Safety Assessment of Methylxanthines as Used in Cosmetics.

The Expert Panel for Cosmetic Ingredient Safety (Panel) assessed the safety of three methylxanthines, Caffeine, Theobromine, and Theophylline, as used in cosmetics. All of these ingredients are reported to function as skin-conditioning agents in cosmetic products. The Panel reviewed the data relevant to the safety of these ingredients and concluded that Caffeine, Theobromine, and Theophylline are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

Placentation-related processes in a human first-trimester extravillous trophoblast cell line (HTR-8/SVneo cells) are affected by several xenobiotics.

Our aim was to investigate the effect of some xenobiotics on placentation-related processes in an extravillous trophoblastic cell line (HTR-8/SVneo cells). Amphetamine, MDMA, theophylline, and fluoxetine, but not nicotine, cocaine, and caffeine, had a negative effect on cell proliferation rates, culture growth, viability, or migratory capacity. These compounds have a detrimental effect in placentation-related processes of HTR-8/SVneo cells.

Methylxanthines, seizures, and excitotoxicity.

Clinical evidence, in particular the wide use of theophylline as a bronchodilator, suggests that methylxanthines can cause seizures in patients without known underlying epilepsy. Theophylline is also known to be an added risk factor for seizure exacerbation in patients with epilepsy. The proconvulsant activity of methylxanthines can best be explained by their antagonizing the brain's own anticonvulsant adenosine. Recent evidence suggests that adenosine dysfunction is a pathological hallmark of epilepsy contributing to seizure generation and seizure spread. Conversely, adenosine augmentation therapies are effective in seizure suppression and prevention, whereas adenosine receptor antagonists such as methylxanthines generally exacerbate seizures. The impact of the methylxanthines caffeine and theophylline on seizures and excitotoxicity depends on timing, dose, and acute versus chronic use. New findings suggest a role of free radicals in theophylline-induced seizures, and adenosine-independent mechanisms for seizure generation have been proposed.

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.

Food-Drug Interaction between the Adlay Bran Oil and Drugs in Rats.

Adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) contains various phytonutrients for treating many diseases in Asia. To investigate whether orally administered adlay bran oil (ABO) can cause drug interactions, the effects of ABO on the pharmacokinetics of five cytochrome P450 (CYP) probe drugs were evaluated. Rats were given a single oral dose (2.5 mL/kg BW) of ABO 1 h before administration of a drug cocktail either orally or intravenously, and blood was collected at various time points. A single oral dose of ABO administration did not affect the pharmacokinetics of five probe drugs when given as a drug cocktail intravenously. However, ABO increased plasma theophylline (+28.4%), dextromethorphan (+48.7%), and diltiazem (+46.7%) when co-administered an oral drug cocktail. After 7 days of feeding with an ABO-containing diet, plasma concentrations of theophylline (+45.4%) and chlorzoxazone (+53.6%) were increased after the oral administration of the drug cocktail. The major CYP enzyme activities in the liver and intestinal tract were not affected by ABO treatment. Results from this study indicate that a single oral dose or short-term administration of ABO may increase plasma drug concentrations when ABO is given concomitantly with drugs. ABO is likely to enhance intestinal drug absorption. Therefore, caution is needed to avoid food-drug interactions between ABO and co-administered drugs.

Engineering riboswitch in L. major: From prediction to conceptualization.

Post-transcriptional gene regulation is a vital process to regulate expression of the key genes in the eukaryotic cell. Such processes are essential for pathogens which reside inside the host cell. One such pathogen is Leishmania major, which causes cutaneous leishmaniasis. The parasite lives inside the macrophages of mammalian host (mostly human). Inside the macrophage, Leishmania genes show complex host-pathogen interaction regulating a plethora of gene expression. Till date, most of the studies have shown this kind of regulation with respect to the host macrophages. Here, based on an extensive in silico analysis, we have hypothesized a novel Theophylline binding riboswitch mediated post-transcriptional regulation of a gene i.e. RNA Polymerase III subunit1 (Lmjf_09_1060), an essential gene for the parasite's survival both in its promastigote as well as in its amastigote form. Later, we have conceptualized the working of the identified putative Theophylline binding riboswitch cassette in in vitro using E. coli based reporter assay, wherein, a reporter gene (eGFP) is used instead of RNA Polymerase III subunit1 gene and apparently have shown the downregulation of the reporter gene (eGFP) expression under the influence of in silico identified Theophylline binding riboswitch.

