. two hours after the last theophylline dosing. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 10, 12, and 24 h post-injection. Samples were left to clot and then centrifuged to yield serum. Milk samples were collected before and at 0.5, 1, 2, 4, 6, 8, 10, 12, 24, 48, and 72 h post-injection from each goat by hand milking. Tylosin serum concentrations were determined by high-performance liquid chromatography (HPLC). Tylosin concentrations versus time were analyzed by a noncompartmental method. Tylosin Cmax significantly declined from 1.73 ± 0.10 to 1.01 ± 0.11 µg/ml, and attained Tmax values of 2 and 1 h, respectively in theophylline-pretreated goats. Moreover, theophylline pretreatment significantly shortened the elimination half-life (t1/2el) from 6.94 to 1.98 h, t1/2ka from 0.62 to 0.36 h and the mean residence time (MRT) from 8.02 to 4.31 h, also Vz/F and AUCs decreased from 11.91 to 7.70 L/kg and from 12.64 to 4.57 µg*h/ml, respectively, consequently, theophylline enhanced the clearance (Cl/F) of tylosin from the body. Similarly, tylosin milk concentrations were significantly lower in theophylline-pretreated goats than in goats that received tylosin alone and were detected up to 24 and 72 h in both groups, respectively. Moreover, the t1/2el and AUCs were significantly decreased from 14.68 ± 1.97 to 4.72 ± 0.48 h, and from 181 to 67.20 µg*h/ml, respectively. CONCLUSIONS: The withdrawal period for tylosin in goat milk is at least 72 h. Theophylline pretreatment significantly decreases serum and milk tylosin concentrations to subtherapeutic levels, which could have serious clinical consequences such as failure of therapy. This means that after administering tylosin to goats, milk from these animals should not be consumed for at least 96 h to ensure that the milk is free from residues of the antibiotic.

Self-reported caffeine consumption miss-matched consumption measured by plasma levels of caffeine and its metabolites: results from two population-based studies.

IMPORTANCE AND OBJECTIVE: Self-reported caffeine consumption has been widely used in research while it may be subject to bias. We sought to investigate the associations between self-reported caffeine consumption and plasma levels of caffeine and its two main metabolites (paraxanthine and theophylline) in the community. METHODS: Data from two population-based studies (SKIPOGH1 and 2 (N = 1246) and CoLaus|PsyCoLaus (N = 4461)) conducted in Switzerland were used. Self-reported caffeine consumption was assessed using questionnaires. Plasma levels of caffeine and its metabolites were quantified by ultra-high performance liquid chromatography coupled to a tandem quadrupole mass spectrometer. RESULTS: In both studies, mean log plasma levels of caffeine and its two metabolites were over 6.48 (plasma levels = 652 ng/ml) when no caffeine consumption was reported. Subsequently, nonlinear associations between log plasma levels and self-reported caffeine consumption were observed in SKIPOGH, with a change of the slope at 3-5 cups of espresso per day in SKIPOGH1 but not SKIPOGH2. In CoLaus|PsyCoLaus, increased daily consumption of caffeinated beverages was associated with increased log plasma levels with a change of the slope at 3 cups. In both studies, declared caffeine consumption higher than 3-5 cups per day was not associated with higher plasma levels of caffeine and its metabolites. CONCLUSION: Self-reports of no or low caffeine consumption and consumption of more than 3-5 cups of coffee should be interpreted with caution, with possible under- or over-estimation. Quantifying plasma levels of caffeine and its metabolites may contribute to a better estimation of caffeine intake.

Caffeine Intoxication, in Which the Theophylline Level Served as an Indicator of the Treatment Course and the Caffeine Level Could Be Measured.

A 51-year-old man presented with sudden-onset palpitations and dyspnea that had started 8 h earlier. The patient was restless and tachypneic and had persistent vomiting upon arrival. His sensorium and oxygen saturation levels rapidly declined three hours after arrival, and he was placed on a ventilator. On hospitalization day 2, he was removed from the ventilator and claimed that he had consumed a large amount of energy drinks (oral caffeine intake, approximately 1 g). The theophylline level on arrival had been elevated (9.0 µg/mL). Caffeine intoxication should be considered in patients presenting with restlessness, tachypnea, frequent vomiting, lactic acidosis, and electrolyte abnormalities.

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.

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.

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

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

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.

Niveles salivales de teofilina en niños asmáticos: una alternativa para el monitoreo terapéutico / Salivary levels on theofilin asthmatic children: alternative for terapeutic monitory

Con el objetivo de evaluar la aplicabilidad del monitoreo terapeútico de teofilina en muestras de saliva, se estudió la relación entre niveles séricos y salivales de la droga en un grupo de 20 niños asmáticos entre 7 y 18 años de edad, en tratamiento con una teofilina de liberación lenta. En muestras simultáneas de sangre y de saliva extraídas en estado estacionario y 6 horas después de una dosis se encontró una relación lineal, con una correlación significativa (r=0,96, SD 1,4 mcg/ml). Si bien se obtuvo una buena correlación entre niveles séricos y salivales, la variabilidad del 56%del rango terapeútico, no ofrece la precisión requerida para estimar niveles séricos de teofilina a partir de niveles salivales

