Serum Theophylline Concentrations Research Articles

Serum Theophylline Concentrations in very Preterm Neonates Receiving Intravenous Aminophylline for Apnea

Objective: To determine the percentage of neonates who achieved therapeutic theophylline level (TTL) after receiving standard IV loading/maintenance aminophylline doses. To assess factors associated with achieving therapeutic theophylline concentrations and to describe adverse effects of aminophylline. Materials and Methods: This was a pilot, cross-sectional study. Preterm neonates ≤34 weeks’ gestation for which aminophylline was indicated for treatment of apnea were enrolled. Standard IV aminophylline dosage is 8 mg/ kg loading dose, followed by 1.5 mg/kg maintenance dose every 8 hours. Serum theophylline concentrations were measured prior to the 8th maintenance dose. Descriptive statistics, univariate and multivariate analyses were performed. Results: Twenty-five neonates (52% female) were enrolled: mean (standard deviation) gestational age and birth weight were 30.4 (2) weeks and 1,277 (415) grams, respectively. Aminophylline was initiated at a median (25%tile, 75%tile) postnatal age of 4 (1, 8) days. Baseline heart rate prior to the loading dose was 153 (13) beats-per-minute. Sixty percent of neonates achieved a therapeutic theophylline level. In the univariate analysis, being male and postnatal age ≤5 days were associated with successfully achieving a TTL. After adjusting for gender, postnatal age ≤5 days was the only factor associated with achieving a TTL (adjusted odds ratio 17.7, 95% confidence interval: 1.9, 164.4). Tachycardia and feeding intolerance were observed in 44% and 24% of neonates, respectively. Conclusion: Current IV aminophylline dosing conditions in Thailand achieved TTL in approximately two-thirds of neonates, suggesting therapeutic drug monitoring is beneficial for guiding dosing. A higher maintenance dose could be considered for neonates older than 5 days.

AHA statement addresses growing list of drugs that induce arrhythmias

AHA statement addresses growing list of drugs that induce arrhythmias

Formulation of Extended Release Theophylline Tablets Experimental, Modelling and Bioequivalence Studies

Extended release drugs formulations are intended to continuously release medication over a prolonged period, after a single dose. Drugs which have a narrow therapeutic window and a moderate half life are good candidates for such formulations. One approach to such formulations is to embed the drug in a matrix which 'would act as a release retardant. We describe here our studies on the formulations of an extended release theophylline tablet using polymer matrices. Different acrylate copolymers sold in the market under the "Eudragit" label were subjected to experiment. Microcrystalline cellulose and calcium sulphate dihydrate were used as filler excepients. The theophylline release patterns of the different formulations were studied, at 37aC in phosplate buffers. The theophylline concentration were measured by Ul/ absorption spectroscopy A careful study of the release patterns of different formulations let to a formulation using Eudragit=E RSPO, a trimenthylammonioethyl methacrylate copolymer and calcium sulphate dihydrate, which conformed with the following release pattern in accordance with USP 25. Time (hours) % Drug Released 1 10 - 30 2 30 - 55 4 55 - 80 8 >80 This formulations 'was used to prepare tablets with two dosages, paediatric dose (125 mg) and adult dose (250 mg). The adult dose was subjected to a bioequivalence study against an established commercially available slow release 250 mg formulation (Neulin 250 SR, 3M Pharmaceuticals, Australia) Twenty healthy male volunteers participated in the study. Theophylline concentrations in serum were determined by Fluorescence Polarization Immunoassay. There was no significant difference between the two formulations in basic bio availability and pharmacokinetic parameters (AUC CiliaIa'nd Tlllal The new Theophylline ER 125 mgformulation developed is nOH'being manufactured by the State Pharmaceutical Manufacturing Corporation (SPMC). a. State Pharmaceutical Manufacturing Corporation, Sri Johne Kothalawala Estate, Ratmalana, Sri Lanka 071-1815117 b. Dean Faculty 0.( Natural Science, University of Sri Jayawrdanapura, Nugegoda c. Pharmacology Division, Faculty of Medicine, University of Sri Jayawrdanapura, Nugegoda.

