Artificial Caries Lesion Characteristics after Secondary Demineralization with Theobromine-Containing Protocol.

Developing artificial caries lesions with varying characteristics is needed to adequately study caries process in vitro. The objective of this study was to investigate artificial caries lesion characteristics after secondary demineralization protocol containing theobromine and fluoride. Sixty bovine enamel slabs (4 × 3 mm) were demineralized using a Carbopol-containing protocol for 6 days. A baseline area (2 × 3 mm) was protected with acid-resistant nail varnish, after which specimens were exposed for 24 h to a secondary demineralization protocol containing acetic acid plus one of four fluoride/theobromine combinations (n = 15): theobromine (50 or 200 ppm) and fluoride (0 or 1 ppm). Specimens were sectioned and analyzed using transverse microradiography for changes in mineral content, lesion depth, and surface layer mineralization. Data was analyzed using paired t-test and analysis of variance followed by Bonferroni test at 0.05 significance level. After secondary demineralization, fluoride-containing groups had significantly deeper lesions (p = 0.002 and 0.014) compared to the group with 0 ppm fluoride and 50 ppm theobromine. Mineral content and lesion depth were significantly different compared to baseline for all groups. Theobromine did not show an added effect on mineral uptake. Theobromine-containing groups exhibited particularly deep lesions with a more uniform mineral profile in the presence of fluoride.

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.

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.

Comparing the cardiovascular therapeutic indices of glycopyrronium and tiotropium in an integrated rat pharmacokinetic, pharmacodynamic and safety model.

Long acting inhaled muscarinic receptor antagonists, such as tiotropium, are widely used as bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Although this class of compounds is generally considered to be safe and well tolerated in COPD patients the cardiovascular safety of tiotropium has recently been questioned. We describe a rat in vivo model that allows the concurrent assessment of muscarinic antagonist potency, bronchodilator efficacy and a potential for side effects, and we use this model to compare tiotropium with NVA237 (glycopyrronium bromide), a recently approved inhaled muscarinic antagonist for COPD. Anaesthetized Brown Norway rats were dosed intratracheally at 1 or 6h prior to receiving increasing doses of intravenous methacholine. Changes in airway resistance and cardiovascular function were recorded and therapeutic indices were calculated against the ED50 values for the inhibition of methacholine-induced bronchoconstriction. At both time points studied, greater therapeutic indices for hypotension and bradycardia were observed with glycopyrronium (19.5 and 28.5 fold at 1h; >200 fold at 6h) than with tiotropium (1.5 and 4.2 fold at 1h; 4.6 and 5.5 fold at 6h). Pharmacokinetic, protein plasma binding and rat muscarinic receptor binding properties for both compounds were determined and used to generate an integrated model of systemic M2 muscarinic receptor occupancy, which predicted significantly higher M2 receptor blockade at ED50 doses with tiotropium than with glycopyrronium. In our preclinical model there was an improved safety profile for glycopyrronium when compared with tiotropium.

Forskolin: genotoxicity assessment in Allium cepa.

Forskolin, a diterpene, 7ß-acetoxy-8,13-epoxy-1α,6ß,9α-trihydroxy-labd-14-en-11-one (C22H34O7) isolated from Coleus forskohlii, exerts multiple physiological effects by stimulating the enzyme adenylate cyclase and increasing cyclic adenosine monophosphate (cAMP) concentrations. Forskolin is used in the treatment of hypertension, congestive heart failure, eczema, and other diseases. A cytogenetic assay was performed in Allium cepa to assess possible genotoxic effects of forskolin. Forskolin was tested at concentrations 5-100 µM for exposure periods of 24 or 48 h. Treated samples showed significant reductions in mitotic index (p < 0.05) and increases in the frequency of chromosome aberrations (p < 0.01) at both exposure times. The treated meristems showed chromosome aberrations including sticky metaphases, sticky anaphases, laggard, anaphase bridges, micronuclei, polyploidy, fragments, breaks, and C-mitosis. Forskolin may cause genotoxic effects and further toxicological evaluations should be conducted to ensure its safety.

Antitussive, expectorant and bronchodilating effects of ethanol extract of Sorghum bicolor (L.) Moench roots.