Small Heterodimer Partner Regulates Circadian Cytochromes p450 and Drug-Induced Hepatotoxicity.

The role of small heterodimer partner (SHP) in regulation of xenobiotic detoxification remains elusive. Here, we uncover a critical role for SHP in circadian regulation of cytochromes P450 (CYPs) and drug-induced hepatotoxicity. Methods: The mRNA and protein levels of CYPs in the livers of wild-type and SHP-/- mice were measured by quantitative real-time polymerase chain reaction and Western blotting, respectively. Regulation of CYP by SHP was investigated using luciferase reporter, mobility shift, chromatin immunoprecipitation, and/or co-immunoprecipitation assays. Results: The circadian rhythmicities of xenobiotic-detoxifying CYP mRNAs and proteins were disrupted in SHP-deficient mice. Of note, SHP ablation up-regulated Cyp2c38 and Cyp2c39, whereas it down-regulated all other CYP genes. Moreover, SHP regulated the expression of CYP genes through different mechanisms. SHP repressed Lrh-1/Hnf4α to down-regulate Cyp2c38, E4bp4 to up-regulate Cyp2a5, Dec2/HNF1α axis to up-regulate Cyp1a2, Cyp2e1 and Cyp3a11, and Rev-erbα to up-regulate Cyp2b10, Cyp4a10 and Cyp4a14. Furthermore, SHP ablation sensitized mice to theophylline (or mitoxantrone)-induced toxicity. Higher level of toxicity was correlated with down-regulated metabolism and clearance of theophylline (or mitoxantrone). In contrast, SHP ablation blunted the circadian rhythmicity of acetaminophen-induced hepatotoxicity and alleviated the toxicity by down-regulating Cyp2e1-mediated metabolism and reducing formation of the toxic metabolite. Toxicity alleviation by SHP ablation was also observed for aflatoxin B1 due to reduced formation of the toxic epoxide metabolite. Conclusion: SHP participates in circadian regulation of CYP enzymes, thereby impacting xenobiotic metabolism and drug-induced hepatotoxicity.

Regulatory respiratory data refinement with reduced animal usage.

INTRODUCTION: Assessment of effects of potential drug candidates on the respiratory system is part of the regulatory preclinical safety assessment conducted prior to first in human trials (FTIH). Commonly, this is carried out utilizing head out plethysmography (HOP) or whole body plethysmography (WBP) which record only ventilatory parameters. When dosing via the inhaled route a more thorough respiratory assessment, including a direct measure of airway mechanics, is desirable. The aim of the present work was to improve the strategy for respiratory safety testing by a) evaluating a telemetered pleural pressure - HOP (PP-HOP) model and b) evaluating a crossover study design protocol in the WBP model to reduce variability and animal usage. METHODS: For the PP- HOP model, rats were surgically implanted with a telemetry device for measurement of pleural pressure. Animals were placed in HOP tubes and respiratory function assessed when exposed to methacholine at doses of 0 (saline only), 0.42, 1.6 and 3.8 mg/kg. WBP assessment was performed in rats in a crossover study design when treated with theophylline at doses of 0 (saline only), 3, 10 and 30 mg/kg. RESULTS: Data from the PP-HOP study confirmed the expected changes in ventilatory parameters and airway mechanics in response to inhaled methacholine, including an increase in pulmonary resistance and decrease in tidal volume. Data from the WBP crossover study demonstrated similar sensitivity and statistical power to detect changes in respiratory rate and tidal volume to a standard parallel group design. CONCLUSION: Measurement of PP-HOP in a stand-alone safety pharmacology study in conjunction with HOP assessment conducted as part of a toxicology study, represents an improved respiratory testing strategy for inhaled drugs. For compounds administered by other routes, we conclude that use of WBP using a crossover dosing design is a suitable alternative to parallel dosing groups, with a significant reduction in animal numbers and no loss of statistical power.

