In Vivo Evaluation of Taste-Masked Fast-Disintegrating Sublingual Tablets of Epinephrine Microcrystals.

In community settings, IM injection of 0.3 mg epinephrine (Epi) using an auto-injector is the drug of choice for treatment of anaphylaxis. Previously, a taste-masking (TM) formulation of fast-disintegrating sublingual tablets (FDSTs) was developed in our lab. Also, Epi was micronized (Epi-MC) successfully and reduced the previously achieved bioequivalent sublingual Epi dose to 0.3 mg IM injection by half using non-taste-masked fast-disintegrating sublingual tablets (TM-FDSTs). Our objective for this study was to evaluate the sublingual absorption of Epi-MC using TM-FDST. These sublingual Epi tablets have potential for out-of-hospital treatment of anaphylaxis and are suitable for human studies. TM-FDSTs containing Epi-MC were manufactured by direct compression. The rate and extent of Epi absorption from our developed 20 mg Epi-MC-TM-FDSTs (n = 5) were evaluated in rabbits and compared to the previous result from 20 mg Epi-MC in non-TM-FDSTs and EpiPen® auto-injector. Blood samples were collected over 1 h, and Epi concentrations were measured using HPLC with electrochemical detection. Mean ± SEM AUC0-1 h and Cmax from 20 mg Epi-MC-TM-FDSTs (733 ± 78 ng/ml/min and 30 ± 8 ng/ml) and 20 mg Epi-MC-non-TM-FDSTs (942 ± 109 ng/ml/min and 38 ± 4 ng/ml) were not significantly different (p > 0.05) from each other or from EpiPen® (592 ± 50 ng/ml/min and 28 ± 3 ng/ml) but were significantly higher (p < 0.05) than endogenous Epi after placebo FDSTs (220 ± 32 ng/ml/min and 8 ± 1 ng/ml). Mean ± SD Tmax was not significantly different (p > 0.05) among all formulations. Epi-MC-TM-FDSTs formulation improved Epi absorption twofold and reduced the required bioequivalent dose by 50%, similar to results obtained using non-TM-FDSTs. The incorporation of TM excipients did not interfere with the absorption of Epi-MC.

An aptamer nanopore-enabled microsensor for detection of theophylline.

This paper reports an aptamer-based nanopore thin film sensor for detecting theophylline in the buffer solution and complex fluids including plant extracts and serum samples. Compared to antibody-based detection, aptamer-based detection offers many advantages such as low cost and high stability at elevated temperatures. Experiments found that this type of sensor can readily detect theophylline at a concentration as low as 0.05µM, which is much lower than the detection limit of current lab-based equipment such as liquid chromatography (LC). Experiments also found that the aptamer-based sensor has good specificity, selectivity, and reasonable reusability with a significantly improved dynamic detection range. By using the same nanopore thin film sensors as the reference sensors to further mitigate the non-specific binding effect, the theophylline in plant extracts and serum has been detected. Only a small amount (~1µL) of plant extracts or serum samples is required to measure theophylline. Its low cost and ease-of-operation make this type of sensor suitable for point-of-care application to monitor the theophylline level of patients in real time.

Efficacy and safety of nebulized glycopyrrolate for administration using a high efficiency nebulizer in patients with chronic obstructive pulmonary disease.

AIMS: To establish the dose-response for pharmacodynamics (bronchodilatation), safety and pharmacokinetics for a nebulized formulation of the long acting muscarinic antagonist glycopyrrolate (EP-101) with a high efficiency nebulizer in patients with chronic obstructive pulmonary disease (COPD). METHODS: Patients with moderate to severe COPD (GOLD II/III), with reversible lung function, were enrolled into this randomized, double-blind, placebo-controlled, six period crossover study (n = 42). Patients received single doses of EP-101 (12.5-400 µg) and placebo via a high efficiency nebulizer (eFlow® PARI nebulizer), with washout between treatments. Plasma pharmacokinetics were assessed in a subset of patients (n = 11). RESULTS: All treatments were well tolerated with similar adverse event rates reported with placebo and at all doses. There were no clinically relevant changes in heart rate, systolic and diastolic blood pressure or in ECG parameters including QTc interval. Following treatment with EP-101 at all doses there was a rapid bronchodilator response within 5 min. Significant improvements in mean change from baseline FEV1 at 24 h were reported at doses ≥ 50 µg compared with placebo, with a clear dose-response relationship. Mean changes in FEV1 were 0.10 l (95% CI 0.06, 0.14) and 0.12 l (95% CI 0.08, 0.16) for 100 µg and 200 µg, respectively. CONCLUSION: Single doses of EP-101 ranging from 12.5 µg to 400 µg were well tolerated. EP-101 delivered by high efficiency nebulizer device produced a rapid onset of bronchodilatation with clinically meaningful improvements in lung function maintained over a 24 h period at all doses >50 µg.