ETHNOPHARMACOLOGICAL RELEVANCE: Root of Sorghum bicolor (L.) Moench (RSB) is an herbal medicine in Traditional Chinese Medicine, still used in some rural areas in Central China as an alternative remedy to treat cough and asthma. AIM OF THE STUDY: The study was aimed at evaluating the antitussive, expectorant and bronchodilating effects of ethanol extract of RSB, support its folk use with scientific evidence, and lay a foundation for its further researches. MATERIALS AND METHODS: RSB was extracted with 80% ethanol aqueous in reflux conditions, solutions were concentrated in reduced pressure, and lyophilized in vacuum to yield the RSB extract. Antitussive evaluations were carried out with three different models including ammonia liquor induced mice cough, capsaicin induced mice cough, and citric acid induced guinea pigs cough; phenol red secretion experiments in mice were performed to evaluate the expectorant ability; bronchodilating effects were evaluated with a bronchoconstrictive challenge induced by acetylcholine chloride and histamine in guinea pigs. RESULTS: In all the three antitussive tests, treatment of RSB significantly inhibited the frequency of cough, and prolonged the cough latent period in animals. And high dose of RSB (200mg/kg in mice and 100mg/kg in guinea pigs) created therapeutic activities as good as standard antitussive drug codeine phosphate (20mg/kg). In the expectorant evaluation, 50, 100 and 200mg/kg RSB treatment had significantly increased the amount of phenol red output for 0.39, 1.18, and 1.96 folds in mice tracheas. In the bronchodilating test, RSB treatment at 100mg/kg extended the preconvulsive time for 44.84% compared with that of before treatment in guinea pigs. CONCLUSIONS: RSB is an effective alternative medicine for the treatment of cough with potent antitussive, expectorant and bronchodilating activities.

Genotoxicity and carcinogenicity studies of bronchodilators and antiasthma drugs.

This survey is a compendium of genotoxicity and carcinogenicity information of bronchodilators and antiasthma drugs. Data from 46 marketed drugs were collected. Of these 46 drugs, 25 (54.3%) did not have retrievable genotoxicity or carcinogenicity data. The remaining 21 (45.7%) had at least one genotoxicity or carcinogenicity test result. Of these 21 drugs, 10 had at least one positive finding: three tested positive in at least one genotoxicity assay, eight in at least one carcinogenicity assay, and one of them gave positive results in both genotoxicity assay and carcinogenicity assay. Concerning the predictivity of genetic toxicology findings for the result(s) of long-term carcinogenesis assays, 15 drugs had both genotoxicity and carcinogenicity data: seven of them (46.6%) were neither genotoxic nor carcinogenic, 6 (40.0%) were carcinogenic in at least one sex of mice or rats but tested negative in genotoxicity assays, 1 (6.7%) tested positive in genotoxicity assay but was non-carcinogenic, and 1 (6.7%) gave positive responses in both genotoxicity and carcinogenicity assay. Only 11 (23.9%) of the 46 drugs considered had all data required by current guidelines for testing of pharmaceuticals, but a large fraction of them were developed and marketed prior to the present regulatory climate.

Cardiovascular side effects of aminophylline in meconium-induced acute lung injury.

As inflammation plays an important role in the pathogenesis of neonatal meconium aspiration syndrome (MAS), anti-inflammatory agents including inhibitors of phosphodiesterases (PDE) are increasingly used in the treatment. To evaluate side effects of PDE inhibitors, this study analyzed changes in blood pressure, heart rate (HR) and heart rate variability (HRV) during and after intravenous aminophylline in the animal model of MAS. Oxygen-ventilated rabbits were given meconium intratracheally (25 mg/ml, 4 ml/kg) or saline. Thirty minutes later, the animals were treated by intravenous aminophylline (Syntophyllin, 2 mg/kg) or saline (sham-treated controls). A second dose of the treatment was given 2 h later. During (5 min) and immediately after (5 min) the treatment, and during 5 h after the treatment, mean blood pressure in the femoral artery (MAP), HR and HRV were evaluated. In meconium-instilled animals, increases in MABP, HR, and HRV were observed already 5 min after aminophylline administration, while in saline-instilled animals aminophylline increased HR and caused inconsistant changes in HRV parameters compared to sham-treated animals. Within 5 h after the treatment administration, MAP, HR, and HRV parameters gradually returned to the initial values. Concluding, intravenous aminophylline may lead to acute cardiovascular changes. Thus, if aminophylline is used for treatment of MAS, its possible cardiovascular effects should be considered, particularly in patients with cardiovascular instability.

