Pharmacokinetics of a 503B outsourcing facility-produced theophylline in dogs.

Theophylline is an important drug for treatment of canine chronic bronchitis and bradyarrhythmias, but new products require validation since pharmacokinetics in dogs can vary by formulation. A new, 503B outsourcing facility-produced theophylline product (OFT) is available for veterinary use. Outsourcing facilities have many advantages over traditional compounding sources including current good manufacturing practice compliance. The purpose of this study was to establish the pharmacokinetics of OFT in dogs. Eight healthy dogs received 11 mg/kg intravenous aminophylline and 10 mg/kg oral OFT followed by serial blood sampling in a two-way, randomized, crossover design with 7-day washout. Plasma theophylline concentrations were quantified by liquid chromatography-mass spectrometry. Bioavailability, maximum concentration, time to maximum concentration, half-life and area under the curve were: 97 ± 10%, 7.13 ± 0.71 µg/mL, 10.50 ± 2.07 h, 9.20 ± 2.87 h, and 141 ± 37.6 µg*h/mL, respectively. Steady-state predictions supported twice daily dosing of the OFT, but specific dosage recommendations are hindered by lack of a canine-specific therapeutic range for plasma theophylline concentration. These findings suggest that the OFT is well absorbed and can likely be dosed twice daily in dogs, but future pharmacodynamic and clinical studies are needed to establish a definitive therapeutic range for theophylline in this species.

No Requirement for Targeted Theophylline Levels for Diuretic Effect of Aminophylline in Critically Ill Children.

OBJECTIVES: To determine the relationship between theophylline trough levels and urine output in critically ill children administered aminophylline as adjunctive diuretic therapy. DESIGN: Retrospective cohort study. SETTING: The PICU of a tertiary care children's hospital. PATIENTS: A mixed population of medical/surgical including postoperative cardiothoracic surgery patients less than 18 years old. INTERVENTIONS: Electronic medical records of all PICU patients admitted from July 2010 to June 2015 were reviewed, and patients who received aminophylline as diuretic therapy were identified. MEASUREMENTS AND MAIN RESULTS: Patient cohort data including demographics, daily aminophylline, furosemide and chlorothiazide dosing, theophylline trough levels, fluid intake, urine output and total fluid balance, blood urea nitrogen, and creatinine levels were abstracted. Multivariate analysis based on a generalized estimating equations approach demonstrated that aminophylline administration, when analyzed as a categorical variable, was associated with an increase in urine output and decreased fluid balance. However, aminophylline dosing, when analyzed as a continuous variable, was associated with neither an increase in urine output nor decreased fluid balance. Theophylline trough levels were not correlated with urine output at 24 hours (p = 0.78) and were negatively correlated with urine output at 48 hours (r = 0.078; p < 0.005). CONCLUSIONS: Aminophylline administration provided a measure of increased diuresis, regardless of dosage, and theophylline trough levels. Therefore, achieving a prescribed therapeutic trough level may not be necessary for full diuretic effect. Because, as opposed to the diuretic effect, the side effect profile of aminophylline is dose-dependent, low maintenance dosing may optimize the balance between providing adjunctive diuretic effect while minimizing the risk of toxicity.

Using pharmacokinetic modelling to improve prescribing practices of intravenous aminophylline in childhood asthma exacerbations.

OBJECTIVE: To evaluate physiologically based pharmacokinetic modelling (PBPK) software in paediatric asthma patients using intravenous aminophylline. METHODS: Prospective clinical audit of children receiving iv aminophylline (July 2014 to June 2016), and in-silico modelling using Simcyp software. RESULTS: Thirty-eight admissions (25 children) were included. Children with aminophylline levels ≥10 mg/l had equivalent clinical outcomes compared to those <10 mg/L, and adverse effects occurred in 57%. Therapeutic drug monitoring (TDM) data correlated well with PBPK model. PBPK modelling of a 5 mg/kg iv loading dose (≤18yr) shows a mean Cmax of 8.99 mg/L (5th-95th centiles 5.5-13.7 mg/L), with 70.3% of subjects <10 mg/L, 29.4% achieving 10-20 mg/L, and 0.1% > 20 mg/L. For an aminophylline infusion (0-12 y) of 1.0  mg/kg/h, the mean steady state infusion concentration was 16.4 mg/L, (5th-95th centiles 5.3-32 mg/L), with 26.8% having a serum concentration >20 mg/L. For 12-18yr receiving 0.5  mg/kg/h infusion, the mean steady state infusion concentration was 9.37 mg/L (5th-95th centiles 3.4-18 mg/L), with 59.8% having a serum concentration <10 mg/L. CONCLUSION: PBPK software modelling correlates well with clinical data. Current aminophylline iv loading dosage recommendations achieve levels <10 mg/l in 70% of children. Routine TDM may need altering as low risk of toxicity (>20 mg/l).