Free radicals and theophylline neurotoxicity : an experimental study.

Free radicals play a crucial role in health and disease and both reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in CNS effects like excitotoxicity. Theophylline, a re-emerging drug for the treatment of obstructive airway disease, has a narrow therapeutic index which precludes its safe use. The present study evaluated the possible involvement of free radicals in theophylline induced seizures in mice. Aminophylline (100-250 mg/kg) consistently induced seizures and post-ictal mortality, and conventional anticonvulsants and adenosine agonists were ineffective in antagonizing them. Further, phosphodiesterase inhibitors, per se, also did not show any significant seizurogenic potential. Pretreatments with antioxidants, ascorbic acid, alpha-tocopherol and melatonin, all dose dependently reduced seizure incidence and mortality after aminophylline, whereas, antioxidant depletion potentiated such excitotoxicity. Pretreatments with the NO synthase inhibitors, L-NAME and 7-NI blocked aminophylline seizures, whereas, the NO mimetics, L-arginine and glyceryl trinitrate, tended to potentiate this phenomenon. Sub-effective doses of aminophylline (100 mg/kg) also induced seizures when combined with subthreshold intensity of electroshock, and such seizures were similarly antagonized by the antioxidants and NO synthase inhibitors. Biochemical assay of brain homogenates showed that aminophylline seizures were associated with enhancements in brain MDA and NOx (NO metabolites) levels, whereas, SOD activity was reduced, and these changes were attenuated after melatonin and L-NAME pretreatments. The pharmacological and biochemical data are strongly suggestive of the involvement of both ROS and RNS during theophylline-induced seizures.

Potential risks of maternal administration of Mucophylline on the pups of albino rats during lactation.

The present study was undertaken to evaluate the potential risks of the mucolytic and broncholytic drug, Theophylline derivatives (Mucophylline) maternally administered on the pups. The nursing rats orally administered from 1st postpartum day (PPD) to 21th PPD with two different doses 30.83mg/kg (low dose) and 66.61mg/kg (Human equivalent dose (HED)). On the 21th PPD, the postnatal developmental signs, skeletal malformation and the histopathology of neonatal liver, kidney and brain were examined. Our results showed that Mucophylline induced a significant reduction in the neonatal weight and length, delayed, weak and incomplete ossification, wavy ribs and the neonatal liver revealed histopathological changes, pyknotic hepatocytes, cytoplasmic vacuolization, dilated sinusoid and necrotic area. Kidney revealed alternation changes, enlargement of the glomerulus, renal tubules degeneration and lymphatic infiltration. Brain (cerebral cortex and cerebellum) showed neurodegenerative changes, vacuolization of neuropil, congested and dilated blood vessel and dark stain neurons. Our results showed that the activities of non-enzymatic (GSH) and enzymatic (GST, CAT) antioxidants were insignificantly decrease in both neonatal brain and liver tissues of rats administered with 30.83mg/kg and 61.66mg/kg of Mucophylline and insignificant increase in MDA levels in both neonatal brain and liver tissues. However, significant reduction (P≤0.05) in the content of GR was recorded in neonatal brain tissue of rats administered with 30.83mg/kg and 61.66mg/kg of Mucophylline during lactation period in comparison with control. These support and proof the potential risks of the maternal administration of Mucophylline on pups.

Human Umbilical Cord Blood-Derived Neural Stem Cell Line as a Screening Model for Toxicity.

