Efficacy and safety of combined doxofylline and salbutamol in treatment of acute exacerbation of chronic obstructive pulmonary disease

SUMMARY OBJECTIVE: The aim of this study was to investigate the efficacy and safety of combined doxofylline and salbutamol in the treatment of acute exacerbation of chronic obstructive pulmonary disease. METHODS: A total of 68 acute exacerbation of chronic obstructive pulmonary disease patients were randomly divided into control group (34 cases) and experimental group (34 cases), who received the doxofylline treatment and combined doxofylline and salbutamol treatment for 1 week, respectively. During the treatment, the remission time of typical respiratory manifestations was recorded, and the adverse reactions were observed. At the end of treatment, the treatment efficacy was evaluated. Before and after treatment, the pulmonary function indexes and serological indicators were detected. RESULTS: After treatment, compared with control group, in experimental group, the effective rate of treatment was significantly increased (p<0.05), the remission time of typical respiratory manifestations was significantly shortened (p<0.05), the pulmonary function indexes were significantly improved (p<0.05), the serum high-sensitivity C-reactive protein and cystatin C levels were significantly decreased, respectively (p<0.05), and the serum prealbumin level was significantly increased (p<0.05). In addition, the adverse reaction rate had no significant difference between two groups (p>0.05). CONCLUSIONS: In the treatment of acute exacerbation of chronic obstructive pulmonary disease, the combined use of doxofylline and salbutamol can quickly relieve the respiratory symptoms, mitigate the pulmonary dysfunction, and reduce the inflammatory response, thus promoting the outcome of patients.

Opioid-free general anesthesia and induced recovery from anesthesia in a patient with myotonic dystrophy type-1: a case report / Anestesia geral sem opioide e recuperação induzida da anestesia em paciente com distrofia miotônica tipo-1: relato de caso

Abstract Myotonic dystrophy type-1 (Steinert disease) is an autosomal dominant, progressive multisystem disease in which myotonic crisis can be triggered by several factors including pain, emotional stress, hypothermia, shivering, and mechanical or electrical stimulation. In this report, dexmedetomidine-based general anesthesia, in combination with a thoracic epidural for laparoscopic cholecystectomy in a patient with Steinert disease, is presented. An Aintree intubation catheter with the guidance of a fiberoptic bronchoscope was used for intubation to avoid laryngoscopy. Prolonged anesthetic effects of propofol were reversed, and recovery from anesthesia was accelerated using an intravenous infusion of theophylline.

Resumo A Distrofia Miotônica (DM) tipo-1 (Doença de Steinert) é uma doença multissistêmica progressiva autossômica dominante em que a crise miotônica pode ser desencadeada por vários fatores, incluindo dor, estresse emocional, hipotermia, tremores e estímulo mecânico ou elétrico. O presente relato descreve anestesia geral realizada com dexmedetomidina em combinação com peridural torácica para colecistectomia laparoscópica em paciente com Doença de Steinert. Para evitar laringoscopia, a intubação traqueal foi realizada utilizando cateter de intubação Aintree guiado por broncofibroscopia óptica. Os efeitos anestésicos prolongados do propofol foram revertidos e a recuperação anestésica foi acelerada pelo uso de infusão intravenosa de teofilina.

Treatment of moderate chronic obstructive pulmonary disease (stable) with doxofylline compared with slow release theophylline--a multicentre trial.

An open, randomised trial was conducted at Burdwan Medical College and Midnapore Medical College in West Bengal to investigate therapeutic efficacy and tolerability of doxofylline compared with slow release theophylline in 75 patients (45 males and 30 females) aged between 40 and 70 years who had been suffering from moderate chronic obstructive pulmonary disease. After one week of washout, the two drugs were administered orally to two groups one of 40 patients on doxofylline (400mg twice daily) and 35 patients on slow released theophylline (400mg once a day at evening); treatment and follow-up lasted 4 weeks on both groups patients. Both drugs significantly increased spirometric parameter (doxofylline p<0.01 and theophylline p<0.04) and significantly reduced salbutamol consumption (p<0.001 for both drugs). Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects: (Doxofylline 8 and theophylline 25) or number of drop-out side-effects (doxofylline 5 and theophylline 10). From these results, doxofylline seemed to be a good alternative to theophylline in the treatment of chronic obstructive pulmonary disease.