Concentraçöes séricas de teofilina em crianças tratadas com cápsulas abertas e fechadas de uma teofilina de açäo prolongada: teolong / Theophylline blood level concentrations in children treated with open and closed capsules of a sustained release theophylline: teolong

Este estudo avalia as concentraçöes séricas da teofilina na monitorizaçäo dos pacientes pediátricos. Quarenta crianças (de três a 12 anos) com asma comprovada foram admitidas ao acaso num grupo de tratamento com as cápsulas abertas ou num grupo de cápsulas fechadas de uma teofilina de açäo retardada, durante oito dias. A dose diária foi de 8 a 10 mg/Kg/dia, administradas de 12 em 12 horas. No último dia da investigaçäo, as concentraçöes séricas de teofilina foram obtidas antes da dose matinal, 4 e 8 horas mais tarde. Os resultados näo indicaram diferenças com significaçäo estatística entre as duas formas de adminsitraçäo, nas concentraçöes médias de teofilina. As concentraçöes séricas de teofilina permaneceram entre 10 e 20 mcg/ml, na maioria dos casos. Devido as variaçöes individuais na absorçäo e no metabolismo, os níveis sangüineos de teofilina deveriam ser realizados regularmente, ao se usar a droga. Os autores näo puderam correlacionar as reaçöes adversas com as concentraçöes séricas de teofilina. A aderência e a tolerância medicamentosas foram boas, sugerindo que os microgrânulos de açäo prolongada da teofilina säo úteis no manuseio clínico a longo prazo da asma brônquica. Novos estudos com maior número de casos säo também recomendados

Teofilina en el asma crónico infantil ¿Es su uso correcto en nuestro medio? / Theophylline in child chronic asthma: is its use warranted in our country?

Se realizó una evaluación de la manera en que las teofilinas son empleadas en nuestro medio, para el tratamiento del asma crónico en la infancia. Se estudiaron 40 niños con edades comprendidas entre 2 y 15 años, de ambos sexos, portadores de asma, en tratamiento con teofilina a permanencia y que concurrieron por primera vez a nuestra consulta. Se valoraron las formas farmaéuticas de teofilina empleadas, las dosis e intervalos interdosis, así como la aplicación de monitoreo terapéutico de teofilina con niveles séricos para la individualización de dosis. Se comprueba que sólo el 45 por ciento de los pacientes estudiados recibían formas farmacéuticas de teofilina adecuadas. Las dosis resultaron ser muy inferiores a las requeridas, con dosis total media de 11,5 mg/kg/día (rango: 1,2 a 23 mg/kg/día). Los intervalos interdosis fueron muy prolongados para los preparados empleados. Como consecuencia, el 77,5 por ciento de los pacientes presentaron niveles séricos de teofilina en rango subterapéutico. En ninguno de los casos se aplicaron las pautas de dosificación para la individualización de las dosis de teofilina

Comparación de las concentraciones de teofilina en suero y saliva después de la administración de una teofilina de liberación sostenida en un grupo de lactantes, preescolares y escolares / Comparisson of the theophyllin concentrations in serum and saliva after the administration of a slow-release theophyllin in infants, preschool, and school children

La variación en las concentraciones de teofilina en el suero y saliva obtenidas después de la ingestión de una teofilina de acción sostenida (Elixine lentocaps R), fué estudiada antes y después de la última dosis matinal al cuarto día de tratamiento, en un grupo de pacientes asmáticos cuyas edades fluctuaron entre los 5 meses y 10 años. La muestra de saliva se obtuvo colocando algodón estéril directamente en el conducto de Stenon y la teofilina se midió simultáneamente en sangre y saliva por enzimoinmunoensayo (Emit-Syva). Se obtuvo una muy buena correlación saliva/suero, con una relación entre 0,50-0,60 en todos los tiempos analizados. Una dosis de teofilina de aproximadamente 15 mg/kg peso/día parece ser la adecuada para alcanzar un nivel útil del fármaco. Este medicamento produce niveles aceptables, tanto cuando se ingiere la cápsula cerrada como cuando los gránulos se administran mezclados con alimentos, sin masticarlos. Sin embargo, la concentración máxima alcanzada no es predecible, y es independiente de la dosis administrada, por lo que se hace indispensable la medición de los niveles alcanzados. En la gran mayoría de los pacientes fué posible administrar el fármaco cada 12 horas, pero hubo un 37% de los enfermos en que la fluctuación de la concentración de teofilina en las 24 horas fué mayor de 100%. Se concluye que es posible monitorizar la teofilina sérica a través de la medición de su concentración en la saliva. Dada la variabilidad individual de las concentraciones de teofilina alcanzadas en el estado estacionario, sería aconsejable tomar 2 muestras, una antes de recibir el fármaco y otra aproximadamente 4 horas post ingesta, que es cuando se alcanza la concentración máxima en la mayoría de los niños. La medición de niveles de teofilina utilizando inmuno-enzimo-ensayo es rápida, específica, reproducible y fácil de realizar