Enhancement of inflammatory mediator release by beta(2)-adrenoceptor agonists in airway epithelial cells is reversed by glucocorticoid action.

BACKGROUND AND PURPOSE: Due to their potent bronchodilator properties, beta(2)-adrenoceptor agonists are a mainstay of therapy in asthma. However, the effects of beta(2)-adrenoceptor agonists on inflammation are less clear. Accordingly, we have investigated the effects of beta(2)-adrenoceptor agonists on inflammatory mediator release. EXPERIMENTAL APPROACH: Transcription factor activation, and both release and mRNA expression of IL-6 and IL-8 were examined by luciferase reporter assay, elisa and real-time RT-PCR in bronchial human epithelial BEAS-2B cells or primary human bronchial epithelial cells grown at an air-liquid interface. KEY RESULTS: Pre-incubation with beta(2)-adrenoceptor agonists (salbutamol, salmeterol, formoterol) augmented the release and mRNA expression of IL-6 and IL-8 induced by IL-1beta and IL-1beta plus histamine, whereas NF-kappaB-dependent transcription was significantly repressed, and AP-1-dependent transcription was unaffected. These effects were mimicked by other cAMP-elevating agents (PGE(2), forskolin). Enhancement of cytokine release by beta(2)-adrenoceptor agonists also occurred in primary bronchial epithelial cells. Addition of dexamethasone with salmeterol repressed IL-6 and IL-8 release to levels that were similar to the repression achieved in the absence of salmeterol. IL-6 release was enhanced when salmeterol was added before, concurrently or after IL-1beta plus histamine stimulation, whereas IL-8 release was only enhanced by salmeterol addition prior to stimulation. CONCLUSIONS AND IMPLICATIONS: Enhancement of IL-6 and IL-8 release may contribute to the deleterious effects of beta(2)-adrenoceptor agonists in asthma. As increased inflammatory mediator expression is prevented by the addition of glucocorticoid to the beta(2)-adrenoceptor, our data provide further mechanistic support for the use of combination therapies in asthma management.

Theophylline-induced changes in mouse electroencephalograms.

Theophylline can induce life-threatening seizures in humans, especially in infants, but the mechanism of induction remains unknown. We investigated the effects of orally administered theophylline on mouse electroencephalograms (EEGs). ddY mice, which are generally completely free of seizures, were used for the experiments. While EEGs, used as controls, showed no paroxysmal spike discharges, theophylline induced clear spike discharges. This study demonstrated that theophylline administered at doses that achieve low serum concentrations can cause spike discharges in mouse EEGs even without causing clinical seizures, indicating that theophylline plays a potent role in subclinical epileptogenicity.

Aclidinium bromide, a novel long-acting muscarinic M3 antagonist for the treatment of COPD.

Aclidinium bromide is a novel, inhaled, long-acting antimuscarinic agent being developed by Almirall Prodesfarma SA and Forest Laboratories Inc as a once-daily treatment for COPD. In preclinical studies, aclidinium bromide demonstrated a comparable profile to tiotropium bromide, with a slightly quicker onset of action but shorter duration of action. Clinical trials have demonstrated an unquestionably interesting pharmacological profile characterized by a faster rate of onset of the smooth muscle relaxing activity than tiotropium bromide and a rapid plasma hydrolysis in human plasma to inactive metabolites that may account for its favorable cardiovascular safety profile. However, the disappointing efficacy results of the recent phase III trials have cast doubt on the real advantage of introducing this drug on the market. Discussions with the FDA concluded that more trials are needed to assess selected dosing regimens, including higher and/or more frequent doses. At the time of publication, further phase III trials with aclidinium bromide were ongoing, and the developing companies were also extending development to combinations of aclidinium bromide with formoterol or an undisclosed inhaled corticosteroid.

[A Meta-analysis of high-dose epinephrine in children with cardiopulmonary arrest].

