An assessment of mutagenicity, genotoxicity, acute-, subacute and subchronic oral toxicity of paraxanthine (1,7-dimethylxanthine).

Paraxanthine or 1,7-dimethylxanthine is a natural dietary component and the main metabolite of caffeine in humans. A battery of toxicological studies was conducted in accordance with international guidelines to investigate mutagenicity, genotoxicity and acute and repeated-dose oral toxicity in rats of synthetic paraxanthine (ENFINITY™, Ingenious Ingredients, L.P., >99% purity). There was no evidence of mutagenicity in a bacterial reverse mutation as well as in an in vitro mammalian chromosomal aberration test. There was no evidence of genotoxicity in an in vivo mammalian erythrocyte micronucleus test as well as in an in vitro mammalian cell gene mutation test. An acute oral toxicity test resulted in a LD50 value of 1601 mg/kg bw/d. Paraxanthine did not cause mortality or toxic effects in a subacute 28-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. Paraxanthine also did not cause mortality or toxic effects in a subchronic 90-day repeated-dose oral toxicity study at daily doses of 75, 150, or 300 mg/kg bw/d (each group n = 10 per sex), administered by gavage. The no observed adverse effect level (NOAEL) determined from the 90-day study was greater than or equal to 300 mg/kg bw/d, the highest dose tested, for both male and female Wistar rats.

The effect of doxofylline in asthma and COPD.

Theophylline is still one of the most widely prescribed drugs for the treatment of asthma and COPD in developing countries because the majority of asthma and COPD medicines are largely unavailable and also because it is a cheap option. In any case, its anti-inflammatory effects and capacity to reverse corticosteroid resistance deserve consideration, but it can induce numerous side effects and drug-drug interactions and frequently requires measurement of drug levels in plasma. In order to overcome the problems posed by theophylline, other xanthines have been developed. Doxofylline is a newer generation xanthine with both bronchodilating and anti-inflammatory activities and for this reason it has been called "novofylline". It differs substantially from theophylline at the pharmacological level. Clinical studies have shown substantial differences between doxofylline and theophylline. In particular, efficacy/safety profile of doxofylline is better than that of theophylline.

Captagon: use and trade in the Middle East.

BACKGROUND: Fenetheylline, a psychostimulant drug, often branded as Captagon, is a combination of amphetamine and theophylline. Since the cessation of its legal production in 1986, counterfeited products have been produced illicitly in south-east Europe and far-east Asia. Its profitable trade has been linked to terrorist organizations, including Islamic State of Iraq and the Levant. This study aims to reach up-to-date data, concerning the Captagon e-commerce and use in the Middle East. METHODS: A multi-staged and multi-lingual literature search was carried out. A list of prespecified keywords was applied across medical and paramedical databases, web and Dark web, search engines, social communication media, electronic commerce websites, media networks, and the Global Public Health Intelligence Network database. RESULTS: The use of Captagon as a stimulant in terrorist settings has been marginally covered in the literature. Data can widely be retrieved from Google and AOL search engines, YouTube, and Amazon e-commerce websites, and to a lesser extent from Alibaba and eBay. On the contrary, Middle Eastern e-commerce websites yielded almost no results. Interestingly, the Dark web generated original data for Captagon e-commerce in the Middle East. CONCLUSION: Further investigations are needed on the role that psychoactive drugs play in terrorist attacks and civil war zones. Unless a comprehensive methodological strategy, inclusive of unconventional methods of research, is implemented, it will not be feasible to face such a threat to humanity.

Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti-inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double-blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant-reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014.

Assessment of the rewarding effects of dimenhydrinate using the conditioned place preference paradigm in mice.

Dimenhydrinate (DIM) is an over-the-counter antihistamine consisting of diphenhydramine (DIP) and 8-chlorotheophylline (CTP). Medical use of DIM is for prevention of nausea and motion sickness. Recently, it has been reported that DIM may be used alone or in combination with other drugs for recreational purposes due to its euphoric and hallucinogenic effects. To investigate the putatively rewarding properties of DIM and its constituents DIP and CTP, we used a conditioned place preference (CPP) test in mice. DIM significantly induced CPP at a dose of 30 mg/kg. Neither DIP (3, 10, and 30 mg/kg) nor CTP (3, 10, and 30 mg/kg) alone induced CPP. Because neither DIP nor CTP resulted in CPP, the rewarding property of DIM appears to be caused by the sum of the effects of its constituents. In addition, low doses of DIM (3 mg/kg), co-administered with low doses of cocaine (7.5 mg/kg), significantly induced CPP, while neither low-dose DIM (3 mg/kg) nor low-dose cocaine (7.5 mg/kg) administered separately induced CPP. This result suggests the liability of DIM use in combination with other abused drugs to create a stronger effect.