What is new in the management of childhood asthma?

The prevalence of asthma has increased in developed countries. The efficacy of available drugs in those with severe persistent disease is limited. This has led to a renewed search for the reasons for failures of the existing treatment and for novel concepts. Treatment with inhaled corticosteroids, and to a much lesser extent theophylline, can reduce the survival of inflammatory cells including eosinophils. Emerging trends in treatments for asthma could include strategies to alter the cytokine/chemokine balance. It is evident that the current ICS are already very efficient and safe, it will be difficult to introduce further improved formulations. Perhaps the most fruitful effort shall be in developing patient friendly easy to use targeted delivery systems. The newer therapies are planned for the several upstream targets and may have potential to prevent the disease. Various potential therapies are being worked upon like-targeting prevention of T cell activation, modulation of Th-1/Th-2 differentiation, inhibition of Th-2 related cytokines, Th-1/Th-2 modulation, inhibition of downstream mediators etc. The new strategy shall perhaps lie with matching the patients and their disease with the most suitable therapy.

Influence of cellulose polymers type on in vitro controlled release tablets containing theophylline

In this study, the effect of ethylcellulose (EC) and 6 types of hydroxypropylmethylcellulose (Methocel® K100M, K100MPRCR, K15MPRCR, K4MPRCR, K4M PR and E4MCR) on release profile of theophylline from matrix tablets was evaluated. Formulations tablets were prepared by either wet granulation or direct compression technique. The tablets were evaluated for physical characteristics and in vitro release of drug was performed as described in USP 30 ed. (Test 3). All formulations with cellulose polymer produced tablets easily and with physicals characteristics in accordance with official limits. Drug dissolution tests showed that formulations with 15 percent of Methocel® K4MPR, 15 percent of Methocel® K4MPRCR and 30 percent of Ethocel® N10STD, obtained by direct compression method, complied with official specifications, in terms of release profile and diffusion was the main mechanism involved in theophylline delivery.

Os efeitos das variáveis das formulações na liberação da teofilina a partir da hidroxipropilmetilcelulose (HPMC) e etilcelulose (EC) em comprimidos matriciais foram estudados. Formulações de comprimidos foram preparadas pelos métodos da granulação úmida ou compressão direta usando diferentes viscosidades de HPMC. Propriedades físico-químicas dos comprimidos e liberação do fármaco foram estudadas conforme dissolução descrita no Teste 3 da Farmacopéia Americana 30ed. Ensaios "in vitro" mostraram que as formulações com 15 por cento de Methocel® K4MPR, 15 por cento de Methocel® K4MPRCR e 30 por cento de Ethocel® N10STD obtidas por compressão direta apresentaram bom perfil de liberação de teofilina e a difusão foi o principal mecanismo envolvido na liberação.

Involvement of adenosinergic receptors in anxiety related behaviours.

In the present study, the effect of adenosine (A1 and A2 receptor agonist), caffeine (A2A receptor antagonist), theophylline (A2A receptor antagonist) and their combination was studied in anxiety related behaviours using elevated zero maze and elevated plus maze paradigms and compared their various behavioural profiles. Adenosine (10, 25, 50,100 mg/kg) significantly showed anxiolytic effect at all the doses, whereas caffeine (8, 15, 30, 60 mg/kg) and theophylline (30, 60 mg/kg) showed psychostimulatory action at lower doses and anxiogenic effect at higher doses. Pretreatment with caffeine (8, 15, 30 mg/kg) and theophylline (30 mg/kg) reversed the anxiolytic effect of adenosine. The study suggested the involvement of adenosinergic receptor system in anxiety related behaviours.