Age-Associated Theophylline Metabolic Activity Corresponds to the Ratio of 1,3-Dimethyluric Acid to Theophylline in Mice.

Age is known as one of influencing factor for theophylline (TP)-metabolizing capacity. In a previous our study, the ratio of TP and its major metabolite 1,3-dimethyluric acid (DMU) in serum (DMU/TP) is a useful index to estimate TP-metabolizing capacity, and this value markedly increased by influencing factor, such as the history of smoking. However, it is unknown whether DMU/TP values in serum reflect age-associated changes of TP-metabolizing capacity. In this study, the effect of age on the DMU/TP values in serum were investigated using mice of different age due to the limited blood sampling in human. The concentrations of TP and its metabolites in mouse serum were simultaneously measured using HPLC. As observed in human serum, serum TP concentrations were closely correlated with DMU concentration in mice, which indicates that the DMU/TP ratio is a good indicator of TP metabolic ability in mice. When TP was administered subcutaneously in 2-28-week-old mice, age-associated changes in the DMU/TP ratio in mice were observed. In conclusion, age-associated changes in TP-metabolizing capacity can be estimated by the DMU/TP ratio in serum.

A retrospective study of theophylline-based therapy with tracheal collapse in small-breed dogs: 47 cases (2013-2017).

Theophylline acts as a bronchodilator and has an anti-inflammatory effect. In addition, theophylline can be applied in patients where there are concerns regarding the side-effects of corticosteroids. This retrospective case series evaluated theophylline-based therapy in tracheal collapse (TC) canine patients. Forty-seven dogs with TC that received theophylline-based therapy during 2013–2017 were investigated. A fluoroscopic examination was performed to diagnose and grade TC. Theophylline was prescribed (7.5–30 mg/kg PO q12h) and the theophylline serum concentrations were measured. Coughing was assessed using a coughing scoring scale. The mean coughing score decreased after the theophylline-based therapy compared with that observed before treatment. Clinical improvements were observed in 46/47 patients (97.9%). As the intrathoracic TC grading increased, the final theophylline dosage also increased (p value 0.019). The symptom-free period (SFP) with therapy was 189.7 ± 194.45 days (range, 0–720 days) and there was no statistically significant correlation between the SFP and age, sex, or TC grade on fluoroscopy. Although theophylline has generally been used as a third-line treatment, it was used as the main treatment in this study and most patients showed improvements. Dogs have a wider therapeutic index of serum concentrations than humans, and any undesirable effects were easily overcome. With further research, this therapy may prove to be a useful approach, but its safety for long-term use in the treatment of canine TC patients needs to be established.

Serum theophylline after multiple dosing with transdermal gels in cats.

Our objectives were, first, to determine if therapeutic serum theophylline concentrations could be achieved using long-term, once-daily dosing of transdermal theophylline and, secondarily, to evaluate the difference between two transdermal theophylline formulations. Seven healthy cats, 1-10 years of age, were evaluated in a two-way, randomized, double-blinded, crossover study. Participants received transdermal theophylline at 15 mg/kg for 21 days in either pluronic lecithin organogel (PLO) or Lipoderm formulation. On day 22, blood was collected 2, 6, 14 and 24 h after dosing. After a 14 day washout period, blood was collected to verify non-detectible theophylline concentrations. The alternate formulation was administered for 21 days, and sampling was repeated. Serum theophylline concentrations were determined using an automated immunoassay. Serum concentrations were compared between formulations using a two-way random-measures ANOVA and over time within a formulation using a repeated-measures ANOVA. Therapeutic serum theophylline concentrations were achieved for 2/7 cats in each group. Of 56 serum theophylline measurements obtained, only seven (13%) were within the therapeutic range. No significant difference was detected in drug concentrations achieved by the transdermal formulations at any time point. In addition, no significant difference in serum theophylline concentrations was noted between time points for PLO ( P = 0.751) or Lipoderm ( P = 0.107). Once-daily transdermal dosing of theophylline does not reliably achieve therapeutic concentrations. Individual cats may achieve therapeutic concentrations. No significant difference was noted between PLO and Lipoderm formulations. Therefore, transdermal theophylline formulations should not be considered as a first-line therapy in feline asthma patients.