Pharmacokinetic changes of unbound theophylline are due to plasma protein binding displacement and CYP1A2 activity inhibition by baicalin in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Baicalin is one of the major bioactive constituents of Scutellariae Radix, the root of Scutellariae baicalensis Georgi and possesses a wide variety of pharmacological properties. AIM OF THE STUDY: To elucidate the effect of baicalin on the pharmacokinetics of theophylline in rats, focusing on plasma protein binding displacement and inhibition effect on CYP1A2 in vivo and in vitro. MATERIALS AND METHODS: The study was a randomized, three-period crossover design. Nine rats were given saline (control) or 450 mg/kg baicalin (dosage regimen A or B). Dosage regimen A was administered once at 0 h. Dosage regimen B was divided into three dosages (225,112.5, 112.5 mg/kg) and was given at 0, 2 and 4 h, respectively. Then theophylline (5 mg/kg, i.v.) was administered immediately. The effect of baicalin on CYP1A2 activity was determined by metabolism of phenacetin in vitro and plasma protein binding of theophylline was determined by ultrafiltration. RESULTS: C(max) decreased from (12.4 ± 1.6) to (8.7 ± 0.9) and (8.6 ± 2.0) mg/L, T(1/2) increased by 116 and 96%, V(d) increased by 51 and 49% for total theophylline in rats treated with dosage regimen A and B of baicalin, respectively. Cmax was significantly increased, V(d) decreased by 43 and 29% for unbound theophylline in rats treated with dosage regimen A and B of baicalin, respectively (P < 0.01). T(1/2) of unbound theophylline increased by 104% only in rats treated with dosage regimen B. No significant effects on the CL and AUC of both total and unbound theophylline were observed in the rats treated with dosage regimen A, but the CL decreased and AUC increased for total theophylline and CL decreased for unbound theophylline in the group treated with dosage regimen B (P < 0.05). Correlation analysis showed that the mean unbound theophylline (%) and mean baicalin concentration was in good correlation (P < 0.01). Baicalin decreased metabolism of phenacetin and exhibited a mixed-type inhibition in rat liver microsomes, with a K(i) value of 88.1 µM in vitro. Moreover baicalin was a competitive displacer of theophylline from plasma protein in vitro. CONCLUSIONS: The changes in Cmax, T(1/2), CL and AUC of theophylline due to baicalin may be attributed to two mechanisms, plasma protein binding displacement and CYP1A2 activity inhibition.

Effect of decursin on the pharmacokinetics of theophylline and its metabolites in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Decursin is used as a traditional Asian medicine to treat various women's diseases. AIM OF THE STUDY: Herb-drug interaction has become a serious problem since herbal medicine is extensively used in the modern world. This study investigates effects of decursin, on the pharmacokinetics of theophylline, a typical substrate of cytochrome P450 1A2 enzyme, in rats. MATERIALS AND METHODS: After decursin pretreatment for 3 days, on the fourth day rats were administered decursin and theophylline concomitantly. The blood theophylline and its major metabolites (1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU)) levels were monitored with LC-MS/MS. RESULTS: The results indicated that the clearance, elimination rate constant (K(el)) of theophylline was significantly decreased and area under concentration-time curve (AUC), C(max), half-life was increased in decursin (25mg/kg) pretreatment when theophylline (10mg/kg) was given. In the presence of decursin, the pharmacokinetic parameters of three metabolites (1-MX, 1,3-DMU, and 1-MU) were affected and the differences were statistically significant about AUC(24)(h) parameter. CONCLUSION: Our results suggest that patients who want to use CYP1A2-metabolized drugs such as caffeine and theophylline should be advised of the potential herb-drug interaction, to reduce therapeutic failure or increased toxicity of conventional drug therapy.