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.

comparison study between theophylline and placebo in passage of ureteral stones

Considering the high prevalence of urinary system stones and that nonmedical treatments have more costs and side effects, we decided to evaluate the effect of theophylline in the passage of ureteral stones. One hundred and fifty patients with ureteral stones were assigned into groups A and B, whose age, sex, size of stone, and location of stone were matched together. Patients' ages ranged from 17 to 67 years. In group A theophylline [200 mg BID] was administered and group B received placebo for six weeks. Both groups were followed up by visits every fortnight and radiological assessment was performed at the end of the sixth week. The proportion of patients whose stones were passed was compared between the two groups. In group A with theophylline consumption 46 out of 75 [61.3%] passed their stones. The mean duration between the initiation of the treatment with theophylline and stone passage was18.3 days. In group B with placebo, the stone passage occurred in 31 out of 75 [41.3%] patients [p<0.032] and the mean duration was 24.8 days [p<0.05]. With regard to the findings of this study, it seems that theophylline can increase the rate of ureteral stone passage and as well, accelerate it

Lactic acidosis associated with the usual theophylline dose in a patient with asthma

Metabolic and electrolyte abnormalities, including hypokalemia, hyperglycemia and lactic acidosis, are associated with theophylline overdose. However, we report an unusual case of sinus tachycardia, lactic acidosis, hypokalemia and hyperglycemia associated with the usual theophylline dose in a patient with asthma. The theophylline dose was 200 mg orally twice daily. Three hours after administration of the third dose, the patient experienced palpitation. An electrocardiogram showed a sinus tachycardia. Arterial blood gas analysis revealed a mixed metabolic acidosis and respiratory alkalosis. Serum lactate level was 51 mmol/L (normal 0.7~2.1 mmol/L). Biochemistry results were sodium 136 mEq/L, chloride 99 mEq/L, potassium 1.9 mEq/L and glucose 204 mg/dL. Our case suggests that a possibility of theophylline-associated metabolic abnormalities should be considered when an asthmatic patient given the usual theophylline dose presents with lactic acidosis, hypokalemia and hyperglycemia of unknown etiology.

Theophylline toxicity in Thai children.

Theophylline is a useful drug in the treatment of respiratory diseases with bronchospasm but it has very narrow safety margin. The study was carried out in 44 admitted Thai children with plasma theophylline levels > 20 microg/ml to determine the association between blood levels and symptoms of theophylline toxicity. The prevalence of theophylline toxicity (plasma theophylline level > 20 microg/ml) in Thai children is about 11%. Thirty-four percent of the patients who had theophylline levels less than 30 microg/ml and 78% of those who had levels more than 30 microg/ml had symptoms of theophylline toxicity. The symptoms were related to the gastrointestinal tract (34%), cardiovascular system (18.2%), neurological system (6.8%) and metabolism (54.5%). The possible causes of theophylline toxicity were respiratory tract infection, theophylline overdosage, interaction with other drugs, impairment of liver function, congenital heart disease and theophylline usage in neonates. Theophylline is still a useful drug but should be used with caution. Theophylline levels should be checked in every child who receives theophylline.

Influence of kinnow juice on the pharmacokinetics of sustained release theophylline in healthy male volunteers.

The effect of kinnow juice on the pharmacokinetics of a single dose of sustained release theophylline was investigated in healthy male volunteers. In a two phased open cross-over randomized study, ten healthy male volunteers were given sustained release theophylline (300 mg) along with 300 ml of water or kinnow juice, a routinely used citrus juice in India. Blood samples were collected at different time points from 0-48 hours. Plasma was assayed for theophylline by a HPLC method and various pharmacokinetic parameters were calculated and compared. The theophylline levels were lower at all the time points with kinnow juice co-administration as compared to water but were significantly so only during the absorption phase from 1-4 hours. The values for all the pharmacokinetic parameters evaluated were on the lower side with kinnow juice except Tmax which was slightly delayed. None of these alterations was found to be significantly different. The results indicate that since there is an interference with the absorption of the drug, the patients may be advised not to consume kinnow juice when taking a slow release theophylline preparation and the monitoring of plasma concentrations of theophylline in patients who routinely consume kinnow juice in their diet might be helpful in better management of these patients.