The aim was to investigate whether a human neural stem cell (NSC) line derived from human umbilical cord blood (hUCB) can be used for toxicity study. Toxicity of both neurotoxic environmental xenobiotics, methyl mercury chloride (CH3HgCl), lead acetate (CH3COOPb), and chlorpyrifos (CP), and non-neurotoxic insecticide, dichlorvos, as well as non-neurotoxic drugs, theophylline and acetaminophen were assessed. Additionally, differentiation of neuronal and glial cell lines derived from hUCB was elucidated. It was observed that CH3HgCl was more toxic to human NSCs in comparison to CH3COOPb and CP. The minimum inhibitory concentration (MIC) value against NSCs was 3, 10, and 300 mg/L, in each staining process, acridine orange/ethidium bromide (AO/EB) staining, 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) assay, and Hoechst staining, for CH3HgCl, CP, and CH3COOPb, respectively. CH3HgCl had the LC25 value as 10.0, 14.4, and 12.7 mg/L, by staining method mentioned in succession. CP had the LC25 value as 21.9, 23.7, and 18.4 mg/L; similarly, CH3COOPb had LC25 values, successively as 616.9, 719.2, and 890.3 mg/L. LC50 values ranged from 18.2 to 21.7 mg/L for CH3HgCl, 56.4 to 60.2 mg/L for CP, and 1000 to 1460.1 for CH3COOPb. Theophylline, acetaminophen, and dichlorvos had no impact on the viability of NSCs. This work justified that hUCB-NSC model can be used for toxicity study.

Fenethylline (Captagon) Abuse - Local Problems from an Old Drug Become Universal.

Fenethylline is a theophylline derivative of amphetamine having stimulant effects similar to those of other amphetamine-type derivatives. Fenethylline was used as medicament for hyperactivity disorders in children, narcolepsy and depression, but it has also been used as a drug of abuse under the common name of 'captagon'. Unlike other drugs of abuse, the clandestine synthesis of fenethylline is simple, using inexpensive laboratory instrumentation and raw materials legal to obtain. A review of all the existing knowledge of fenethylline is reported, concerning its chemistry, synthesis, pharmacology and toxicology, legislation, its prevalence and use as drug of abuse, as well as its analysis in biological or seized samples. Published or reported captagon-related cases and seizures are also presented. All the reviewed information was gathered through a detailed search of PubMed and the Internet. The primary drug market for fenethylline (as captagon) has traditionally been countries located on the Arabian Peninsula but also North Africa since 2013. In Arab countries, millions of captagon tablets are seized every year which represents one-third of global amphetamines seizures within a year. Furthermore, three of four patients treated for drug problems in Saudi Arabia are addicted to amphetamines, almost exclusively in the form of captagon. Significant information on fenethylline is provided for pharmacologists, toxicologists and forensic pathologists. Fenethylline, although old, has recently been introduced to the drug market, especially in Arab countries. Continuous community alertness is needed to tackle this current growing phenomenon.

Neuropharmacology of theophylline induced stuttering: the role of dopamine, adenosine and GABA.

Developmental stuttering is a poorly understood speech disorder that starts out in childhood and some individuals continue to stutter throughout their lives. Stuttering is a disruption in smooth and fluent speech. Some stuttering primarily involves vocal blocks, which are spasms of the laryngeal musculature while prolongations, and repetitions of sound occur in other cases. Acquired stuttering, on the other hand, can occur at all ages and can be caused by brain injury and by pharmacological agents. Theophylline-induced stuttering is form of acquired stuttering. It is a rare side effect of theophylline therapy, but it provides interesting clues to the pharmacological mechanisms involved in stuttering. Theophylline-induced stuttering may involve the disrupt the optimal balance between excitatory and inhibitory neurotransmission throughout the brain by inhibiting GABA receptors. The disruption of the optimal balance between excitatory and inhibitory neurotransmission can also cause dysfunction in white matter fiber tracts such as those that connect the Broca's area to the motor cortex. This leads to a hyperexitation of the motor cortex which may mimic the motor cortex hyperexitability that exists in developmental stuttering. Theophylline also enhances dopaminergic neurotransmission through the inhibition of adenosine receptors and this may mimic the hyperdopaminergic state that exists in the brain of developmental stutterers. Theophylline causes the greatest release of dopamine in the basal ganglia through the inhibition of adenosine and GABA receptors. This may also cause dysfunction in the basal ganglia similar in some ways to the dysfunction that exits in developmental stuttering. Pharmacological enhancement of dopaminergic neurotransmission by other drugs been reported to cause stuttering in fluent individuals and to aggrevate dysfluency in stutterers.