Factors affecting the efficacy and safety of aminophylline in treatment of apnea of prematurity in neonatal intensive care unit

The factors affecting the safety and efficacy of aminophylline use in the treatment of apnea of prematurity (AOP) in the neonatal intensive care unit (NICU) are not clear. In this study, we aimed to evaluate the potential factors affecting the efficacy and safety of aminophylline in AOP treatment at standard doses and to determine appropriate patients for this therapy. Over a 3-year period (January 2012 to December 2014), the medical records of 206 preterm infants with apnea who were admitted to the NICU of our hospital to receive aminophylline infusions were retrospectively reviewed. These infants were subjected to routine theophylline monitoring by reversed-phase high performance liquid chromatography. The primary outcome measures were the efficacy of aminophylline treatment and adverse reactions observed upon administration. One-hundred and twenty-seven (61.65%) infants were considered to have undergone effective therapy and classified accordingly. Gestational age, body weight at the initiation of aminophylline, and serum theophylline concentration were identified as protective factors of therapeutic efficacy. Receiver operating characteristic (ROC) analysis indicated cutoff values of 30.36 weeks for gestational age and 1.69kg for body weight at initiation of aminophylline administration for ensuring high efficacy of aminophylline for AOP. Fifty-three (25.73%) infants had adverse reactions. Birth weight and serum concentration of theophylline were associated with an increased risk of adverse reactions, with odds ratios of 0.167 and 1.346, respectively. The ROC curves indicated a birth weight cutoff value of 1.48kg. Infants with apnea and gestational age >30.36 weeks, body weight at initiation of aminophylline treatment above 1.69kg, and birth weight >1.48kg are suitable for treatment with aminophylline. Monitoring of serum theophylline concentration should be implemented in the absence of clinical response or in case of suspected adverse reactions.

Decrease of the affinity of theophylline bind to serum proteins induced by flavonoids and their synergies on protein conformation

In this study, the single and simultaneous interactions of theophylline and flavonoids with human serum albumin (HSA) were studied by multi-spectroscopic and molecular docking approaches. The influences of flavonoids on the binding constant (Kb) and the binding distance (r) of theophylline bind to HSA were determined and the changes of HSA conformation caused by the synergies of theophylline and flavonoids were investigated. Because theophylline, rutin and baicalin are all bond to the same binding site, the competitive bind of theophylline and flavonoids to HSA leads to the reduction of the Ka value of theophylline binding to HSA. The addition of rutin and baicalin can increase the value of r of theophylline binding to HSA, which further confirm the existence of the competitive bind of theophylline and flavonoids to HSA. Additionally, the results of synchronous fluorescence, three-dimensional fluorescence and circular dichroism spectra indicate that the presence of rutin and baicalin can give rise to the further changes of HSA conformation. These results suggest that the intake of flavonoid-rich food and beverages can increase the serum concentrations of theophylline and induce a high incidence of toxic symptom in clinic.

Prediction of serum theophylline concentrations and cytochrome P450 1A2 activity by analyzing urinary metabolites in preterm infants.

The purpose of this study was to explore clinical markers reflecting developmental changes in drug clearance by preterm infants. Preterm infants administered aminophylline or theophylline to treat apnoea of prematurity were enrolled in this study. Trough and one of 2h, 4h or 6h post-dose blood samples and urine samples were collected during steady state, to determine the concentrations of theophylline and its targeted metabolites. CYP1A2*1C and CYP1A2*1F genotypes were analyzed. Total, renal and nonrenal clearances of theophylline were calculated, and cytochrome P450 1A2 (CYP1A2) activity was obtained from the ratio of 1-methyluric acid and 3-methylxanthine to theophylline in urine. Multiple linear regression analysis was performed to evaluate the relationships between theophylline clearance and the clinical characteristics of preterm infants. A total of 152 samples from 104 preterm infants were analyzed. A strong association between the serum trough and urine theophylline concentrations was found (P<0.001). Total, renal and nonrenal clearances of theophylline were 0.50±0.29mlkg-1 min-1 , 0.16±0.06mlkg-1 min-1 and 0.34±0.28mlkg-1 min-1 , respectively. CYP1A2 activity correlated positively with the postnatal age and postmenstrual age. However, CYP1A2 genotype was not associated with CYP1A2 activity, which was significantly associated with nonrenal clearance. CYP1A2 activity, postnatal age , weight and 24-h urine output were significantly associated with total theophylline clearance. CYP1A2 activity can be monitored using noninvasive random urine samples, and it can be used to assess developmental changes in theophylline clearance by preterm infants.