Drug release from carbomer 934 matrices

The main objective of this investigation was to describe the mechanismof drug release from Carbomer 934 hydrogel matrices and to evaluate the effect of polymer level, diluent type, and matrix restriction using customized device (that permits only one surface of the tablet to be exposed to the dissolution medium) on theophylline release from Carbomer matrices. Formulations containing theophylline (10 percent), Carbomer (10 percent, 30, 50 percent), direct compressible diluent (lactose fast flo, Avicel PH-101, Emcompress) and magnesium stearate (0.75 percent) were compressed at a target tablet weight of 450 mg and target hardness of 7-9 Kp. USP Apparatus 1, was used to test the drug release and Korsmeyer equation was used to describe the mechanism of drug release from Carbomer matrices. Results show that the release profile and release mechanism from Carbomer matrices were influenced by Carbomer level, diluent type, and matrix restriction. In general the release mechanism was anomalous (non-Fickian) except for 10 percent and 30 percent Carbomer level and in Avicel PH-101 matrices, where, the release mechanism appears to follow super case II where, the n exponent has value greater than 0.89. All formulations selected appear to follow zero order release only up to 120 minutes. Restriction of tablet surface resulted in a shift toward Fickian release. This study demonstrated that it is possible to modify the drug release mechanism and rate, by changing polymer level, diluent type, and imposing physical restriction on the surface of the matrix.

El control de los desencadenantes inhalables disminuye el requerimiento prolongado de farmacoterapia en pacientes asmáticos / Control of inhalable triggering factors decrease pharmacotherapy requirement in patients with asthma

Los conocimientos adquiridos durante la última década de investigación sobre la inmunopatología del asma han demostrado que el proceso inflamatorio es un factor preponderante de la enfermedad. Además de la herencia, la presencia de desencadenantes inhalables son los elementos predisponibles más importantes. El presente trabajo constituye un estudio clínico terapéutico longitudinal, diseñado para valorar el efecto de la combinación del uso de farmacoterapia y control medio-ambiental, en 45 pacientes asmáticos pediátricos procedentes de la consulta de Inmunología Clínica. Los pacientes admitidos en el estudio, presentaron por lo menos dos crisis asmáticas mensuales durante los últimos cuatro meses. Al ingresar en nuestra consulta, los pacientes recibieron tratamiento farmacológico único con teofilina (grupo A), beclometasona (grupo B) o salbutamol (grupo C), durante las dos primeras semanas, combinado con medidas específicas de control de desencadenantes inhalables. Después de un período de observación de 6 meses, se evidenció mejoría clínica estable, asociado a una modificación favorable del FEVI, CVF y PEF, disminución significativa de los niveles séricos de IgE en los tres grupos (p<0,02; 0,005 y 0,02 respectivamente) independientemente del fármaco utilizado. Durante el estudio se monitoreo la cantidad de ácaros, presentes en muestras tomadas de las viviendas, observándose una disminución de los mismos, asociado con la mejoría clínica de los pacientes. Sólo en aquellos pacientes en quienes persistieron los síntomas (grupo A 31 por ciento, grupo B 29 por ciento y grupo C 9 por ciento) se comprobó que las medidas de control de desencadenantes ambientales no se cumplieron cabalmente. Esos pacientes mejoraron notoriamente al sistematizar la aplicación de las medidas higiénicas sin requerir nuevamente de farmacoterapia. estos resultados nos permiten sugerir que la disminución de los desencadenantes inhalables es fundamental para el control de los pacientes asmáticos, en combinación con una farmacoterapia

Comparative study of the pharmacokinetic characteristics of slow release theophylline oral preparations in Thai children with persistent asthma.

Significant differences in the rate and extent of absorption exist between slow release theophylline (SRT) preparations. The pharmacokinetic characteristics of Xanthium were compared with those of Theo-Dur in twelve Thai children with stable persistent asthma by randomized, double blind, crossover study. Serum theophylline concentrations (STCs) were determined by fluorescence polarization immunoassay. The pharmacokinetic parameters were estimated by using a computer program (Topfit 2.0). The STCs, at steady state after different doses, were predicted by using the modified Wagner-Nelson Equation. The mean resident time (MRT) and apparent T1/2 were significantly larger for Xanthium, but the Cmax and AUC0-infinity of Xanthium were significantly lower than those of Theo-Dur. The Frel of Xanthium was 80.1% relative to Theo-Dur. The appropriate dosing interval of both preparations for Thai children was twice a day.