High-dose continuous nebulized levalbuterol for pediatric status asthmaticus: a randomized trial.

OBJECTIVE: To assess the use of high-dose continuous levalbuterol (LEV), the single active (R)-enantiomer of racemic albuterol (RAC), in the treatment of status asthmaticus. STUDY DESIGN: Children age 6 to 18 years with severe asthma exacerbation were enrolled in this randomized, double-blind trial if they failed initial emergency department (ED) therapy with RAC and systemic steroids. Subjects received equipotent doses of RAC (20 mg/hour) or LEV (10 mg/hour) within a standardized inpatient protocol. Blood samples for measurements of albuterol enantiomer, potassium, and glucose levels were obtained from the first 40 subjects. The median time until discontinuation of continuous therapy was compared using the rank-sum test, and other outcomes were compared using general linear mixed models. RESULTS: A total of 81 subjects (40 in the RAC group and 41 in the LEV group) were enrolled; the 2 groups were similar at baseline. Both groups tolerated continuous therapy with similar changes in heart rate and serum potassium and glucose levels but higher serum (S)-albuterol concentrations in the subjects treated with RAC. The median time for continuous therapy was similar in the RAC and LEV groups (18.3 hours vs 16.0 hours), as were the other clinical measures. CONCLUSIONS: Substituting high-dose continuous LEV for RAC did not reduce the time on continuous therapy and had similar adverse effects in children who had failed initial treatment with RAC.

The effect of coenzyme Q10 on the pharmacokinetic parameters of theophylline.

Interaction of a drug with other drugs and dietary supplements is becoming an emerging issue for patients and health insurance authorities due to awareness of adverse drug event. In this study, we examined the effects of coenzyme Q10 (CoQ10), one of the most popular dietary supplements, on the pharmacokinetic parameters of theophylline in rats. The pharmacokinetic parameters of theophylline changed significantly when the drug was administered after five consecutive days of pretreatment with CoQ10. Time to reach maximum plasma concentration of theophylline delayed when the drug was administered after the pretreatment with CoQ10. Maximum plasma concentration and area under the curve of theophylline were about two-fold increased and other pharmacokinetic parameters such as half-life and volume of distribution were also changed significantly. Therefore, although CoQ10 is generally considered a safe dietary supplement, it appears that patients on theophylline therapy should use caution when they take CoQ10.

Herb-drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats.

Herbal medicines have received great attention as alternative medicines in recent years and are also referred to as a dietary supplement or health food. Ginkgo biloba extract (GBE) is one of the most popular herbal medicines. However, little is known about the metabolic interactions between GBE and clinically used drugs. This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window used for the treatment of asthma. Commercial GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30% (GBE 10 mg/kg, P<0.05) and 70% (GBE 100 mg/kg, P<0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After oral administration of theophylline (10 mg/kg), the AUC(0-24h) of theophylline was reduced by 40% following pretreatment with GBE (100 mg/kg, P<0.01). These results demonstrate that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.

Effects of Cassia auriculata and Cardospermum halicacabum teas on the steady state blood levels of theophylline in rats.

The effects of concurrent administration of herbal tea prepared from dried flowers of Cassia auriculata or aerial parts of Cardospermum halicacabum and steady state serum levels of theophylline was investigated in Wistar rats. Results obtained demonstrate that a significant increase in the steady state levels of theophylline occur when this drug is administered concurrently with herbal tea prepared from either of the above plants. C. auriculata and C. halicacabum enhanced the steady state levels of theophylline by 32.5% (p < 0.02) and 48.2% (p < 0.02), respectively, when compared with the levels in animals receiving theophylline alone for the same time period. Herbal teas prepared from C. auriculata or C. halicacabum should therefore be avoided by patients treated with theophylline as these herbal teas have the potential to influence the bioavailability of the prescription drug.