Determination of flumazenil in serum by liquid chromatography-mass spectrometry: Application to kinetics study in acute diazepam overdose.

BACKGOUND/AIM: Flumazenil is benzodiazepine receptor antagonist. It has been studied for a various indications, including reversal of sedation after surgery or diagnostic procedures, awakening of comatose patients in benzodiazepine overdose, or for symptomatic treatment of hepatic encephalopathy. Some drugs, like theophylline, may prolong its elimination half-life. Considering the long half-life of diazepam and its metabolites, concomitant use of theophylline may reduce the need for repeated dosing of flumazenil in patients with acute diazepam poisoning. The aim of this study was to introduce a reliable and accurate method for determining the concentration of flumazenil after therapeutic application in patients with acute poisoning, and using that method to assess whether the kinetics of flumazenil change in the presence of aminophylline (combination of theophylline and ethylenediamine in a 2:1 ratio) applied as concomitant therapy. METHODS: Blood samples from patients with acute diazepam poisoning that received flumazenil at the dose of 0.5 mg, or the same dose with 3 mg/kg of body weight of aminophylline, were collected 1, 3, 10, 30, 60, 120 and 240 min after its intravenous administration. Samples were prepared by solid-phase extraction on Oasis HLB cartridges with ethylacetate as extracting agens. Flumazenil was determined by liquid chromatography with mass spectrometry (LC-MS) in single ionmonitoring mode at m/z 304. Separation of flumazenil from matrix compound was performed on Lichrospher RP-8 column usingthe mixture of acidic acetonitrile and 20 mM of ammonium acetatein water (55 : 45) as a mobile phase. RESULTS: The applied analitycal method showed excellent recovery (94.65%). The obtained extracts were much cleaner than the extracts obtained by the sameextractant in the process of liquid-liquid extraction. The limit ofdetection of the LC-MS method described in this paper was 0.5 ng/mL and the limit of quantitation was 1 ng/mL. In the patientstreated with both flumazenil and aminophylline, the eliminationconstant for flumazenil was significantly lower and the elimination half-life was longer (p < 0.05) in comparison with the same parameters in.the patients who received flumazenil alone. CONCLUSION: The applied LC-MS method for the determination of flumazenil in serum samples of patients with acute diazepam poisoning is rapid, sensitive, precise and specific. Concomitant use with theophylline significantly prolonged elimination of flumazenil during the treatment of acute poisonings with diazepam.

Studies on pharmacokinetics and bioavailability of aminophylline in partridge chickens.