Caracterización de los pacientes portadores de enfermedad pulmonar obstructiva crónica y su respuesta a ipratropio y teofilina / Characterization of chronic obstructive pulmonary disease patients and their response to ipratropium and theophylline

La respuesta clínica y funcional a dos broncodilatadores, bromuro de ipratropio y teofilina en enfermedad pulmonar obstructiva crónica fue evaluada en 62 pacientes, procedentes del programa de enfermedades bronquiales obstructivas del Instituto Nacional del Tórax. Conjuntamente se describen las características clínicas, radiológicas y de laboratorio de los 62 pacientes. El estudio duró 6 meses y los pacientes recibieron bromuro de ipratropio 40 mg 4 veces al día por vía inhalatoria o teofilina oral 200 mg 2 veces al día. Por distribución aleatoria se dividieron en dos series : ipratropio (n=30) y teofilina (n=32) realizándose cambio de terapia a los 3 meses. Los pacientes fueron sometidos mensualmente a un seguimiento clínico y funcional durante el tiempo de duración del estudio. Al final del período de tratamiento, la disnea mejoró solo durante el período con ipratropio (p<0,01), aunque no se apreció cambios significativos en la función pulmonar con ninguno de los dos medicamentos. Durante el período con ipratropio se presentó una menor frecuencia de reacciones adversas severas (p < 0,05)

Theophylline clearance in undernourished asthma patients.

Theophylline clearance is altered by many drugs and diseases that may be associated with undernutrition. Therefore, we studied theophylline clearance in 12 undernourished [body mass index (BMI) less than 19] and 12 well nourished asthma patients (body mass index more than 19). Uncoated theophylline tablet (200 mg, 300 mg dose 5 mg/kg approx) was administered orally to each asthma patient after 12 hours overnight fasting. Serum theophylline concentrations were estimated after 2, 4, 6, 8 hours of drug administration and it was calculated from log conc: time curve. Undernourished asthma patients had a mean theophylline clearance of 85.6 (SE = 6.2) ml/hr/kg while it was 125.6 (SE = 3.8) ml/hr/kg in well-nourished asthma patients. The difference between two groups was highly significant (p < 0.01). We conclude that theophylline clearance is significantly lower in undernourished asthma patients and they will require a lower maintenance dose of theophylline.

Intersubject variability of serum theophylline concentration after single dose of uncoated controlled release theophylline tablet administration in asthmatic patients.

Various reports indicate significant intersubject variation in the rate of absorption of controlled release theophylline products that are commercially available. Serum theophylline concentration was estimated in 17 asthma patients treated with controlled release theophylline tablet (mean dose: 5.6 +/- 0.6 mg/kg, mean body wt: 49.82 +/- 9.05 kg). The mean maximal concentration (Cmax) of 5.57 +/- 1.65 micrograms/ml occurred at mean time of maximal concentration (Tmax) of 3.3 +/- 1.36 (mean +/- SD) hours. Mean minimal concentration (Cmin) was 3.164 +/- 1.1 micrograms/ml (mean +/- SD) at mean time of minimal concentration (Tmin) of 5.77 +/- 1.77 (mean +/- SD) hours. The mean percent fluctuation was 112.95 +/- 183.45 (mean +/- SD) but in 4 out of 17 patients, percent fluctuation was 107.29 to 823.10. Therefore, 23.5% patients treated with controlled release theophylline tablet had wide fluctuations in serum theophylline concentration.

A single-dose comparison of three slow-release theophylline oral preparations in healthy Thai volunteers.

The study was done to compare the pharmacokinetic characteristics of three slow-release theophylline (SRT) preparations. Twelve healthy nonsmokers were randomly assigned a single dose of the following treatments at weekly intervals: Theo-Dur, Theo-24 or Xanthium orally, or aminophylline intravenously. Serially collected serum samples were analyzed for theophylline with use of fluorescence polarization immunoassay (FPIA). All three SRT preparations showed reliable absorption characteristics, but Theo-Dur had a shorter Tmax and MRT and a higher Ka. The pharmacokinetic characteristics of Theo-24 and Xanthium were similar except that Xanthium had lower bioavailability. Using single dose data for simulation of steady state pharmacokinetics, we found that a once-a-day dosage regimen with either Theo-24 or Xanthium would maintain serum levels within the therapeutic range for average non-smoking young adults whereas more frequent dosing intervals with Theo-Dur would be more appropriate. Our results argue against open substitution of SRT preparations without, close monitoring of the serum theophylline concentrations when a change is made.