OBJECTIVE: Epinephrine has a place in the treatment of pediatric cardiopulmonary arrest but has been controversy concerning its optimal dose. This meta-analysis aimed to seek for evidences of the effectiveness of different doses of epinephrine in children with cardiac arrest and to evaluate the effectiveness of high-dose versus standard-dose epinephrine in children with cardiac arrest. METHOD: Published papers on randomized controlled trials (RCTs) and prospective clinical controlled trials (CCTs) were electronically searched from MEDLINE (1966 to September 2006), EMBASE (1974 to June 2006), the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2006), CBM (1998 to 2006) and CNKI (1994 to 2006). We also had searched the related references and manual retrieval 10 professional academic journals about epinephrine treatment of pediatric cardiopulmonary arrest (1998 to 2006). The search strategy was made according to the collaborative review group search strategy. At first, we found 546 articles. Second, we excluded 474 of them through reading the title, abstract, excluding non-randomized, non-controlled trials and non-clinical studies. Finally, we identified 4 papers through searching for original articles and telephone contact with some of the authors after excluding 68 papers. Then we performed the meta-analysis by RevMan 4.2.7. For homogenous dichotomous data (P > or = 0.1, I(2) < or = 50%) we calculated fixed effects model, relative risk (RR), 95% confidence intervals (CI), For heterogeneity Dichotomous data (P < 0.1, I(2)>50%) we calculated random effects model, relative risk (RR) and 95% confidence intervals (CI). RESULT: Four trials involving 360 cases were included. The results of meta-analysis indicated that there were no statistical difference in recovery of spontaneous circulation [RR = 1.28, 95% CI (0.93, 1.77)]. Perondi, Patterson and Cheng xiuyong's study compared the rate of survival at 24 hours and showed statistical heterogeneity (P = 0.01, I(2) = 0.77). The random effects model indicated that there were no significant difference [RR = 1.40, 95% CI (0.43, 4.55)]. The sensitivity analysis showed that after deleting Perondi's group there were no statistical heterogeneity. Fixed effects model indicated that there were significant difference [RR = 2.50, 95% CI (1.52, 4.11)]. T When the rates of survival to hospital discharge were compared among the 4 studies, there was statistical heterogeneity (P = 0.07, I(2) = 0.58), the random effects model indicated that there were no statistical difference [RR = 1.78, 95% CI (0.42, 7.50)], There were no heterogeneity after Cheng Xiu-yong group was deleted. CONCLUSION: Higher doses of epinephrine in children with cardiopulmonary arrest may not increase the rate of recovery of spontaneous circulation, the rate of survival at 24 hours, the rate of survival to hospital discharge and worsen the neurological outcomes. Adverse reactions is difficult to monitor and evaluate because of the current restrictions on medical technology.

New MultiPEG-conjugated theophylline derivatives: synthesis and pharmacological evaluations.

The successful conjugation of active theophylline molecules to two new multifunctional high-molecular weight poly(ethylene glycol) derivatives (MultiPEG) and their pharmacokinetic evaluations are reported. The drug loading was increased up to six times in comparison with commercial PEG of the same molecular weight. A clear increase of the time of persistence within the body and a concomitant improvement of the overall pharmacokinetic properties of those prodrugs were also observed. These studies sustain the use of these new PEG-based polymeric supports as a valuable alternative for an effective drug delivery system.

Potential protective properties of a stable, slow-releasing nitric oxide donor, GEA 3175, in the lung.