Uncertainty factors for chemical risk assessment. human variability in the pharmacokinetics of CYP1A2 probe substrates.

A 100-fold uncertainty factor is used to derive acceptable daily intakes for compounds causing thresholded toxicity. The 10-fold factor for human variability can be further subdivided into two factors of 10(0.5) (3.16) to allow for toxicokinetics and toxicodynamics. The validity of the human kinetic subfactor has been analysed in relation to CYP1A2 metabolism using published in vivo pharmacokinetic parameters selected to reflect chronic exposure (metabolic and total clearances and area under the plasma concentration-time curve: CLm, CL and AUC) and acute exposure (the peak plasma concentration, C(max)). The variability in CYP1A2 activity in healthy adults, based on data after oral and intravenous dosage (CLm, CL and AUC), ranged from 34 to 42%. The variability in C(max) was 21%. The default kinetic factor of 3.16 would cover at least 99% of the healthy adult population, assuming that the data were log-normally distributed, but would give lower protection for some subgroups (pregnant women at term, healthy elderly, patients with liver disease), and was inadequate for neonates. This analysis of in vivo kinetic data for CYP1A2 substrates illustrates the importance of quantifying human variability in specific metabolic pathways, and of identifying potentially susceptible subgroups of the human population, in order to determine the scientific validity of uncertainty factors.

Concurrent administration of donepezil HCl and theophylline: assessment of pharmacokinetic changes following multiple-dose administration in healthy volunteers.

AIM: The aim of the study was to evaluate the pharmacokinetics of theophylline administered alone, and in combination with donepezil HCl, following multiple-dose administration of both drugs in healthy volunteers. METHODS: This was an open-label, randomized, two-period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received either titrated-dose theophylline alone, or in combination with donepezil (5 mg, once daily) for 10 consecutive days. On day 10 of each treatment period, serial blood samples for the determination of theophylline concentrations in plasma were measured up to 24 h. Treatment periods were separated by a 3-week, drug-free washout. Plasma concentrations of theophylline were determined by HPLC with UV detection. RESULTS: No statistically significant differences in theophylline pharmacokinetics (Cmax, AUC or tmax) were observed between theophylline administered alone and in combination with donepezil. No clinically significant changes in vital signs, ECG parameters or clinical laboratory tests were observed in any subject during any treatment period. CONCLUSIONS: Concurrent administration of donepezil HCl does not alter the pharmacokinetic profile of theophylline following multiple-dose administration of both drugs in healthy volunteers. These findings suggest that donepezil may be safely co-administered with theophylline without a need for dose modification or additional monitoring procedures.

Effect of oral theophylline on resting energy expenditure in normal volunteers.

BACKGROUND: The aim of this study was to investigate the contribution of regular treatment with oral theophylline to the increase in resting oxygen consumption observed in patients with chronic airflow limitation who are receiving bronchodilator therapy. METHODS: Resting oxygen consumption (VO2) and carbon dioxide production (VCO2) were measured in 10 normal subjects (six men, age 21-48 years, weight 50-85 kg) before and after 11 days of treatment with either placebo or theophylline in a double blind manner, in twice daily oral doses ensuring trough serum concentrations between 8.4 and 13.5 mg/l. An open canopy method was used to measure VO2 and VCO2 and in all test conditions this was extended for 60 minutes after an inhalation of 800 micrograms of salbutamol super-imposed on the background placebo or theophylline treatment. RESULTS: Resting VO2 and heart rate were increased during theophylline treatment compared with placebo by 6.5% and 8.4% respectively. Salbutamol inhalation transiently increased VO2, VCO2, and heart rate in all tests but this was not modified by background theophylline treatment. CONCLUSION: Oral theophylline treatment causes a sustained increase in resting oxygen consumption and heart rate but does not modify the metabolic response to acutely inhaled salbutamol.

The physician as private attorney general.

A physician whose patient suffered permanent injuries due to a prescribed theophylline-based medication successfully sued the drug manufacturer under the Washington State Consumer Protection and Product Liability Acts. He claimed damages for injury to his professional reputation and for his personal physical and emotional distress. Evidence showed that the drug company had engaged in deceptive trade practices by concealing from physicians information about the risks associated with use of theophylline. On appeal, the Washington Supreme Court affirmed the physician's claim under the Consumer Protection Act but reversed the award of damages under the Product Liability Act. The court decided that, although the Consumer Protection Act normally applies to the ultimate user of a product, physicians are appropriate parties under the act in the case of medication injuries due to the special relationship between physicians and drug manufacturers, in which manufacturers deal directly with the prescriber, not with the patient. The prescribing physician may be a "private attorney general" under the act because the manufacturer caused harm to his professional reputation. The physician, however, could not recover damages for personal distress after injuries experienced by his patient because such damages are available only under the Product Liability Act, a law that applies to parties directly injured by a product, their relatives, and certain bystanders witnessing the injury.

