Choline Theophyllinate Research Articles

Development of a Stability Indicating Method and Study of Forced Degradation Pathway of Choline Theophyllinate and Salbutamol by Liquid Chromatography–Mass Spectrometry

Development of a Stability Indicating Method and Study of Forced Degradation Pathway of Choline Theophyllinate and Salbutamol by Liquid Chromatography–Mass Spectrometry

Biocompatible amphiphilic conetwork based on crosslinked star copolymers: A potential drug carrier

ABSTRACTA series of amphiphilic conetworks (APCNs) is synthesized through crosslinking of well‐defined tri‐arm star diblock copolymers via atom transfer radical polymerization. A new three‐arm initiator is synthesized to initiate the polymerization of 2‐hydroxyethyl methacrylate (HEMA) via “core‐first” method. The resulting star HEMA homopolymers with well‐defined molecular weight and narrow polydispersity are used as macroinitiator to incorporate allyl methacrylate to get the star diblock copolymers. Then, the precursors with allyl pendant groups are fully crosslinked with polyhydrosiloxanes through hydrosilylation. The so‐prepared APCNs exhibit unique properties of microphase separation of hydrophilic (HI) and hydrophobic (HO) phases with small channel size, a variable swelling capacity, excellent biocompatibility, and outstanding mechanical strength (2 ± 0.5 MPa). The properties of APCNs depend on the ratio of HI to HO, which can be regulated via precise synthesis of the star diblock copolymers. The APCNs show well‐controlled drug release to choline theophyllinate, suggesting a promising intelligent drug carrier for controlled release. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 53, 2537–2545

Synthesis, characterization and biological activity of diorgano and triorganotin (IV) complexes of Chlordiazepoxide, Choline theophyllinate and Phenobarbitone sodium

In an attempt to develop novel metal-based drugs with a different therapeutic profile to cisplatin, a new series of diorganotin (IV) and triorganotin (IV) complexes of R2SnA2 (R = Me, n-Bu, n-Oct and Phenyl) and R3SnA2 (R = n-Bu) where A is the anion of Chlordiazepoxide (L1H) {(2Z)-7-chloro-2-(methylimino)-5-phenyl-3,4-dihydro-2H-1,4-benzodiazepin-4-ol}, Choline theophyllinate (L2H) {(2-hydroxyethyl)trimethylazanium; 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-ide} and Phenobarbitone sodium (L3H) {5-ethyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione} have been synthesized. These resulting complexes were characterized by elemental analysis, UV, IR, NMR (1H, 13C and 119Sn) studies. On the basis of these spectroscopic studies, it was proposed that diorganotin (IV) complexes of Chlordiazepoxide, Choline theophyllinate and Phenobarbitone sodium having 1:2 stoichiometry show tetrahedral geometry. Triorganotin (IV) complexes of Chlordiazepoxide and Choline theophyllinate having 1:2 stoichiometry show trigonal bipyramidal geometry. The ligand molecules in these complexes appear to be bound to the tin atom through the hydroxyl oxygen in Chlordiazepoxide, Choline theophyllinate and Phenobarbitone sodium. The biological activity of all these complexes was screened against six indicator strains: Bacteriodes fragilis, Salmonella enterica, Listeria monocytogenes, Pseudomonas aeruginosa, Escherichia coli and Vibrio cholerae. The antibacterial activity is found maximum for n-Bu2Sn(L2)2 which is most effective against all indicator strains used. n-Bu2Sn(L1)2 is effective against Pseudomonas aeruginosa and Vibrio cholerae while Me2Sn(L3)2 and Ph2Sn(L3)2 show good inhibitions against Bacteriodes fragilis and Salmonella enterica.

Well-defined biodegradable amphiphilic conetworks

A series of amphiphilic conetworks (APCNs) with well-defined molecular structures were prepared via a copper-catalyzed 1,3-dipolar azide–alkyne cycloaddition (CuAAC) of tetrakis(2-propynyloxymethyl)methane (TMOP), diazide end-functionalized triblock copolymers of poly(e-caprolactone) with poly(ethylene glycol) (N3-PCL-PEG-PCL-N3). The so-prepared APCNs exhibit unique properties of ordered nanophase separation of hydrophilic (HI) and hydrophobic (HO) phases, and a variable swelling capacity both in water and organic solvent. The morphology, surface properties and thermal behavior of the APCNs were investigated by scanning electron microscopy (SEM), water contact angle (WCA), and differential scanning calorimetry (DSC), respectively. The physical properties of APCNs depended on the ratio of HI–HO, which can be regulated via precise synthesis of N3-PCL-PEG-PCL-N3. The analysis of an in vitro cell viability assay suggests that the APCNs have excellent biocompatibility. The prepared APCNs are excellent carriers for controlled drug release. The hydrophilic choline theophyllinate and hydrophobic 5-fluorouracil (5-FU) were loaded into the APCNs simultaneously as model drugs to study the release from APCNs. The well-controlled drug release is attributable to the well-defined molecular structure and tunable HI/HO composition of the APCNs.