Evaluation of pro-convulsant risk in the rat: spontaneous and provoked convulsions.

INTRODUCTION: The aim of the present study was to evaluate the utility of different tests performed in the absence or presence of factors promoting seizures in order to evaluate the pro-convulsant effects of drugs. We studied the effects of theophylline in the rat since this is a well-known pro-convulsant substance in humans. METHODS: The occurrence of spontaneous convulsions following administration of theophylline was evaluated by observation in the Irwin Test and by measuring brain activity using video-EEG recording in conscious telemetered animals. Theophylline was also tested in the electroconvulsive shock (ECS) threshold and pentylenetetrazole (PTZ)-induced convulsions tests, two commonly used models of provoked convulsions. RESULTS: In the Irwin test, theophylline induced convulsions in 1 out of 6 rats at 128 mg/kg. Paroxysmal/seizure activity was also observed by video-EEG recording in 4 out of the 12 animals tested at 128 mg/kg, in presence of clonic convulsions in 3 out of the 4 rats. Paroxysmal activity was observed in two rats in the absence of clear behavioral symptoms, indicating that some precursor signs can be detected using video-EEG. Clear pro-convulsant activity was shown over the dose-range 32-128 mg/kg in the ECS threshold and PTZ-induced convulsions tests. DISCUSSION: Evaluation of spontaneous convulsions provides information on the therapeutic window of a drug and the translational value of the approach is increased by the use of video-EEG. Tests based on provoked convulsions further complement the evaluation since they try to mimic high risk situations. Measurement of both spontaneous and provoked convulsions improves the evaluation of the pro-convulsant risk of novel pharmacological substances.

Theophylline Pharmacokinetics in Foetal Sheep: Maternal Metabolic Capacity is the Principal Driver.

Understanding theophylline pharmacokinetics (PK) in the foetus is essential to prevent in utero toxicity and optimize prophylactic therapies. Previous studies in pregnancy have been obfuscated by maternal dosing and inadequate sampling in the foetus; both render modelling of foetal PK difficult. Six ewes carrying singleton foetuses received theophylline (60 mg) into the foetal jugular vein. Blood samples were drawn from the foetus and ewe over 36 hr. Serum concentrations were measured. Maternal and foetal pharmacokinetic parameters were estimated. Foetal non-compartmental pharmacokinetic parameters were as follows: half-life 7.37 ± 1.22 hr; volume of distribution 44.62 ± 11.45 L; area under the curve 14.82 ± 2.71 hr/(µg/mL); and clearance 4.15 ± 0.70 L/hr. Rapid theophylline distribution across the placenta was observed. Maternal non-compartmental pharmacokinetic parameters were as follows: half-life 6.54 ± 2.44 hr; volume of distribution 32.48 ± 9.99 L; area under the curve 16.28 ± 4.53 hr/(µg/mL); and clearance 3.69 ± 1.47 L/hr. Foetal and ewe serum concentration-time profiles were fit together into a 3-compartment population pharmacokinetic model, and parameters were as follows: central volume 1.38 ± 0.11 L; 2nd peripheral compartment volume 3.11 ± 0.29 L; 3rd peripheral compartment volume 60.14 ± 6.02 L; elimination clearance 9.89 ± 0.90 L/hr; distribution clearance between central and 2nd compartment 30.87 ± 2.31 L/hr; and distribution clearance between 2nd and 3rd compartments 13.89 ± 1.11 L/hr. Cytochrome P4501A expression was robust in maternal liver; negligible activities were observed in placenta, foetal liver and foetal kidney. In vitro protein binding of theophylline was 30% lower in foetal serum compared to maternal serum (29.7 ± 4.4 versus 42.0 ± 3.6%-bound). Free concentrations were lower in the foetus than in the ewe, suggesting active transport across placenta. In summary, foetal clearance of theophylline is attributable to rapid distribution into the maternal circulation across the placenta followed by greater maternal protein binding and metabolic activity.

A prospective evaluation of elevated serum theophylline concentrations to determine if high concentrations are predictable.

