Comparison of the in vitro dissolution properties and in vivo steady-state pharmacokinetics of two sustained-release theophylline preparations

The sustained-release properties and relative bioavailability of Theolin^® Retard and Pharphylline^® Retard were studied in eight healthy adults after treatment for five days with twice daily 450 mg, respectively 425 mg. During the day-time dosing interval on the fourth and fifth day theophylline plasma concentrations were assayed by HPLC. After intake of Theolin^® Retard, minimum theophylline plasma concentrations were significantly higher, fluctuations in theophylline plasma concentrations were significantly smaller andt ₇₅ (the period within a dosing interval during which the plasma concentration exceeds 75% of the maximal concentration) was significantly longer than after Pharphylline^® Retard. Maximal concentrations and AUC values were not significantly different. For both products the plasma concentration time-curves on day 5 were significantly lower than on day 4.In vitro dissolution tests confirmed the more sustained release of theophylline from Theolin^® Retard. These results indicate an equal extent of absorption from the two products but better sustained-release properties for Theolin^® Retard.     

Effects of methylxanthine drugs on pyrogen-induced hyperthermia.

The hyperthermic response to pyrogen was not potentiated by caffeine or theophylline administered i.p. into cats or rabbit. Injection of these drugs into the anterior hypothalamus or into the third cerebral ventricle in cats was also without effect on pyrexia. These results support the hypothesis that cyclic AMP in the anterior hypothalamus does not mediate pyrogen-induced hyperthermia in cats.     

The effect of theophylline alone and in combination with ouabain on the isolated dog heart

Summary A comparative study of the inotropic effects of theophylline and ouabain as well as a study of the interaction between the two pharmacological agents were carried out in the nonfailing Starling heart-lung preparation modified to permit metabolic studies. Single doses of theophylline ranging between 100 to 200 mg added to the venous reservoir produced consistent increases in myocardial contractile force, as gauged by the maximal rate of rise of left ventricular pressure, dp/dt, 73%; systemic output, 28%; coronary output, 277%; total cardiac output, 41%; heart rate, 27%; left ventricular work, 45% and myocardial oxygen consumption, 43%. In addition, systolic time decreased consistently by 15%. 20 min and 30 min after the onset of an ouabain infusion of 5g per min, which was started 15 min after the addition of theophylline, there was further increase in dp/dt to 87% and 107%, respectively, with no significant change in the remaining parameters from the levels attained 15 min after the administration of theophylline. As compared to ouabain administered alone, ouabain administered at peak effect of theophylline led to an earlier occurence of ventricular arrhythmias and death. It may be concluded from this study that maximally effective doses of theophylline brought about an increase in dp/dt which is greater than that brought about by maximal therapeutic doses of ouabain. Secondly, ouabain administered after the peak effect of theophylline was exerted led to an additional increase in dp/dt implying that the mechanisms underlying the inotropic action of each drug are different. Thirdly, at constant aortic pressure, heart rate, left ventricular enddiastolic and left atrial pressures, ouabain in the presence of theophylline brought about an increase in myocardial contractility, as gauged by an increase in dp/dt, without a concomitant increase in myocardial oxygen consumption, thus confirming earlier results obtained with ouabain alone. Fourthly, ouabain administered at peak effect of theophylline led to an earlier occurrence of ventricular arrhythmias and death.This work was supported by a grant from the Lebanese National Research Council.     

Naloxone antagonizes theophylline-induced potentiation of morphine inhibition of a nociceptive reaction in rats

In the rat, theophylline has been shown to potentiate the effect of morphine on the threshold for vocalisation after withdrawal of stimulation. This response to painful stimulation is considered to be integrated at the level of the thalamus-hypothalamus-rhinencephalon. Naloxone antagonized the effect of the combined treatment with morphine and theophylline, suggesting pharmacological specificity for morphine. Moreover, the theophylline-induced enhancement of this pharmacological response to morphine was attenuated after pimozide pretreatment, indicating an underlying dopaminergic mechanism.     

Inhibition of cardiac sympathetic neurotransmission by adenosine

Experiments were performed to study the effect of adenosine on sympathetic neurotransmission to the myocardium. Adenosine administration to pentobartial-anesthetized dogs resulted in decrerease in blood pressure and significant impairment of cardioacceleration produced of stimulation of cardiac sympathetic nerves. The positive chronotropic effect of intravenous norepinephrine was not affected by adenosine. The blood pressure lowering as well as the inhibitory effect of adenosine on cardiac sympathetic nerve function could be significantly antagonized by theophylline. These results provide in vivo evidence in support of the hypothesis that adenosine caused inhibition of sympathetic neurotransmission via an action on purinergic receptors located on sympathetic nerve terminals.     