Chemiluminometric determination of choline-related substances in pharmaceutical preparations by dot-blot.

A simple and reliable method of assaying succinylcholine chloride, oxtriphylline (choline theophyllinate) and acetycholine chloride in pharmaceutical preparations, based on conversion to choline, is provided by combination of chemiluminometry of choline and dot-blot technique. Recoveries of 102 and 97% for choline chloride in Quelicin injection and Choledyl 200 tablets matrices, respectively, and of 99% for acetylcholine chloride in Miochol solution matrix could be achieved using simple choline chloride standards in phosphate buffer pH 8.6. Accordingly, matrix-matched standards were found redundant. Favourable results obtained in preparations-matched media including limits of detection of 37-39 pmol microliters-1 of choline chloride, together with accuracies of 0-2% and RSDs ranging from 4 to 7% are the further evidence of the suitability of the method.

The Effect of Steroids on Theophylline Absorption

The effect of hydrocortisone on plasma theophylline concentrations was evaluated in 20 patients suffering from chronic bronchitis or stable bronchial asthma. Choline theophyllinate (400 mg) was orally administered every 12 h for 8 days and blood samples were taken every 2 h during the day for the measurement of theophylline concentrations. Intravenous bolus injections of 500 or 1000 mg hydrocortisone on day 5 or day 7, respectively, did not significantly alter plasma theophylline concentrations.

Pharmacokinetic study of controlled‐release choline theophyllinate in elderly patients

SummaryControlled‐release choline theophyllinate tablets (Sabidal SR 270, Zyma) were administered to 17 elderly patients aged between 68 and 86 years (mean 76 ± 7 years) until steady state was obtained. The dosage form was one tablet every 12 hours for four days.Plasma theophylline concentrations were measured by high‐performance liquid chromatography after the first dose and during the fourth day for a 12‐hour period. The tablets showed evidence of controlled‐release properties: the maximum plasma concentration (10.8 ± 2.5 mg/1) was obtained after 3.4 ±1.6 hours. The mean trough level was 6.6 ±1.5 mg/1 and the difference between the peak and trough levels was 4.1 ± 1.2 mg/1. The mean steady‐state plasma theophylline concentration was 8.5 ± 2.2 mg/1. The mean elimination half‐life was 14 ± 7 hours. The mean volume of distribution was 0.8 ± 0.4 l/kg. The mean total body clearance was 0.05 ± 1/h/kg. All values, the half‐life excepted, were found to be within the ranges for the patients reported in the literature. The values show the usual interindividual variation.

Transdermal delivery of theophylline to premature infants using a hydrogel disc system.

1. Preterm infants show incompletely developed skin with reduced barrier function. The possibility of transdermal delivery of theophylline from hydrogel discs swollen with choline theophyllinate has been investigated. 2. Drug loaded hydrogel discs 2 cm2 in area were applied to the abdomen and occluded. Serum theophylline concentrations were measured in twenty-one infants of less than 31 weeks gestation. 3. Therapeutic concentrations were achieved in 18 individuals, and maintained for up to 15 days after repeated application of discs. A correlation between maximum serum drug concentration and transepidermal water loss, gestation and birthweight was demonstrated.

The Pharmacokinetics and Efficacy of Slow-Release Theophylline with Asymmetric Dosing in Asthmatic Chinese

Fifteen Chinese subjects with stable asthma were given asymmetric doses of slow-release choline theophyllinate (Theobret) according to body weight; patients under 60 kg (132 lb) received 180 mg at 9 AM and 360 mg at 9 PM for six days (period 1), followed by 180 mg at 1 PM and 360 mg at 9 PM for six days (period 2); for those over 60 kg, the regimen was the same, except that they received 270 mg during the daytime and 540 mg at night. At the end of each period of treatment, concentration of theophylline was measured over 24 hours. Five patients experienced side effects, and two of these were withdrawn from the study. In the remaining 13 patients, optimal concentrations of the drug were attained during most of the 24 hours, and there were only minor pharmacokinetic differences between the two periods of treatment. Compared with observations before treatment, the total symptom score was unchanged, but the peak expiratory flow rate in the morning and evening improved, and the use of inhaled bronchodilator drugs decreased significantly. There was a trend towards progressive improvement as the duration of treatment increased, suggesting that the therapeutic effect of theophylline may lag behind the attainment of optimal concentrations. We conclude that asymmetric dosing regimens of slow-release theophylline are effective and rational in maintenance therapy for asthma and that lower total daily dosages may be more appropriate in Chinese patients when compared to those recommended for white subjects.