PURPOSE: To evaluate prospectively whether serum theophylline concentrations of 25 mg/L and greater were predictable (and presumably preventable) by use of basic pharmacokinetic calculations. DESIGN: Prospective study. PATIENTS: Fifty-five patients with a serum theophylline concentration of at least 25.0 mg/L were evaluated initially and if subsequent elevated theophylline concentrations occurred. INTERVENTIONS: The predicted steady-state serum theophylline concentration was calculated from the dosage rate divided by the predicted clearance to determine how many elevated concentrations (greater than 20 mg/L) were predictable. Predicted clearances were 0.04 L/kg/hour for normal subjects less than 70 years of age and 0.02 L/kg/hour for patients with congestive heart failure, chronic obstructive pulmonary disease, or liver disease. Estimated clearances were determined and compared with predicted clearances. If patients did not have steady-state concentrations, additional calculations were made. MAIN RESULTS: From 6,368 consecutive theophylline determinations, 69 (1.08%) samples from 55 patients were 25 mg/L or higher. Predictably high concentrations occurred in 23 of 33 (69.7%) fully evaluable cases. These concentrations occurred because of a failure to consider decreased elimination clearance from congestive heart failure, chronic obstructive pulmonary disease, or hepatic disease. Five fatalities occurred, and in two cases, theophylline appeared to contribute to the patient's death. Three other patients experienced syncope. The predicted elimination clearance of theophylline of 0.02 L/kg/hour was too high in eight patients over 70 years old with cardiac or pulmonary disease. Nursing and pharmacy oversights were identified as three patients were given two theophylline products simultaneously. CONCLUSIONS: Most elevated theophylline concentrations are predictable (and preventable) by basic pharmacokinetic calculations. Patients experiencing elevated theophylline concentrations often had comorbid conditions and were greater than 60 years of age. The dosage rate of theophylline (mg/hour) can be estimated from predicted clearance (L/kg/hour) times desired steady-state serum concentration (mg/L).

Theophylline toxicity: clinical features of 116 consecutive cases.

PURPOSE: To examine the predisposing factors, clinical and laboratory characteristics, management, course, and outcome of consecutive cases of theophylline toxicity in an outpatient setting. PATIENTS AND METHODS: Toxicology records and hospital charts of consecutive patients with a serum theophylline concentration (STC) greater than 30 mg/L (167 mumol/L) identified in the emergency departments (EDS) of a University Medical Center and a Veterans Administration Medical Center were reviewed. RESULTS: Ten percent and 2.8% of 5,557 consecutive STCs measured in the EDs over 2 years were greater than 20 mg/L (111 mumol/L) and greater than 30 mg/L (167 mumol/L), respectively. One hundred sixteen cases with STC greater than 30 mg/L were identified. Fourteen (12%) and 102 (88%) were due to acute overdose and chronic overmedication, respectively. Principal predisposing factors included patient and/or physician dosing errors and conditions or medications that reduce theophylline clearance. One or more toxic manifestations were present in 109 (94%) cases. Fifty percent of patients had mild toxicity, 38% had moderate toxicity, and 7% had severe or life-threatening toxicity. Seven (6%) patients died when STC was still in the toxic range and/or as a result of toxicity. Acute overdose was associated with higher peak STC (p less than 0.001), younger age (p less than 0.01), and greater mortality (p less than 0.05) than chronic overmedication. Peak STC correlated significantly with the severity of toxicity for patients with acute overdose (p less than 0.01) but not for patients with chronic overmedication. All three patients with acute overdose and fatal toxicity had peak STCs greater than 100 mg/L (555 mumol/L) and fulminant toxicity, whereas the four patients with chronic overmedication who died during toxicity had peak STCs in the 40 to 60 mg/L (222 to 333 mumol/L) range and most died of respiratory failure rather than directly from toxicity. Patients with acute overdose who had the delayed onset of severe or life-threatening toxicity and/or died from toxicity were accurately identified using previously published criteria for prophylactic charcoal hemoperfusion. In contrast, the predictive value of the criteria applied to patients with chronic overmedication was poor. Two patients with acute overdose underwent charcoal hemoperfusion, but died. No patient with chronic overmedication received charcoal hemoperfusion. CONCLUSION: Toxic-range STCs are relatively common in the ED population, occur primarily as a result of patient and physician dosing errors, and cause a broad range of toxic manifestations of varying severity. Peak STC correlates with the severity of toxicity and outcome for acute overdose but not chronic overmedication intoxication. Previously published criteria for prophylactic charcoal hemoperfusion accurately identify patients with acute overdose but not patients with chronic overmedication at risk for serious complications and death.