Cardiostimulatory effects of cyclic 3′,5′-adenosine monophosphate and its acylated derivatives

Summary The effects of cyclic 3,5-AMP and of two acylated derivatives, dibutyryl (DBA) and dihexanoyl-3,5-AMP (DHA) were investigated in isolated perfused hearts of guinea pigs, rats and rabbits.In guinea pig hearts, DBA (Ca- and Na-salt) and DHA-Na in high doses (10 moles) produced strong and long lasting increases in the rate and amplitude of contractions, coronary flow, and moderate increases in phosphorylase activity in the majority of experiments. The positive ino- and chronotropic effects occured 3–5 min after injection of the drug, mostly in a fluctuating manner with several maxima. Theophylline augmented the effects of DBA-Na and revealed positive inotropic actions of non substituted 3,5-AMP.In rat hearts, similar, but more pronounced and dose-dependent effects were observed after 1, 5 and 10 moles DBA-Na. Propranolol (50 g) did not block the action of 10 moles DBA-Na. Non substituted 3,5-AMP, 5-AMP and ATP in doses of 10 moles had no significant positive inotropic effects.In rabbit hearts, DBA-Na (50 moles) produced moderate, non fluctuating rises in the amplitude of contraction.The results provide evidence that under certain conditions cyclic 3, 5-AMP itself, like its acylated derivatives DBA and DHA, may produce strong and direct positive inotropic and chronotropic effects in the heart. These findings support the view that cyclic 3,5-AMP is the cellular mediator of the cardiostimulant actions of substances that increase its rate of production in the myocardial cell.The excellent technical help of Mrs. Vera Bauer is gratefully acknowledged by the authors.     

Determination of theophylline and its metabolites in human urine by high-performance liquid chromatography

High-performance liquid chromatographic method with UV detection was developed for the determination of theophylline and its metabolites, in human urine using β-hydroxyethyl theophylline (β-HET) as an internal standard. For extraction of urine sample, quality control sample and xanthine-free blank urine were mixed with decylamine (ion-paring reagent) and β-HET. After saturation with ammonium sulfate, the mixture was then extracted with organic solvent at pH values of 4.0∼4.5. All separations were performed with ion-pair chromatography using decylamine as an ion-pairing reagent and 3 mM sodium acetate buffered mobile phase (pH 4.0) containing 1% (v/v) acetonitrile and 0.75 mM decylamine. The detection limits of theophylline, 1,3-DMU, 1-MU, 3-MX and 1-MX in human urine were 0.17, 0.17, 0.39, 0.19 and 0.19 μg/ml, based on a signal-to-noise ratios of 3.0. The mean intraday coefficients of variation (C.V.s) of each compound on nine replicates were lower than 2.0%, while mean interday C.V.s on three days were lower than 1.6%. All separations were finished within 40 minutes.     

Convulsive Effect of Theophylline in Conscious and Anaesthetized Guinea-pigs

Abstract: In urethane-anaesthetized guinea-pigs, the effect of theophylline (theo) on heart rate, arterial blood pressure, respiration rate and limb movements were recorded. Continuous intravenous infusion of theo initially increased the respiratory and heart rates and lowered the arterial blood pressure. After infusion of about 50 mg/kg of theo, the cardiovascular effects reached a maximum and were then only slightly changed until the terminal stage. A tonic stretching of the limbs (at 155 ± 15 mg/kg) preceded generalized seizures of clonic tonic convulsions which were recorded after infusion of 367 ± 25 mg/kg of theo. At this stage, respiration was highly irregular. PaO₂ started to fall and PaCO₂ to rise, while a plasma acidosis developed rapidly. The convulsions progressed in frequency and intensity and were terminally associated with respiratory and cardiovascular collapse. The convulsive effects of theophylline were similar to those observed in conscious guinea-pigs after 250 mg/kg of theo orally. The present findings agree with the view that the convulsive effect is a primary life-threatening action of theophylline. The method described may be of use in the search for new, less toxic xanthine drugs.     

A characteristic of the rate response which is common to several compounds that stimulate the heart.

Chronotropic effects of increasing concentrations of histamine, epinephrine, norepinephrine (when catecholamine uptake is blocked by amitriptyline), theophylline and caffeine were observed using isolated atrial pairs. Linear transformations of the dose-response curves for all the agents revealed similar straight line relationships. Inverse plots of the data of the chronotropic response to these compounds produces a series of linear curves analogous to similar plots of enzymatic activity. It has been well documented that all these agents have the common property of increasing cyclic AMP levels. Therefore, the present results lend support to the concept that cyclic AMP may play a critical role at some step in the regulation of the heart rate.     

RP-HPLC法同时测定人血浆中茶碱和多索茶碱的浓度

目的:建立以反相高效液相色谱法同时测定人血浆中茶碱和多索茶碱浓度的方法。方法:色谱柱为XterraRP18,流动相为甲醇-水(35:65),流速为1.0mL·min-1,检测波长为269.9nm,柱温为35℃,内标为非那西丁。结果:茶碱和多索茶碱浓度分别在1.563～50μg·mL-1(r=0.9995)、0.3125～10μg·mL-1(r=0.9999)范围内线性关系良好;茶碱、多索茶碱提取回收率分别为32.53%～35.08%、31.88%～34.55%,方法回收率分别为92.82%～109.41%、90.68%～102.72%,日内、日间RSD均<15%。结论:本方法快速、灵敏、准确,可用于同时测定人血浆中茶碱和多索茶碱的浓度。关键词茶碱;多索茶碱;反相高效液相色谱法;血药浓度监测