Veterinary medicine plays a significant role in the development of animal husbandry. Drugs residual in food would follow the food-chain coming into human body, which might bring hidden dangers to people. Chicken is the prime source of meat food, whose quality is important for our life and health. Therefore, it is necessary to realize the withdrawal period and establish an efficient, sensitive and accurate method for monitoring the metabolic process of drugs in chicken body. In this paper, the pharmacokinetics of aminophylline in partridge chicken after intravenous and oral administration was investigated using a sensitive high-performance liquid chromatography method. Plasma concentration-time profiles of aminophylline were analyzed by a non-compartmental model using Topfit 2.0. Following intravenous and oral administration, the peak concentrations (C max) were found to be (16.5 ± 3.0) µg/mL at (0.08 ± 0) h and (7.4 ± 1.5) µg/mL at (1.83 ± 1.11) h, respectively. The elimination half-time (t 1/2) after intravenous and oral administration were, respectively, (13.1 ± 4.17) h and (11.65 ± 1.14) h. Areas under the plasma concentration-time curve (AUC) were (209.6 ± 22.8) µg h mL(-1)(AUC0-t ) and (219.5 ± 28.3) µg h mL(-1) (AUC0→∞ ) after intravenous, and (165.1 ± 37.0) µg h mL(-1)(AUC0-t ) and (179.3 ± 35.6) µg h mL(-1) (AUC0→∞ ) after oral administration. Mean retention time (MRT) after intravenous and oral administration were, respectively, (14.06 ± 0.86) and (15.27 ± 0.62) h. The total clearance rates (CLtol) were (0.77 ± 0.10) mL min(-1) kg(-1) of intravenous and (0.97 ± 0.20) mL min(-1) kg(-1) of oral administration. The apparent distribution volume (V d) was (0.87 ± 0.27) and (0.97 ± 0.20) L kg(-1), respectively, for intravenous and oral administration. The absolute bioavailability (F) after oral administration was (83.1 ± 11.7) %. The results showed that aminophylline in partridge chickens had a longer elimination half-time, a smaller clearance rate, as well as a higher absolute bioavailability for oral administration. Therefore, aminophylline in partridge chickens produced a long healing efficacy and oral administration can achieve a good absorption which could meet the requirement.

[Investigation of pharmacokinetics and pharmacodynamics of different doses of aminophylline in very low birth weight infants].

OBJECTIVE: To study the pharmacokinetic and pharmacodynamic features of different doses of aminophylline in very low birth weight (VLBW) infants with different postmenstrual ages, weights, and ages (in days). METHODS: A total of 40 VLBW infants with apnea were enrolled. After an intravenous loading dose of 5 mg/kg aminophylline, they were randomized into two groups with different maintenance doses of aminophylline (1 mg/kg and 2 mg/kg, once every 8 hours). Blood concentrations of aminophylline and liver and renal functions were monitored at 8 hours, 3 days, and 7 days after the loading dose. Attacks of apnea were documented. Pharmacokinetic data of aminophylline were compared between the two groups. RESULTS: The steady-state plasma concentration of aminophylline and plasma clearance in the 2 mg/kg group were significantly higher than those in the 1 mg/kg group (P<0.05). However, the elimination half life was shorter in the 2 mg/kg group (P<0.05). Days of apnea attacks within 7 days after birth in the 2 mg/kg group were significantly fewer than in the 1 mg/kg group (P<0.05). Aminophylline plasma clearance was positively correlated with age (in days) after birth and postmenstrual age in both groups. CONCLUSIONS: In VLBW infants, pharmacokinetics and pharmacodynamics are different when different maintenance doses of aminophylline are given. The maintenance dose of 2 mg/kg is associated with a better effect in the treatment of apnea. Postmenstrual age and age (in days) should be considered during the adjustment of dose, and routine blood concentration monitoring should be performed.

Aminophylline infusion for status asthmaticus in the pediatric critical care unit setting is independently associated with increased length of stay and time for symptom improvement.

INTRODUCTION: The role of aminophylline in the treatment of severe acute asthma in the pediatric critical care unit (PCCU) is not clear. We sought to examine the association of aminophylline treatment with PCCU length of stay and time to symptom improvement. MATERIAL AND METHODS: Patients with severe acute asthma who were admitted to our PCCU and received aminophylline infusion were retrospectively compared with similar patients who did not receive aminophylline. The primary outcome measure was functional length of stay (i.e. time to which patients could be transferred to a general pediatric ward bed). A secondary outcome was time to symptom improvement. RESULTS: Adjusted functional length of stay was longer for subjects who received aminophylline (n = 49) than for the patients who did not (n = 47) (hazard ratio 0.396, p < 0.001), as well as the time for symptom improvement (hazard ratio 0.359, p < 0.001). In the group of subjects receiving aminophylline, those with a serum theophylline level ≥ 10 mcg/ml (therapeutic) (n = 31) had longer functional length of stay (hazard ratio 0.457, p = 0.0225) and time to symptom improvement (hazard ratio 0.403, p = 0.0085) than those with levels < 10 mcg/ml (sub-therapeutic) (n = 18). CONCLUSIONS: The addition of aminophylline to therapy with corticosteroids and inhaled ß-agonists was associated with statistically and clinically significant increases in functional length of stay and time to symptom improvement in the PCCU. This potential morbidity supports the National Asthma Education and Prevention Program guideline proscribing aminophylline use in acute asthma.