Characterization of a developmental toxicity dose-response model.

The Rai and Van Ryzin dose-response model proposed for teratology experiments has been characterized for its appropriateness and applicability in modeling the dichotomous response data from developmental toxicity studies. Modifications were made in the initial probability statements to reflect more accurately biological events underlying developmental toxicity. Data sets used for the evaluation were obtained from the National Toxicology Program and U.S. EPA laboratories. The studies included developmental evaluations of ethylene glycol, diethylhexyl phthalate, di- and triethylene glycol dimethyl ethers, and nitrofen in rats, mice, or rabbits. Graphic examination and statistical evaluation demonstrate that this model is sensitive to the data when compared to directly measured experimental outcomes. The model was used to interpolate to low-risk dose levels, and comparisons were made between the values obtained and the no-observed-adverse-effect levels (NOAELs) divided by an uncertainty factor. Our investigation suggests that the Rai and Van Ryzin model is sensitive to the developmental toxicity end points, prenatal deaths, and malformations, and appears to model closely their relationship to dose.

Combination of theophylline and salbutamol for arrhythmias in severe COPD.

We conducted a single-bind placebo controlled study using 24-hour continuous ambulatory electrocardiographic recordings. The arrhythmogenic potential of the combination of salbutamol and theophylline was investigated in 25 ambulatory subjects with severe chronic airflow obstruction (mean age 65 +/- 8 SD, mean FEV1 31 percent +/- 13 SD predicted). Asymptomatic arrhythmias were very prevalent in the study population: 76 percent of the patients had runs of supraventricular tachycardia while 24 percent had runs of ventricular tachycardia. Individual arrhythmia frequency showed greater between-test variability than previously described in non-COPD subjects. The mode of administration of salbutamol may have affected arrhythmia frequency in that subjects using aerosol nebulizers had more ventricular extrasystoles than those using metered dose inhalers. Although the addition of theophylline to salbutamol significantly increased heart rate and supraventricular extrasystoles, there was no statistically significant increase in ventricular arrhythmias.

Food-induced "dose-dumping" from a once-a-day theophylline product as a cause of theophylline toxicity.

Three slow-release preparations of theophylline have received approval from the U.S. Food and Drug Administration (FDA) for "once-daily" dosing indications, amid controversy regarding the appropriateness of this decision. Because of specific concerns regarding data submitted to the FDA in support of the first of these products to be approved, Theo-24, we examined the absorption characteristics of this newly marketed formulation. Eight healthy volunteers received, in a crossover manner, single doses of a theophylline reference solution and Theo-24, taken both fasting and after a breakfast of bacon and eggs. The concentrations of theophylline were measured up to 60 hours after the dose. Absorption of Theo-24 after an overnight fast was very slow, with only 71 +/- 6 percent (mean +/- SE) of the dose ultimately absorbed. In contrast, food caused precipitous "dose-dumping," resulting in dose-normalized peak levels in the serum that averaged 2.3 times higher than after a fasting dose. About half of the dose was absorbed in a four-hour period, generally beginning six to eight hours after the postprandial dose, and complete absorption was then attained within 24 hours (p less than 0.001). Toxic effects of theophylline occurred in four subjects when they took the dose with food whereas no toxic effects occurred during the fasting regimen. Consequently, doses of Theo-24 that would have attained a predicted peak concentration of 15 micrograms/ml after multiple dosing taken without food would, if taken with food, have resulted in larger fluctuations and in peak concentrations in the potentially toxic range for six of the eight subjects.