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects with a new asymmetric dosage regimen.

Pharmacokinetics of a new sustained-release formulation of theophylline sodium glycerinate in healthy subjects was studied. In this study, a new asymmetric dosage regimen was presented to achieve a better accordance with the chronotherapy of asthma. Each of 10 subjects was administered one tablet (equivalent to 0.1 g anhydrous theophylline) in the morning and four tablets in the evening for a consecutive 6 days and blood samples were collected at the predetermined time and analyzed by a validated HPLC method. This new regimen produced a steady and effective level of theophylline in plasma for the whole day, especially in the evening. A lower dose in the morning could reach the effective level (C(min)4.97 +/- 1.60 microg/mL and C(max)10.68 +/- 1.80 micro g/mL over the a.m. dosing interval) and a higher dose in the evening did not result in toxic levels but led to a reasonable concentration range (C(max)9.72 +/- 1.56 microg/mL over p.m. dosing interval), which could maintain a higher plasma theophylline concentration without the risk of serious adverse events and control asthmatic symptoms probably occurring during the night or early in the morning. The results suggested that the proposed asymmetric regimen was necessary, practicable and safe for twice daily sustained-release tablets of theophylline sodium glycerinate and also provides the basis for the clinical dosage regimen of other theophylline formulated products.

Pharmacokinetics and tolerability of formoterol in healthy volunteers after a single high dose of Foradil dry powder inhalation via Aerolizer.

OBJECTIVE: The pharmacokinetics of the long-acting beta2-agonist formoterol fumarate, which is a racemate of the (S,S)- and (R,R)-enantiomers were evaluated in 12 healthy (eight male, four female) volunteers after a single inhaled high dose of 120 microg of formoterol fumarate. The tolerability and safety were also assessed. METHODS: Each volunteer inhaled the single 120-microg dose through the Aerolizer device within 2-5 min, using ten 12-microg dry powder capsules for inhalation. Formoterol, i.e., the sum of both enantiomers, was determined in plasma over 24 h, whereas the separate enantiomers were determined in urine over 48 h. Incidence, seriousness and severity of adverse experiences, electrocardiogram (ECG), including the corrected QT interval (QTc) calculation, systolic blood pressure, heart rate, and plasma potassium levels were recorded. RESULTS: In nine of the 12 volunteers, the peak plasma concentration of formoterol was observed already at 5 min after inhalation. The absorption kinetics were complex, as depicted by multiple peaks or shoulders within 0.5-6 h after inhalation. Mean with (SD; n = 12) of maximum concentration (Cmax) and area under the curve (AUC) of formoterol in plasma were 266 (108) pmol x l(-1) and 1330 (398) pmol x l(-1), respectively. The moderate inter-individual variability in systemic exposure of formoterol reflects the homogeneous pharmacokinetics of the drug. A predominant slow elimination of formoterol from plasma with a mean half-life (t1/2) of 10 h was demonstrated. Assuming linear kinetics in plasma suggested by urinary data, the steady-state trough plasma levels of formoterol for a b.i.d. dosing regimen are predicted to amount to 20% of Cmax. In urine, mean with (SD; n = 10) of the amount excreted over 48 h was 3.61 (0.89)% of dose for the pharmacologically active (R,R)-enantiomer and 4.80 (1.33)% of dose for the (S,S)-enantiomer. The terminal half-lives calculated from the excretion rate-time curves, i.e., 13.9 h and 12.3 h for the (R,R)- and (S,S)-enantiomer, respectively, confirm the slow elimination of formoterol from plasma. The dose inhaled was 10 times the most frequently recommended dose (12 microg) and 5 times the highest recommended dose (24 microg). Ten of 12 subjects experienced mild and transient nervousness. Pulse readings demonstrated the maximum mean increase of 25.8 beats x min(-1) at 6 h. The mean maximum QTc increase was 25 msec at 6 h. Pulse and QTc values returned to baseline or close to baseline values at 24 h or before. Potassium levels in plasma decreased in eight out of 12 subjects; the lowest mean value was 3.53 mmol x l(-1) at 2 h post-dose. The lowest individual potassium measurement was 2.95 mmol x l(-1) between 15 min and 6 h. By 8 h post-dose all values had returned to within the normal ranges. CONCLUSIONS: The extremely fast appearance of formoterol in plasma shows the predominance of airways absorption shortly after inhalation. Due to a terminal elimination half-life of about 10 h, sustained systemic concentrations of formoterol are predicted for a twice daily treatment regimen without noteworthy accumulation. The excreted amounts in percent of dose of the enantiomers in urine and the enantiomer ratio are similar to data reported previously after lower doses and suggest linear kinetics for doses between 12 microg and 120 microg of formoterol fumarate. The expected side effects on heart rate, QTc interval, and plasma potassium were small and had no clinical consequences in spite of the very high dose of 120 microg (5 to 10 times the recommended therapeutic dose of Foradil). It should be noted that the impact of high doses may be greater in patients. Nevertheless these findings provide reassurance on the safety margin of formoterol after accidental and intentional overdosing.