[Investigation on pharmacokinetics of aminophylline in very low birth weight infants].

OBJECTIVE: To investigate the pharmacokinetics of aminophylline in very low birth weight infant. METHODS: This study investigated 104 very low birth weight infants using aminophylline 5 mg/kg treating apnea who were hospitalized in our department during 2011-2012. The blood concentration of aminophylline was measured in 30 min before, 8 h and 5 d after first time loading dose, and was counterchecked every week before aminophylline withdrawal. The pharmacokinetic parameters of aminophylline were calculated and population pharmacokinetic model was established by MW/Pharm3.6 statistical analysis. RESULTS: The average birth weight of these 104 very low birth weight infants was (1.15 +/- 0.23) kg, average gestational age was (31.19 +/- 2.50) weeks. The results of aminophylline pharmacokinetics showed: the plasma clearance was (17.88 +/- 5.61) mL/(kg x h), the apparent volume of distribution was (0.93 +/- 0.18) L/kg, the half life time was (28.6 +/- 7.59) h. The aminophylline plasma clearance was related to creatinine clearance, gestational age and days of age after birth (related coefficient was 0.68, 0.62, 0.56 respectively, P < 0.05),the apparent volume of distribution was related to birth weight (related coefficient was 0.82, P < 0.05). The population pharmacokinetics model established can predict the concentration-time curve of the patients. CONCLUSION: The pharmacokinetics of aminophylline in very low birth weight infant was quite different from adult, which suggest blood concentration monitoring and dose adjustment for the clinical use of aminophylline in low birth weight infants.

Effects of andrographolide on the pharmacokinetics of aminophylline and doxofylline in rats.

Andrographolide, which is one of the main pharmaceutical ingredients in traditional Chinese medicine Andrographis paniculata, can clear heat, detoxify human body, cool blood and reduce swelling, etc. Respiratory tract infectious diseases have been treated with the combination of andrographolide and theophyllines clinically. As andrographolide inhibits the CYP1A2 activity in vitro, it potentially interacts with theophyllines that are mainly metabolized by CYP1A2. Therefore, we herein studied the effects of andrographolide on the pharmacokinetics of aminophylline and doxofylline in rats. The blood drug concentrations of aminophylline, doxofylline and its metabolite theophylline were determined by HPLC. The theophylline AUC(0-t) was significantly elevated confronting the combination of andrographolide and aminophylline compared to that of the control group (P<0.05). Meanwhile, when only aminophylline was used, the theophylline clearance rate was significantly higher than those in the case of combination (P<0.05). The pharmacokinetics parameters of doxofylline and its metabolite theophylline in the individual administration group showed no significantly different from that combined with andrographolide. The results suggest that andrographolide and aminophylline should not be simultaneously administered because the former may raise the risks of side effects by inhibiting the clearance of the latter. In contrast, it is more secure to combine doxofylline with andrographolide owing to the almost intact pharmacokinetics.

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

OBJECTIVES: To establish whether aminophylline, administered at usual doses for rodents in pharmacological studies, induces brain injury in systemic hypoxaemia in guinea-pigs. METHODS: A hypoxaemia (partial oxygen tension of arterial blood (PaO2) = 40-60 mmHg) model was developed by low tidal volume mechanical ventilation in guinea-pigs. KEY FINDINGS: 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. CONCLUSIONS: 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.

Pharmacokinetics of aminophylline delivered to the small intestine and colon using remote controlled capsules.