Nitric oxide (NO), is known to exert vasodilatory, bronchodilatory, and antiplatelet effects, and quantitative or functional NO deficiency has been implicated in various cardio-vascular and airway diseases. NO donors, which are drugs capable of releasing NO either spontaneously or tissue-dependently, represent a way of increasing NO. Here, we review our current understanding of the NO donor, GEA 3175, 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[(methylphenyl)sulphonyl]amino], hydroxide inner salt. GEA 3175 is a mesoionic 3-aryl substituted oxatriazole-5-imine derivative, which is a potent, stable, slow releasing NO donor with important actions in various organ systems. In isolated guinea pig trachea, rat bronchi and bovine and human small bronchioles, GEA 3175 induces potent, long-lasting relaxation. In vivo, in sensitized guinea pigs, GEA 3175 protects against antigen-induced bronchoconstriction. GEA 3175 also exerts potent vasodilatory properties. In isolated human pulmonary arteries, GEA 3175 induces relaxation which is long-lasting and more potent than in airways. In isolated systemic arteries, GEA 3175 is also a potent vasodilator. By intravenous infusion GEA 3175 reduces blood pressure similarly to nitroglycerin. Vascular and bronchiolar relaxations were shown to be mediated via NO dependent pathways. GEA 3175 is also a potent anti-inflammatory agent. Functions of polymorphnuclear cells (PMNs) such as leucotriene B(4) (LTB(4)) - synhesis, chemotaxis and superoxide (O(-) (2)) production are inhibited by GEA 3175. GEA3175 also inhibits upregulation of E-selectin in human umbilical vein endothelial cells (HUVECs) and hence adhesion of neutrophils. Another action of GEA 3175 on the endothelium is inhibition of prostacyclin release. Finally, GEA 3175 has been demonstrated to be an antiplatelet agent. Thrombin-induced platelet aggregation was inhibited by GEA 3175 in a cyclic GMP- and vasodilator-stimulated phosphoprotein (VASP)-phosphorylation-dependent manner. Thus, GEA 3175 has been demonstrated to exert bronchodilatory, pulmonary vasodilatory, antiplatelet as well as anti-inflammatory actions. Given these actions GEA 3175 may represent a potentially useful drug. The exact mechanism whereby GEA 3175 releases NO is, however, still unknown. In addition, most of the studies so far have been performed in isolated tissue preparations. Clearly, further in vivo studies involving animal models are required to clarify safety issues and whether GEA 3175 can be used in the treatment of pulmonary hypertension and/or airway diseases.

Possible role of free radicals in theophylline-induced seizures in mice.

Theophylline is a methylxanthine bronchodilator with a narrow therapeutic index and is prone to induce seizures, the mechanisms for which are not clearly defined. Free radicals have considerable neurotoxic potential and the present study evaluated the possible involvement of these bioactive moieties in aminophylline-induced seizures in mice. Aminophylline (50-250 mg/kg) induced convulsions and mortality in mice in a dose-dependent manner. The anti-oxidants, melatonin (25-100 mg/kg) and N-actylcysteine (100 and 200 mg/kg) attenuated aminophylline seizures and mortality. Similar antagonism of aminophylline seizures was also observed after pretreatments with nitric oxide (NO) synthase inhibitors, L-NAME (3 and 10 mg/kg) and 7-nitroindazole (10 and 30 mg/kg). Further, combined treatment with otherwise sub-effective doses of melatonin and L-NAME or 7-nitroindazole produced marked protective effects against these seizures. Aminophylline-induced seizures enhanced malondialdehyde (MDA) concentrations and NO metabolite (NOx) levels in the brain homogenates of mice, and these were attenuated by melatonin and L-NAME pretreatments. The results are suggestive of the possible involvement of free radicals (reactive oxygen and reactive nitrogen species) in the convulsiogenic effects of aminophylline.

Taquicardia paroxística supraventricular por sobreingesta de salbutamol / Supraventricular paroxysmal tachycardia by overdose of salbutamol

Introducción: La taquicardia es el hallazgo más frecuente tras la ingestión de una dosis de salbutamol superior a la terapéutica. Se trata habitualmente de una taquicardia sinusal refleja secundaria a vasodilatación, siendo poco frecuente que se produzcan arritmias. Caso clínico: Presentamos el caso de un niño de 3 años de edad que presentó un episodio de taquicardia paroxística supraventricular tras la ingesta accidental de una sobredosis de salbutamol. El electrocardiograma de 12 derivaciones mostró una taquicardia paroxística supraventricular a una frecuencia de 250 latidos por minuto. Tras fracasar un intento terapéutico mediante la utilización de maniobras vagales, se administró una dosis de propranolol intravenoso volviendo el paciente a entrar en ritmo sinusal. Conclusión: La taquicardia supraventricular es un efecto secundario de la intoxicación por salbutamol que puede darse en niños previamente sanos. La administración de propranolol en estos casos podría estar indicada y parece segura

Introduction: Synus tachicardia is the most frecuent clinical finding after the ingesion of a salbutamol overdose. It is a common reflex response to vasodilation while cardiac dysrhytmias are rare. Case report:Athree year old boy presented to de emergency department after the accidental ingestion of an overdose of salbutamol. A12 lead ECG showed supraventricular paroxysmal tachicardia with a heart rate of 250 beats per minute. After an unsuccessful therapeutic attempt with vagal manoeuvres, a single dose of intravenous propanolol restored normal sinus rhythm. Conclusion: Supreventricular tachycardia may occur in previously healthy children after a salbutamol overdose. Propanolol administration may be indicated in these cases and seems safe

Acute and subacute toxicities of the saponin mixture isolated from Schefflera leucantha Viguier.