Effect of drug interactions on outcomes of patients receiving warfarin or theophylline.

The effect of drug interactions on costs and other outcomes for hospitalized patients receiving warfarin or theophylline was studied. Data were collected from medical records during a one-year period in two community teaching hospitals in Maryland. The data included demographic information, the duration of study-drug therapy, the number of days spent in the intensive care unit, the length of stay (LOS) in the hospital, the number of prothrombin-time tests and serum theophylline assays, and the test results. A multiple-regression procedure was used to compare outcomes of patients who were prescribed specific drugs interacting with warfarin or theophylline with those of patients who were not. Among warfarin-treated patients, there was a significant difference in each outcome measure (LOS, number of laboratory tests, and test results) between those who received an interacting drug and those who did not; mean LOS was 3.14 days longer in patients given an interacting drug. No significant differences in outcome measures were observed between the two groups of theophylline-treated patients. The cost of the increased LOS attributed to the presence of a drug interacting with warfarin was estimated to range from $779 to $1005 per hospitalization. The cost of additional prothrombin-time tests was estimated at $19-$50. Patients who received warfarin and an interacting drug had an increased LOS, required more laboratory tests, and had longer prothrombin times than patients given warfarin alone; these differences probably led to higher costs.

[Evaluation of the efficacy and safety of mepifylline in oral solution in children with mild and moderate asthmatic crises]. / Valoración de la eficacia y seguridad de la mepifilina en solución oral en niños con crisis de asma leve a moderada.

Efficacy and safety of mepiphylline, a derivative of theophylline, was evaluated in a group of children, aged 6 to 10 years, with mild or moderate acute asthma. A parallel, randomized, double-blind, placebo controlled, prospective study was performed in 40 children. Twenty one of them received mepiphylline in dose of 8 mg/kg/día divided in 3 during 10 days, and 19 (control group) received placebo. Salbutamol aerosols were available in both groups. Clinical and spirometric data were collected before the beginning of the treatment (pre-and-post-nebulized salbutamol), and at the 3rd, 7th and 10th days. Children and parents cooperated with a diary of symptoms, peak-flow measurements and account of salbutamol used. A total relief of symptoms was found in 14 patients in the mepiphylline group and just 8 of the control group, with no significant differences. Neither spirometry nor diary data showed significant differences. Salbutamol was less than 3 days of unnecessary in 13 patients (61.9%) in the mepiphylline group and 8 patients (42.1%) in the control group (p < 0.05; Kolmogorov-Smirnov two samples Test). We conclude that mepiphylline could be a complementary treatment of mild and moderate acute asthma with a good safety in children.

Comparative cost-effectiveness analysis of theophylline and ipratropium bromide in chronic obstructive pulmonary disease. A three-center study.

The charts of 311 patients receiving theophylline (T) and 289 patients receiving ipratropium bromide (IB) for COPD were reviewed to determine the total costs and cost-effectiveness of these 2 agents in 3 different health-care settings. A direct cost-accounting method assessed cost, and a Markov decision-analysis model calculated cost-effectiveness. Costs to treat toxic effects were greater for T versus IB. The types and incidences of toxic effects, by drug, were similar among the three centers. Overall costs for T were $121.40 per patient per therapy-month versus $84.56 per patient per therapy-month for IB, as determined by the cost-accounting method. The marginal cost was $366 for T over IB when extrapolated over 1 year using the Markov model. The Markov model also predicted that patients receiving IB had a greater number of complication-free therapy-months (measurement of effectiveness) than patients receiving T. We conclude that treatment with IB was less costly and more cost-effective than T.

Incidence and cost of hospital admissions secondary to drug interactions involving theophylline.

OBJECTIVE: To determine the incidence and cost of hospital admissions for theophylline toxicity, which occurred as a result of the concurrent use of one of the following medications: cimetidine, erythromycin, or ciprofloxacin. DESIGN: Retrospective chart review (18 months, between June 1989 and November 1990). SETTING: A Department of Veterans Affairs Medical Center. PARTICIPANTS: All patients who were receiving theophylline chronically (913 patients) and also had a prescription for cimetidine (124 patients with 140 treatment courses), erythromycin (66 patients with 93 treatment courses), or ciprofloxacin (39 patients with 59 treatment courses) dispensed. INTERVENTIONS: Each patient's medical record was reviewed to identify hospital admissions within 30 days following the dispensing of the interacting drug. MAIN OUTCOME MEASURES: Admissions were considered to be related to theophylline toxicity if appropriate signs and symptoms were present and the theophylline concentration was above 20 micrograms/mL or had increased significantly from the concentration obtained prior to introduction of the interacting drug. RESULTS: One patient who received cimetidine and one who received ciprofloxacin were admitted for theophylline toxicity (2 of 292 potential interactions, 0.81 percent). Admissions were for 16 and 13 days, respectively, and total costs for the two admissions were $12,864.22 or $44.00, respectively, per potential interaction. The entire admission was not for theophylline toxicity; it appeared that iatrogenic factors contributed to the duration. CONCLUSIONS: The incidence of hospital admissions secondary to theophylline drug interactions with cimetidine, ciprofloxacin, or erythromycin is low, but the admissions represent considerable expense, even when distributed among all patients at risk for the interactions.