Aminophylline-associated irritable behaviour in preterm neonates

AimThis study investigated the effect of aminophylline on behaviour and autonomic function in the preterm period. MethodSubjects were preterm infants cared for in the Oita University hospital from August 2012 to October 2014. The group that was administered aminophylline (Am+) and the group that received no aminophylline (Am−) included 11 cases that exhibited a mean gestational age of 28weeks 5days and a mean birth weight of 1109g and 8 cases that exhibited a mean gestational age of 30weeks 5days and a mean birth weight of 1223g, respectively. Intravenous aminophylline was administered continuously at a dose of 4–6mg/kg/day followed by oral therapy when the infant suffered repetitive apnoea.Two-hour video recordings were obtained every 2weeks, and electrocardiograms were performed simultaneously. Onset-offset and tremulous movements in general movement (GM) optimality list were used as indices of behaviour. Autonomic functions were investigated via heart-rate and heart-rate variability measurements using frequency domain spectral analysis and the MemCalc method. We compared indices in 4 periods: 30–31, 32–33, 34–35 and 36–37weeks gestation. ResultsThe Am+ group exhibited significantly low optimality of tremulous movements at 32–33weeks gestation. The autonomic parameters did not differ significantly between the Am+ and Am− groups. There was no significant correlation between GMs optimality score and serum theophylline concentration. ConclusionAminophylline administration was associated with transient irritable behaviour without autonomic changes in the preterm period.

The Evidence for Intravenous Theophylline Levels between 10-20mg/L in Children Suffering an Acute Exacerbation of Asthma: A Systematic Review.

BackgroundIntravenous theophyllines are a second line treatment for children suffering an acute exacerbation of asthma. Various guidelines and formularies recommend aiming for serum theophylline levels between 10-20mg/l. This review aims to assess the evidence underpinning this recommendation.MethodsA systematic review comparing outcomes of children who achieved serum theophylline concentrations between 10-20mg/l with those who did not. Primary outcomes were time until resolution of symptoms, mortality and need for mechanical ventilation. Secondary outcomes were date until discharge criteria are met, actual discharge, adverse effects and FEV1.Data sourcesMEDLINE, CINAHL, CENTRAL and Web of Science. Search performed in October 2015.Eligibility criteriaInterventional or observational studies utilizing intravenous theophyllines for an acute exacerbation of asthma in children where serum theophylline levels and clinical outcomes were measured.Findings10 RCTs and 2 observational studies were included. Children with serum levels between 10-20mg/l did not have a reduction in duration of symptoms, length of hospital stay or need for mechanical ventilation or better spirometric results compared with levels <10mg/l. Levels above 20mg/l are not associated with higher rates of adverse effects. This study is limited due to heterogeneity in the way theophylline levels were reported and poor surveillance of adverse effects across studies.ConclusionDosing strategies aiming for levels between 10-20mg/l are not associated with better outcomes. Clinicians should rely on clinical outcomes and not serum levels when using intravenous theophyllines in children suffering an acute exacerbation of asthma.