Dissolution of 4 controlled-release theophylline formulations in milk

The disissolution of 4 controlled-release theophylline formulations was studi9d in a low-fat (0.75%) milk and in a buffer of pH 6.5. A flow-injection dialysis-UV spectrophotometric method was developed to determine the drug in the milk samples. Calibration curves were linear up to 250 μg/ml for theophylline and aminophylline and up to 450 μg/ml for choline theophyllinate, with detection limits of 18.5, 5.4, and 14.7 μg/ml, respectively, in a 5.0 ml minimum sample volume. Lower dissolution profiles in milk than in buffer were observed for 3 of the formulations examined. One theophylline formulation exhibited relatively similar dissolution profiles in both media. The use of milk as a food-simulating medium in dissolution studies is suggested for the in vitro evaluation of the release rate of drugs from controlled-release formulations. The proposed technique can be applied in such studies.

Comparing Anhydrous Theophylline with Choline Theophyllinate

Comparing Anhydrous Theophylline with Choline Theophyllinate

Multiple-dose bioavailability study of a sustained-release theophylline product: Choledyl S.A. tablets

The bioavailabilities of two sustained release preparations containing choline theophyllinate (Choledyl S.A. 400 mg and 600 mg tablets) have been studied in 12 healthy volunteers using multiple doses. The extent of bioavailability estimated for each tablet was not significantly different to that of Choledyl elixir. When data were adjusted to give a mean steady-state theophylline concentration of 12.5 mg litre, no significant differences in peak-trough swings were observed between the elixir taken over a 5-h dosage interval and the tablets taken over a 12-h dosage interval. The tablets would therefore appear adequate for use on a twice-daily basis in the majority of patients but in those with short half-lives, e.g. children and smokers, 8 hourly dosing would be more appropriate.

No effect of food on single dose bioavailability of sustained release theophylline ( Sabidal); a comparison between Sabidal and choline theophyllinate solution

No effect of food on single dose bioavailability of sustained release theophylline ( Sabidal); a comparison between Sabidal and choline theophyllinate solution

Food reduces the rate but not the extent of the absorption of theophylline from an aqueous solution.

The effect of food on the rate and extent of absorption of theophylline was studied in healthy adults given a single dose of theophylline (aqueous solution of choline theophyllinate containing 270 mg of theophylline) in the evening either on an empty stomach or together with supper. Food appeared to decrease the absorption rate of theophylline significantly, tmax being prolonged from 1.34 h (mean) to 4.40 h and cmax decreased from 7.82 mg . l-1 to 5.47 mg . l-1. The area under the plasma concentration-time curve (AUC) after drug intake with supper was slightly but not significantly smaller, indicating that theophylline (as a solution of choline theophyllinate) can be taken together with food without substantial loss of the quantity of drug absorbed. The elimination rate was not influenced by concomitant intake of supper.

Chronopharmacokinetics of theophylline after sustained release and intravenous administration to adults.

The influence of time of drug administration on pharmacokinetics of theophylline was studied both after ingestion of a sustained-release tablet, containing choline theophyllinate ( Zy 15061-S. R.; Teovent ; Sabidal ; ZYMA S.A.) and after intravenous infusion of aminophylline to eight healthy volunteers. Both drugs were administered in the morning (10 a.m.) and on a separate occasion in the evening (10 p.m.) after a 12 h period of fasting. After oral administration of a dose of 540 mg theophylline, the drug was steadily absorbed, both during day-time and during night-time. In some subjects absorption was slower in the evening. Maximum theophylline plasma concentrations were reached after 3.3 +/- 0.4 h (mean +/- SD) and 3.9 +/- 1.4 h respectively (not significantly different p greater than 0.05). The maximum plasma concentrations were almost identical after administration in the morning and in the evening (12.6 +/- 3.3 mg X l-1 and 13.1 +/- 1.4 mg X l-1 respectively). There was also no significant difference (p greater than 0.05) between the areas under the plasma concentration-time curves after oral and intravenous administration, both at day-time and at night-time. This finding indicates complete bioavailability of the sustained release tablets on both occasions. After administration of the tablets in the morning the plasma concentration 12 h post dosing was significantly lower than after administration in the evening: c1 12 accounted for 6.0 +/- 2.0 mg X l-1 after intake at 10 a.m. and for 7.9 +/- 2.1 mg X l-1 after ingestion at 10 p.m. (p less than 0.01). A similar observation was done after intravenous administration of the drug: c12 was 6.6 +/- 1.6 mg X l-1 after starting the infusion in the morning and 8.0 +/- 1.8 mg X l-1 after infusing the drug in the evening (p less than 0.01). This phenomenon could be explained by the finding of a significantly prolonged half-life of theophylline during night-time, provided that the plasma concentrations were in the range of 5 to 15 mg X l-1 (which coincides approximately with the therapeutic range of the drug).(ABSTRACT TRUNCATED AT 250 WORDS)