BACKGROUND: A patented remote controlled capsule (RCC) has recently been developed to provide noninvasive drug delivery to selected sites in the human gut that allows assessment of regional gastrointestinal (GI) drug absorption under a normal physiological environment. The objective of this study was to investigate the rate and extent of aminophylline absorption after site-specific delivery of the drug in the GI tract using RCC and a magnetic marker monitoring (MMM) technique. METHODS: This study was conducted in twelve healthy male subjects, in a three-treatment, randomized, crossover manner with a 7-day washout. Eligible subjects received a 150 mg aminophylline dose through an oral administration, or via a remote controlled capsule, delivered to the small bowel or ascending colon. MMM was employed to monitor the GI transit of the RCC, and the radio-frequency signal was used to activate capsules at target sites. Blood samples were obtained at regular intervals until 24 hours post dose/activation. Plasma theophylline concentrations were measured by a TDx System Analyzer. A comparison of the PK profile with the oral dosing route of aminophylline was performed after delivery to the small bowel and colon. RESULTS: The RCC was well tolerated in volunteers. The mean capsule activation time for the small bowel and ascending colon was 2.07 hours and 6.08 hours post dose. Aminophylline had similar absorption profiles from the small bowel compared with the stomach, with an area under the curve (AUC(t)) ratio of 92% vs. the stomach, but a lower absorption profile from the ascending colon, with an AUC(t) ratio of 47.2% vs. the stomach. CONCLUSIONS: The proprietary of the RCC and MMM technique offer the opportunity to obtain data on the intestinal absorption of a drug in humans under noninvasive conditions. Aminophylline is rapidly and efficiently absorbed from the small bowel. While colonic absorption was limited by the poor water condition although effective absorption was observed from the ascending colon. This provides an opportunity for rational development of modified-release formulations as well as alternative dosage forms.

A novel remote controlled capsule for site-specific drug delivery in human GI tract.

Remote controlled capsule (RCC) has been extensively used in the field of site-specific drug delivery. It is a potent tool to study the regional drug absorption of the gastrointestinal (GI) tract that provides pharmaceutical scientists with significant pharmacokinetics data for oral drug formulation development. In present investigations, a patented novel RCC has been devised based on micro-electronic mechanical system (MEMS) technology. Micro-thrusters were for the first time exploited as drug release actuators of RCCs. As the micro-thruster is ignited by a radio frequency (RF) signal, the thrust force generated by the propellants pushes the piston forward and leads to a rapid and complete expulsion of therapeutic agents from the capsule. The micro-thruster merely consumes 120 mW for ignition and the duration time of drug release is decreased to less than 1 s. The feasibility of the novel RCC was evaluated through animal experiments in beagles using aminophylline as the model drug. The novel RCC developed is a promising alternative for site-specific drug delivery in human GI tract.

Novel chronotherapeutic rectal aminophylline delivery system for therapy of asthma.

The aim of this study was to develop a new chronotherapeutic pharmaceutical preparation as a sustained-release suppository for prevention and therapeutic use against bronchial asthma in the early morning. Sustained-release hollow-type (SR-HT) suppositories using sodium alginate (Alg-Na), sodium polyacrylate (PANa) or polyacrylate-PANa co-polymer (PA-PANa) as gelling polymers (gel agent) were prepared and pharmaceutical characteristics of these suppositories were investigated. Type A SR-HT suppositories comprised a suppository shell prepared with oleaginous base and containing aminophylline only or aminophylline with Alg-Na or PANa in the cavity (hollow space). Type B SR-HT suppositories comprised a suppository shell prepared with oleaginous base and gel agent (30%), with aminophylline in the hollow space. In drug-release studies, the acrylate polymer-containing suppositories showed linearity of delayed release rate, providing significantly decreased the highest concentration of theophylline in plasma (C(max)) and delayed the time required to reach C(max) (t(max)) and the mean residence time (MRT) after rectal administrated in rabbits. In particular, suppositories containing PA-PANa maintained significantly higher theophylline concentrations than control suppositories at 12h after rectal administration. Furthermore, histopathological examination indicated that these suppositories using acrylate polymers did not result in rectal lesions. The SR-HT suppository, particularly using PA-PANa as a gel agent, may thus be useful against nocturnal symptoms of asthma. In this study, we confirmed new formulation of sustained-release suppository for chronotherapy of theophylline using oily base material in combination with polymer such as PA-PANa. The hollow-type suppository containing oleaginous base and hydrophilic polymer in the shell could be useful device for rectal administration of various drugs with prolongation of plasma concentration.