Evaluation of theophylline therapeutic drug monitoring service

BackgroundTherapeutic monitoring of theophylline serum levels is required due to its narrow therapeutic range and marked interindividual pharmacokinetic variability. We evaluated therapeutic drug monitoring service for theophylline in Slovenian clinical setting, which currently includes no pharmacokinetic evaluation of measured theophylline serum concentrations. MethodsWe retrospectively evaluated 127 randomly selected theophylline serum level determinations performed in 2010 in a tertiary clinical setting in Slovenia. Demographic data, information on theophylline dosing and blood sampling was collected from patients’ data files. Authors evaluated the appropriateness of the following procedures: indications for theophylline serum concentration measurement, timing of blood sampling and dosage adjustments made after theophylline levels had been reported. On the basis of collected data, population pharmacokinetic model for theophylline was built and further used for the evaluation of dosage adjustments. ResultsOut of 127 cases, 107 (84.3%) had clinically justified indication for theophylline serum level measurement. Near half of measurements (44.9%) were performed before the steady state of theophylline concentrations was established. 65% of measured concentrations were subtherapeutic and the average measured concentration was below therapeutic range (53.1 μmol/L). Despite subtherapeutic concentrations the dose of theophylline was mainly not increased. Pharmacokinetic model enabled the calculation of average optimal daily dose which was significantly higher than the average actual daily dose used (876 mg vs. 572 mg, p &lt; 0.001). ConclusionsTheophylline TDM service should be optimized and pharmacokinetic interpretation of theophylline serum levels should be integrated into clinical practice.

Aminophylline, administered at usual doses for rodents in pharmacological studies, induces hippocampal neuronal cell injury under low tidal volume hypoxic conditions in guinea-pigs

To establish whether aminophylline, administered at usual doses for rodents in pharmacological studies, induces brain injury in systemic hypoxaemia in guinea-pigs. A hypoxaemia (partial oxygen tension of arterial blood (PaO₂) = 40-60 mmHg) model was developed by low tidal volume mechanical ventilation in guinea-pigs. Under hypoxic conditions, aminophylline significantly increased the concentration of brain-specific creatine kinase in the serum in a dose- and time-dependent manner. A reduced number of hippocampal neuronal cells in the CA1 region, an increase in the concentration of neuron-specific enolase (NSE) in cerebrospinal fluid (CSF), an increase in lipid hydroperoxides and a decrease in the ratio of glutathione to glutathione disulfide in the brain tissues were also observed. These effects were not observed when aminophylline at the same doses was administered under normoxic conditions (PaO₂ = 80-100 mmHg). There was no difference in either serum or CSF concentrations of theophylline between normoxic and hypoxic conditions. Another methylxanthine, caffeine, did not increase the concentration of NSE in CSF. Aminophylline potentially induces brain damage under hypoxic conditions. We suggest that aminophylline treatment has adverse effects in patients with hypoxaemia subsequent to respiratory disorders such as asthma.

A clinical trial for therapeutic drug monitoring using microchip-based fluorescence polarization immunoassay

Microchip analysis is a promising method for therapeutic drug monitoring. This led us to evaluate a microchip-based fluorescence polarization immunoassay (FPIA) system for point-of-care testing on patients being treated with theophylline. The sera were collected from 20 patients being treated with theophylline. Fluorescence polarization was measured on the microchip and theophylline concentrations in serum were obtained. Regression analysis of the correlations was done between the results given by the microchip-based FPIA and the conventional cloned enzyme donor immunoassay (CEDIA), and between the results given by the microchip-based FPIA and the conventional particle-enhanced turbidimetric inhibition immunoassay (PETINIA). We successfully carried out a quantitative analysis of theophylline in serum at values near its therapeutic range in 65 s. The results obtained by the microchip-based FPIA correlated well with CEDIA and PETINIA results; the correlation coefficients (R(2)) were 0.986 and 0.989, respectively. The FPIA system is a simple and rapid method for point-of-care testing of drugs in serum, and its accuracy is the same as the conventional CEDIA and PETINIA. It is essential to use real samples from patients and to confirm good correlations with conventional methods for a study on the realization of microchip.

Interaction between pefloxacin and aminophylline in genetically epilepsy-prone rats.

The effects of a chronic treatment with pefloxacin on aminophylline-induced seizures in genetically epilepsy-prone rat have been investigated. Two series of experiments were performed. In the first, animals received pefloxacin orally twice a day for five days, then were administered aminophylline intraperitoneally and the occurrence of seizures was evaluated. In the second series of experiments, theophylline serum concentration was evaluated in rats subject to the same experimental protocol. Pefloxacin significantly, and in a dose-dependent manner, increased the occurrence of seizure phases induced by aminophylline, but did not influence theophylline serum levels measured at different times after the injection of aminophylline. We suggest that additive neurotoxic effects of both pefloxacin and aminophylline might contribute to the increased severity of seizure score. The possible role of GABA-benzodiazepine, excitatory amino acid and purinergic mechanism, and the role of pharmacokinetic factors are discussed.