Comparative assessment of enprofylline and theophylline for chronic obstructive airways disease in the elderly.

Enprofylline, a recently developed xanthine derivative, is a more potent bronchodilator than theophylline. This study compares the efficacy and safety of enprofylline with theophylline for chronic obstructive airways disease (COAD) in elderly subjects. The study was of a randomized double-blind parallel design and commenced with a 1-week reference period when oral bronchodilators were withdrawn. Patients were then treated with either enprofylline or theophylline 150 mg bd for 2 weeks (period 1) followed by 300 mg bd for a further 3 weeks (period 2). Patients recorded peak expiratory flow rate (PEFR) and adverse experiences, if any, in a diary, daily. Of 111 patients recruited for the study, 85 entered active treatment (theophylline, n = 44; enprofylline, n = 41). Mean age was 72 years and mean bronchodilator reversibility was 22%. Enprofylline increased mean morning PEFR by 11% (period 1) and 19% (period 2) whereas theophylline increased PEFR by 13% and 19%, respectively. From the enprofylline group 29% were withdrawn from the study due mainly to headache and nausea/vomiting and from the theophylline group 7% were withdrawn due mainly to nausea/vomiting. Mean plasma concentrations of enprofylline were 2.0 mg l-1 and 3.4 mg l-1, and with theophylline 5.4 mg l-1 and 10.0 mg l-1 at the end of periods 1 and 2, respectively. Enprofylline and theophylline produced similar improvements in lung functions and symptoms of chronic obstructive airways disease, but enprofylline was less well tolerated than theophylline.

Therapeutic risk-assessment model for identifying patients with adverse drug reactions.

The association between factors that place patients at risk for adverse drug reactions (ADRs) and the occurrence of ADRs was examined, and a therapeutic risk-assessment model was developed. Theoretical risk factors for ADRs to digoxin and theophylline were identified through the literature by researchers at a private tertiary-care hospital. Data were then collected from two groups of 67 patient charts each during a 15-month period. One group of charts represented patients who had experienced an ADR to digoxin or theophylline. The other group represented matched control patients who had not experienced an ADR to either drug. ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modifications) ADR codes were assigned by medical records department personnel, and the ADRs were verified by using the Naranjo algorithm. Seven risk factors for each drug were found to be significantly associated with ADRs. A serum digoxin concentration greater than 2.5 ng/mL and elevated blood urea nitrogen were the two best predictors of an ADR to digoxin. The probability of experiencing an ADR to digoxin was 94.1% for a patient with both of these risk factors. A serum theophylline concentration greater than 25 micrograms/mL was the greatest predictor of an ADR to theophylline; the probability of experiencing an ADR to theophylline was 85.2% if a patient had that risk factor. The sensitivity and specificity of the therapeutic risk-assessment model were 92.9% and 61.8%, respectively, for digoxin and 95.8% and 84.0%, respectively, for theophylline. Several laboratory-based screening criteria demonstrated an ability to predict ADRs to digoxin and theophylline.

Applying decision analysis in therapeutic drug monitoring: using decision trees to interpret serum theophylline concentrations.

In the second of a three-part series, decision analysis is applied to therapeutic drug monitoring decisions that affect individual patients, using theophylline concentration and toxicity data to illustrate general concepts. Likelihood ratios and conditional probability curves were developed. The curves were used to determine the probability of toxicity based on the clinician's assessment of patient status and a measured serum theophylline concentration. A decision tree to "rule in" or "rule out" toxicity was constructed. Selection of a serum concentration cutoff level for classifying patients as toxic or nontoxic depends on the probabilities of the possible outcomes of the decision process and the clinician's assessment of the value of each possible outcome; therefore, no single concentration value is best for classifying patients. A decision tree was also constructed for evaluating therapeutic options when the clinician is confronted with adverse effects that may be drug related. In three prototype cases, the expected utility for discontinuing theophylline, continuing the drug at the same dosage, or lowering the dosage was determined and used to evaluate the relative worth of each therapeutic option. A more comprehensive interpretation of the serum theophylline concentration is provided by decision-analysis techniques than by observation of pharmacologic effect alone, because other factors such as merit, risk, and consequences of alternative decisions are considered.