Efficacy and safety of a 10-day course of 400 or 600 milligrams of grepafloxacin once daily for treatment of acute bacterial exacerbations of chronic bronchitis: comparison with a 10-day course of 500 milligrams of ciprofloxacin twice daily.

A randomized, prospective, double-blind, double-dummy, multicenter study investigated the efficacy and safety of 10 days of oral therapy with grepafloxacin at 400 mg once daily, grepafloxacin at 600 mg once daily, or ciprofloxacin at 500 mg twice daily in 624 patients with acute bacterial exacerbations of chronic bronchitis. At the end of treatment, clinical success (cure or improvement) was achieved for 93% (140 of 151), 88% (137 of 156), and 91% (145 of 160) of patients in the groups receiving grepafloxacin at 400 mg, grepafloxacin at 600 mg, and ciprofloxacin, respectively (clinically evaluable population). At follow-up (14 to 28 days posttreatment), the clinical success rates were 87% (124 of 143), 81% (122 of 151), and 80% (123 of 154) in the groups receiving grepafloxacin at 400 mg and 600 mg and ciprofloxacin, respectively. A total of 379 pathogens were isolated from 290 patients, with the most common isolates being Moraxella catarrhalis (21%), Staphylococcus aureus (20%), Haemophilus influenzae (18%), and Streptococcus pneumoniae (7%). For the evaluable population, successful bacteriologic response was obtained at the end of treatment for 96% (92 of 96), 98% (87 of 89), and 92% (82 of 90) of patients receiving grepafloxacin at 400 mg, grepafloxacin at 600 mg, and ciprofloxacin, respectively, and was maintained in 86% (82 of 95), 88% (78 of 89), and 82% (69 of 84) of patients, respectively, at follow-up. All pretreatment S. pneumoniae isolates were susceptible to grepafloxacin, but two strains were resistant to ciprofloxacin. All treatments were well tolerated, with the most frequently reported drug-related adverse events being nausea, taste perversion, and headache. All drug-related adverse events in the grepafloxacin groups were mild or moderate in severity. This study demonstrates that 10-day courses of grepafloxacin given at 400 or 600 mg once daily were as effective, clinically and bacteriologically, as ciprofloxacin given at 500 mg twice daily for the treatment of acute bacterial exacerbations of chronic bronchitis.

[Metabolic, hormonal and nutritional effects of long-term theophylline therapy in preterm infants: a case-control study]. / Effetti metabolici, ormonali e nutrizionali della terapia prolungata con teofillina nei nati pretermine: uno studio caso-controllo.