Therapeutic drug monitoring in community pharmacy — a feasibility study

Abstract A study was carried out to examine the feasibility of providing a community pharmacy based theophylline therapeutic drug monitoring service for asthma patients. Twenty-two patients attending 12 general practitioners (GPs) participated in the study. Their serum theophylline concentrations were measured and via the use of patient medication records an estimate of compliance with the prescribed dosage regimen was made. If the latter was satisfactory and the serum theophylline concentration was not within the target range of 10–20 μg/ml agreed with GPs, a computer program using Bayesian kinetic principles was used to calculate an appropriate dosage adjustment. This dosage adjustment was made after agreement was obtained from each patient's GP. Patients found to be non-compliant were counselled. Follow-up assessments were carried out after three and nine months; compliance was also assessed at 12 months. Eighteen per cent of patients had serum concentrations within the target range at the beginning of the study; this improved significantly (P&amp;lt;0.05, chi-squared) to 72 per cent and 68 per cent at three and nine months, respectively. Compliance data also improved significantly (P&amp;lt;0.01) over the study period, from a baseline of 59 per cent compliant to a final figure of 86 per cent. Both outcome measures indicate the value of the community pharmacy based monitoring service.

Abasic site-based DNA aptamers for analytical applications

We here describe a class of duplex DNA aptamers that possess an abasic site as an active cavity for binding events. A structurally optimised 23-meric duplex (5′-TCT GCG TCC AGX GCA ACG CAC AC-3′/3′-AGA CGC AGG TCT CGT TGC GTG TG-5′, X = abasic site; a propyl linker, T = receptor base) binds to riboflavin with a dissociation constant of 1.9 μM (at 20°C, pH 7.0, I = 0.11 M), and it exhibits a high selectivity for riboflavin over flavin mononucleotide and flavin adenine dinucleotide. A fluorescent signalling aptamer is also developed by the incorporation of fluorescent 2-aminopurine (2-AP) into the duplex to flank the abasic site. This 2-AP-modified abasic site-containing duplex DNA (5′-TCTGC GTCCT PXT TAACG CACAC-3′/3′-AGACG CAGGA TCA ATTGC GTGTG-5′, P = 2-AP, X = abasic site; a propyl linker, C = receptor base) is capable of selectively binding to the bronchodilator theophylline with a dissociation constant of 10 μM (at 5°C, pH 7.0, I = 0.11 M), and it is applicable to monitoring serum theophylline concentrations. In addition, we describe a design strategy for label-free aptamer-based fluorescence-signalling systems based on an abasic site-binding fluorescent ligand. A DNA aptamer against adenosine is examined as a model system, and an abasic site is designed to be incorporated into the aptamer system, so that the adenosine binding causes either a release or binding of abasic site-binding ligands with a clear fluorescent signalling. The designed system is highly selective and sensitive with a detection limit of 1–2 μM for adenosine. These results are discussed as a potential basis for the further development of an aptamer-based analytical assay.

The indication and effectiveness of low-dose erythromycin therapy in pediatric patients with bronchial asthma.