Oploskarakteristieken van enkele cholinetheofyllinaattabletten

Dissolution profiles of choline theophyllinate tablets as obtained from twelve manufacturers (or distributors) and two choline theophyllinate containing trade mark products (Cholegyl® and Dilasmyl®) have been studied, using the apparatus for the disintegration test as described inPh. Eur. ed 1. Tablets have been tested both according to the monograph of ‘plain coated tablets’ and that of ‘enteric coated tablets’. Cholegyl® proved to meet the specifications of enteric coated tablets, but several of the generic products did not and (although chemically equivalent) consequently cannot be considered as being biopharmaceutic equivalents to the trade mark product.

A Clinical Trial of Choline Theophyllinate versus Salbutamol with Placebo Control

Using a randomized double-blind procedure, seventeen patients with chronic airways obstruction completed a placebo-controlled study to compare bronchodilator effects of single doses of choline theophyllinate 400 mg and salbutamol 4 mg. As determined by a range of spirometric measurements, the effects of the two drugs were remarkably similar and there were no statistically significant differences in any of the parameters measured. Both drugs produced highly significant differences in comparison with placebo response. Side-effects were mainly complaints of digital tremor; this was seen in four of the patients after salbutamol and in less pronounced form in two patients after choline theophyllinate.

A comparison of oral choline theophyllinate and beclomethasone in severe perennial asthma in children

Fourteen children with perennial asthma previously treated with beclomethasone dipropionate were studied for four months in a crossover trial to compare the efficacy of choline theophyllinate and beclomethasone dipropionate aerosol in the control of their symptoms. Assessments were made using twice daily peak flow measurements, together with daily records of symptom scores and use of extra salbutamol. Beclomethasone and oral choline theophyllinate together improved control of asthma in comparison with beclomethasone alone. Reduction of the dose of beclomethasone from 400 μg/day caused worsening of asthma. Oral choline theophyllinate did not prevent this deterioration and therefore cannot replace beclomethasone for the long-term treatment of such asthmatic patients.

Dosage schedule for intravenous aminophylline in apnoea of prematurity, based on pharmacokinetic studies.

15 preterm infants were treated for recurrent apnoea with theophylline. 5 were given oral choline theophyllinate, but this was erratically absorbed. 14 were given IV aminophylline on 23 occasions. Apparent volume of distribution of theophylline in 12 infants was 0.71 +/- 0.18 1/kg (mean +/- SD). Plasma clearance rate measured in 11 infants at steady state was 18.6 +/- 4.8 ml/kg per hour. Calculations show that a loading dose of 6.2 mg/kg aminophylline intravenously and maintenance of 4.4 mg/kg per day would produce serum levels of between 6 and 12 mg/l in all but one of the infants studied, with no infant having toxic levels.

Multi-dose comparative study of microcrystalline theophylline and choline theophyllinate

SummaryPreliminary findings are reported of a double-blind trial carried out in patients with chronic obstructive lung disease to compare the plasma theophylline concentrations achieved after oral administration of 125 mg tablets of a microcrystalline theophylline and 200 mg tablets of choline theophyllinate. Measurements were also made of lung function parameters (FEY1 and PEFR). Seven patients were treated for 2 days each with the two theophylline preparations and with placebo. Treatment sequence was randomized and there was at least 1 day in between each period. Dosage levels, providing approximately the same amount of theophylline with both drugs, were 875 mg theophylline or 1400 mg choline theophyllinate on Day 1 and 500 mg theophylline or 800 mg choline theophyllinate on Day 2, given in divided administration. Although the plasma concentrations on the first day barely reached a therapeutic value {normally between 10 and 20 μg/ml) with either preparation, PEFR and FEV1 values were higher than those on placebo. Plasma levels were lower on Day 2 and this was reflected in drug effect. Patients subsequently admitted to the trial have received a higher dosage (increased by 250 mg on Day 1 and 500 mg on Day 2 for theophylline, and by 400 mg and 800 mg, respectively, for choline theophyllinate). Plasma theophylline concentrations on the second day were clearly higher than with the original dosage regimen in the 3 patients so far studied.