Theophylline is widely used in preterm newborns for the prevention of idiopathic apnoeas, but few controlled studies have evaluated its effects on the nutritional and hormonal status of the infant. For this reason we have studied the effect of long term theophylline administration on 16 laboratory parameters concerning the metabolism of proteins, glucose, lipids, hormones and the glomerular function (blood: hemoglobin, glucose, albumin, prealbumin, urea nitrogen, creatinine, cholesterol, triglycerides, apolipoproteins A-I and B-100, IGF-I, IGFBP-3; urine: urea nitrogen, creatinine, C-peptide, GH). A case-control study was performed on 18 healthy preterm infants who were receiving oral theophylline for the prevention of idiopathic apnoeas. The mean duration of therapy at the moment of the balance study was 31 days (SD 12, range 12-51), the mean daily dose was 4.2 mg/kg (SD 1.0), the plasma range of theophylline concentration was 5 to 15 mg/l. As controls, 18 healthy preterm infants of comparable post-conceptional age, body weight and calories/protein intake at the moment of the study, were selected if they had been never treated with theophylline. No statistically significant differences were found between the two groups for the growth velocity or any of the parameters studied. The only notable exception was hemoglobin, which was significantly lower in theophylline treated infants (mean values 10.5 vs 12.7 g/dl, p 0.005 at t test). In synthesis, long term theophylline treatment in preterm infants seems to be safe from the point of view of growth, glucose, protein and lipid metabolism, hormones and glomerular function, but further studies are needed on the effects of theophylline on neonatal erythropoiesis.

Theophylline pharmacokinetics and metabolism in rabbits following single and repeated administration of Capsicum fruit.

Pharmacokinetics and metabolism of theophylline were studied in three groups of male rabbits, after intravenous administration (12 mg/kg), with and without oral ground Capsicum fruit suspension. Compared with control values, plasma theophylline half-life of distribution and of elimination, areas under plasma curves, clearance and volume of distribution did not show any significant difference. On the contrary, the elimination rate constant (k1,0) is significantly different (0.01 < P < 0.05) after a single dose of capsicum and remained unchanged after a repeated dose. Concerning the metabolism of theophylline in rabbits, the results showed that the oral administration of a single dose of Capsicum fruit suspension does not significantly affect the urinary excretion of theophylline and its metabolites--1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU). On the other hand, after a repeated dose of Capsicum fruit for 7 days, the quantity of 1-MU was significantly reduced (0.01 < P < 0.05). In conclusion, it was found that a single dose of Capsicum fruit could affect pharmacokinetic parameters of theophylline (k1,0), while a repeated dose affected the metabolic pathway of xanthine oxidase.

Bronchodilator effects of caffeine in coffee. A dose-response study of asthmatic subjects.

Although caffeine is a universal drug and has multiple pharmacologic and physiologic actions in man, there are surprisingly few objective data about its effect on pulmonary function. We conducted a short-term, double-blind, randomized crossover study in nine asthmatic adults who ingested decaffeinated coffee containing varying amounts of added caffeine (mean of 0.2,2.5,5.6, and 7.2 mg/kg of body weight) on different days. The subjects also ingested decaffeinated coffee and aminophylline (200 mg) on a separate day of study. Baseline and post-drug determinations of serum levels of caffeine and theophylline, forced expired volume and flow, specific airway conductance (Gaw/VL), vital signs, and reported symptoms were obtained. Peak increases in serum caffeine concentrations (mean, 12.4 micrograms/ml +/- 1.5 micrograms/ml) occurred 45 minutes following the highest dose of caffeine (7.2 mg/kg), whereas the peak theophylline level (mean 3.8 micrograms/ml +/- 0.4 micrograms/ml) occurred 90 minutes following oral administration of aminophylline (mean theophylline, 2.6 mg/kg). Comparable peak increases in the forced expiratory volume in one second (FEV1), the forced expiratory flow during the middle half of the forced vital capacity (FEF25-75%), and Gaw/VL occurred at 120 minutes following aminophylline and the highest dose of caffeine, indicating that caffeine is an effective bronchodilator but is only 40 percent as active as an equivalent molar dose of theophylline. Regression analysis revealed statistically significant dose-response relationships between peak increases in serum caffeine concentrations and increases in FEV1, FEF25-75%, and Gaw/VL from baseline values. These findings have diagnostic and therapeutic implications regarding the use of caffeine prior to tests of pulmonary function and as a dietary agent, alone or in combination with theophylline.