Korematsu S, Yamamoto K, Nagakura T, Miyahara H, Okazaki N, Akiyoshi K, Maeda T, Suenobu S-i, Izumi T. The indication and effectiveness of low-dose erythromycin therapy in pediatric patients with bronchial asthma. Pediatr Allergy Immunol 2010: 21: 489–492. © 2010 John Wiley & Sons A/STo elucidate the mechanisms of intractable pediatric bronchial asthma and the indication of low-dose erythromycin (EM) therapy, the serum chemokine levels of and the angiogenic factor were evaluated in 55 pediatric patients with bronchial asthma; 7.4 ± 3.5 yr old, who had been treated with inhaled steroid, leukotriene receptor antagonist, theophylline and others for more than a year. Both the levels of interleukin (IL) 8 (p = 0.036) and vascular endothelial growth factor (VEGF) (p = 0.005) were higher in patients with severe type than those of patients with the milder type, while other chemokine levels such as serum eotaxin and MCP1 did not show the correlation with the severity of bronchial asthma. Induction of therapy with low-dose EM induced improvement of the clinical symptoms in patients with severe type and decrease of their serum chemokine levels: IL8; from 736 ± 88 to 75 ± 85 pg/ml (p < 0.0005), and VEGF; from 352.0 ± 160.5 to 132.2 ± 59.9 pg/ml (p = 0.021) within the next 6 months. Moreover, low-dose EM resulted in a decreased daily peak-trough fluctuation rate of the serum theophylline concentration; (Cmax− Cmin)/Cmin, from 1.3 ± 0.5 to 0.5 ± 0.3, which led to the maintenance of effective serum levels. These results indicated that IL8 and VEGF affect the severity of standard therapies resistance intractable bronchial asthma. Through the suppression of these chemokines and maintenance of effective theophylline levels, low-dose EM therapy improves the symptoms of bronchial asthma.

The influence of serum theophylline concentration on the bronchodilating effect of salbutamol inhalation for bronchial asthma

To examine the effects of serum theophylline concentration on the bronchodilating effect of beta 2-stimulant inhalated by patients with bronchial asthma, 200 micrograms-Salbutamol inhalation test was performed on 30 patients with bronchial asthma (from 17 to 71 years old, averaging 49.7; 3 mild, 15 moderate, 12 severe), who had taken theophylline at various oral doses up to 6 hours before the test. Measurements of respiratory function, serum theophylline concentration, blood pressure, pulse rate and the plasma c-AMP and c-GMP concentrations before and one hour after inhalation revealed that inhalation of 200 micrograms salbutamol significantly increased FVC, FEV1.0, PEF and plasma c-AMP (p less than 0.001). No significant change was noted in plasma c-GMP, diastolic pressure or pulse rate. Systolic pressure significantly decreased (p less than 0.05). Furthermore, no significant correlation was noted between the rates of increase (%) in FVC, FEV1.0 and PEF and those in plasma c-AMP, c-GMP and c-AMP/c-GMP in one hour after inhalation. Inaddlition no significant correlation was noted between the rates of increase in FVC, FEV1.0 and PEF one hour after inhalation and serum theophylline concentrations (0-19.3 and 0-21.5 micrograms/ml before and one hour after inhalation, respectively). The above results suggest that the bronchodilating effect of salbutamol inhalated at dose of 200 micrograms is not influenced by the serum theophylline concentration both before and at one hour after inhalation of salbutamol. The bronchodilating effect of salbutamol seems to be ascribable to an increase of intracellular c-AMP level of bronchial smooth muscle.

Hydrogels based on chitosan–xanthan for controlled release of theophylline

The aim of this paper is theophylline (THP) inclusion into xanthan-chitosan polyionic complex (Xa-CS) and the study of its in vitro and in vivo kinetic release. Xa-CS hydrogel was obtained by ionic complexation between two oppositely charged polysaccharides. THP was loaded into the Xa-CS matrix by diffusion of the drug solution. The obtained samples were characterized by FTIR spectroscopy, SEM microscopy and study of the swelling behavior. THP in vitro release experiments were carried out in conditions mimicking the gastrointestinal environment. The chosen drug dose for in vivo study was 15 mg THP/Kg body weight of THP powder or an equivalent dose in complex form. THP serum concentrations were determined by an HPLC assay. The THP peak serum concentration (C(max)) was 7.18 microg/ml for free THP and AUC(0-48) was 25.76 microg h/ml, while in the case of Xa-CS-THP, C(max) was of 5.72 microg/ml and AUC(0-48) = 45.72 microg h/ml. The in vivo study regarding the behaviour of the obtained formulation, showed an increase bioavailability of THP compared to the raw drug, suggesting the possible application of the complex Xa-CS as an oral controlled drug delivery system in the management of chronic pulmonary obstructive disease.