Pharmacokinetics of intraperitoneally instilled aminophylline, terbutaline and tobramycin in pigs.

INTRODUCTION: Venous catheters are sometimes difficult or even impossible to insert and may also be associated with serious complications. This study was carried out to investigate whether intraperitoneal administration of drugs may be an alternative to the intravenous route in patients with limited vascular access. MATERIALS AND METHODS: Three drugs commonly in use in clinical practise, aminophylline, terbutaline and tobramycin, were administered to pigs intravenously and intraperitoneally in small volumes. Serum concentrations were analysed over a period of 6 h and pharmacokinetic key variables for each drug were calculated. RESULTS: Aminophylline (theophylline), terbutaline and tobramycin were absorbed from the peritoneal space and into systemic circulation. For theophylline, the concentration/time profiles after intraperitoneal and after intravenous administration were almost identical, and the intraperitoneal bioavailability was calculated to 0.94. For terbutaline and tobramycin, the intraperitoneal absorption was delayed without any initial peak. Moreover, the intraperitoneal bioavailability was lower than for theophylline (0.71 and 0.65, respectively). CONCLUSION: The pharmacokinetic properties after intraperitoneal administration differed among the three drugs, but the results are encouraging and provide a basis for further investigation in humans.

Reliability of salivary theophylline in monitoring the treatment for apnoea of prematurity.

OBJECTIVE: To evaluate the reliability of salivary levels of theophylline in monitoring therapy of apnoea of prematurity. STUDY DESIGN: Aminophylline was administered intravenously in 13 infants with apnoea, in a loading dose of 5 mg/kg and maintenance dose of 3 mg/kg, every 8 h. The patients were divided into two groups according to their postconceptional age (PCA): group A, of infants with small PCA (32.8+/-2.0 weeks; n=6 cases), and group B, infants with higher PCA (37.1+/-0.8 weeks; n=7 cases). RESULTS: A total of 57 paired samples of serum and saliva were obtained in all 13 infants. The mean serum level of theophylline was 7.8+/-5.8 microg/ml and the ratio between serum and salivary concentration of theophylline was 1.53+/-0.28. A strong correlation between the serum and salivary concentration of theophylline (r=0.973) was found. Infants with small PCA had significant higher serum concentration of theophylline than those with higher PCA (10.6 vs 5.3 microg/ml; P=0.0002). The difference between the mean ratios of serum/salivary theophylline levels in the two groups was low (1.44 vs 1.62; P=0.0155). CONCLUSION: The strong correlation of theophylline in serum and in saliva recommends the salivary levels as a reliable method for monitoring the treatment of apnoea of prematurity.

Pharmacokinetics of theophylline in Guinea pig tears.

It is well recognized that the theophylline (TP) concentration in human tears correlates well with the free TP concentration in human plasma. However this correlation was found only in a very narrow range of concentrations of TP, and pharmacokinetic analysis of TP in tears has not been carried out for a wide range of concentrations of TP. The aims of this investigation were to develop a simple kinetic model for TP in guinea pig plasma (total [Cf+b] and free [Cf]), cerebrospinal fluid (CSF) [C](CSF) and tears [C](T), and to examine whether [Cf], [Cf+b] and [C](CSF) can be predicted from [C](T) using the resulting kinetic parameters. [Cf+b], [Cf], [C](CSF) and [C](T) were determined by GC/EI-SIM following bolus i.v. injection of TP in doses of 10, 50 and 100 mg/kg into guinea pigs. The wide range of concentrations of [Cf+b] could be quantitatively described by a two-compartment model with non-linear elimination kinetics and individual volume distribution of TP at each dose. [C](T) and [C](CSF) were analyzed using passive diffusion models with and without the pH-partition theory, respectively. The value of [Cf] could be predicted from the value of [C](T). Thus, the measurement of [C](T) which can be collected non-invasively would be a useful method for the therapeutic drug monitoring of TP.

Pharmacokinetic and pharmacodynamic interactions of aminophylline and topiramate in the mouse maximal electroshock-induced seizure model.

The aim of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline (theophylline(2).ethylenediamine) on the anticonvulsant potential of topiramate (a broad-spectrum antiepileptic drug) in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of topiramate were assessed in the chimney test (motor performance). To evaluate pharmacokinetic characteristics of interaction between topiramate and aminophylline, total brain concentrations of topiramate and theophylline were estimated with fluorescence polarization immunoassay technique. Results indicate that aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, markedly attenuated the anticonvulsant potential of topiramate by raising its ED(50) value against maximal electroconvulsions. Aminophylline at a lower dose of 25 mg/kg did not affect significantly the ED(50) value of topiramate in the acute experiment, but the drug markedly increased the ED(50) value of topiramate during the chronic treatment in mice. Only, aminophylline at 12.5 mg/kg, in both acute and chronic experiments, did not affect the antielectroshock action of topiramate in mice. Moreover, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of topiramate in the chimney test. Pharmacokinetic evaluation of total brain concentrations of topiramate and theophylline revealed that topiramate significantly increased total brain theophylline concentrations following both acute and chronic applications of aminophylline. Conversely, aminophylline did not alter total brain concentrations of topiramate in mice. Based on this preclinical study, one can conclude that aminophylline attenuated the antiseizure action of topiramate in the mouse maximal electroshock-induced seizure model and the observed interaction between drugs was both pharmacokinetic and pharmacodynamic in nature.

[Studies on drug release from aminophylline konjac glucomannan matrix tablet].

OBJECTIVE: In vitro aminophylline release from matrix tablets with konjac glucomannan (KGM) were studied to elevate the feasibility of KGM used as carrier materials to prepare matrix tablets. METHOD: KGM hydrophilic matrix tablets were prepared by direct compression method with aminophylline as the model drug. The effects of test methods, pH values, ionic strength of dissolution media and rotation speeds on drug release were studied by in vitro dissolution experiment. RESULT: The MDT value tested by Paddle method was less than that tested by Basket method (P < 0.05). Among the rate of drug release in different dissolution media, distillded water is the fastest, pH 6. 8 PBS is the second, 0.1 mol x L(-1) HCL is the slowest. MDT increased with increasing the ionic strength of dissolution media (P < 0.05). MDT decreased with increasing the rotation speed, but the rate of drug release did not increase when the rotation speed was more than 100 r x min(-1) (P > 0.1). The mechanism of drug release were diffusion and erosion. CONCLUSION: KGM can be used in sustained delivery systems as a good candidate of hydrophilic polymer.

[Study on evaluation index of acupoint transdermal administration--drug delivery coefficient].

OBJECTIVE: To investigate the correlation of skin electric resistance changes with the blood drug content in acupoint transdermal administration, and to establish an new evaluation index for drug delivery efficiency through acupoints. METHODS: Twenty-four rabbits were randomly divided into an observation group and a control group. In the observation group, aminophylline was administrated through "Feishu" (BL 13), "Geshu" (BL 17) and "Danzhong" (CV 17) which are commonly used for treatment of bronchial asthma, and the control group through sham-points on the back. The skin resistance and plasma aminophylline content were determined after application of aminophylline to the points, and their changes with time were observed. The ratio of Css/Rss at stability was defined as delivery coefficient (DC) which reflects the efficiency of delivering drug at acupoints and sham acupoints. RESULTS: Both the plasma aminophylline and the skin resistance value tended to steady about 6-8 h after application of aminophyiophylline. The DC in the acupoints was higher than that in the sham-acupoints (P < 0.01). And there was significant difference as DC of the "Feishu"was significant difference (BL 13) and "Danzhongas DC of the "Feish" (BLCV 17) compared with that of "Geshu" (BL 17) (P < 0.01). CONCLUSION: The bigger the DC is, the higher the efficiency of drug delivery is; the efficiency of drug delivery through acupoints is higher than that through sham-acupoints.