Acute toxicity of the bronchodilator saponin mixture isolated from Schefflera leucantha Viguier leaves was investigated in comparison with the methanol and the water extract of this plant. Oral doses of 5000 mg/kg of the methanol extract, the water extract and the saponin mixture did not produce mortality or significant changes in the general behavior and gross appearance of internal organs of rats. Subacute toxicity of the saponin mixture was evaluated with the dose of 1000 mg/kg, orally for 14 days. An extra group (satellite group) was given saponin mixture and kept for a further 14 days after treatment. All animals did not show signs of toxicity during the experimental period. Liver weights of the saponin-treated and the satellite male groups were higher whereas testis weight were lower than those of the control group which received distilled water. However, the histological examination of various organs revealed that there were no differences between the control and the treated rats. BUN, Cr, AST, ALT and ALP levels increased in saponin-receiving rats. It is possible that the saponin mixture directly impacts on the liver and the kidney functions.

Airway responsiveness and airway remodeling after chronic exposure to procaterol and fenoterol in guinea pigs in vivo.

BACKGROUND: Chronic exposure to fenoterol (FEN), a beta(2)-adrenergic receptor (beta(2)-AR) agonist, was shown to induce both airway hyperresponsiveness and airway remodeling in experimental animals. OBJECTIVE: We wanted to know the effects of chronic exposure to procaterol (PRO), a beta(2)-AR agonist, on airway function and structure, because this agent is widely used as a bronchodilator in Japan. For comparison, the effects of FEN were also examined. METHODS: Aerosolized PRO (0.1 or 1 mg/ml), FEN (1 mg/ml) or vehicle (0.9% NaCl) was given to guinea pigs 3 times a day for 6 weeks. Sublaryngeal deposition of these agents was calculated using radioisotopes. At 72 h after the last inhalation of PRO, FEN or vehicle, the dose-response relationship between lung resistance (R(L)) and intravenously administered acetylcholine (ACh) was measured. After measuring R(L), histological changes in noncartilaginous airway dimensions were evaluated. RESULTS: The amount of sublaryngeal deposition of 0.1 mg/ml PRO in the present study was speculated to be 100 times larger than that of therapeutic dose. ACh concentrations causing 2-fold, 10-fold and maximal increases in R(L) were not different in 4 groups tested. In the smaller membranous airways (<0.4 mm in diameter), but not the larger ones, thickening of adventitial areas was significantly greater in animals treated with beta(2)-AR agonists than in control animals (23 and 25, and 96% higher in animals treated with 0.1 and 1 mg/ml PRO or 1 mg/ml FEN, respectively). The degree of the increase was significantly less in PRO-treated animals than in FEN-treated animals (p < 0.01). CONCLUSION: Our results did not provide any evidence that regular inhalation of PRO at the therapeutic dose might induce bronchial hyperresponsiveness. In addition, huge amounts of PRO only caused a mild thickening of the adventitial areas, suggesting that PRO may be a weak inducer of airway remodeling compared with FEN.

Toxicity of theophylline depends on plasma concentration by single and also repeated dosing in rats.

The purpose of this study was to evaluate the relationship between the in vivo toxicity and plasma concentration of theophylline. Theophylline was administered intravenously in single doses ( 50, 100, 150 and 200 mg kg(-1)once a day) or repeated doses (12.5, 25 and 90 mg kg(-1)/day for 28 days) in rats. Plasma concentrations of theophylline increased dose-dependently in both single and repeated doses, and there were no differences due to effects of 28-times repeated administration. Neither single dose at 50 mg kg(-1)nor repeated dose at 12.5 mg kg(-1)/day injections of theophylline showed toxic signs, in which plasma concentrations of theophylline were less than 110 and 22.5 microg ml(-1), respectively. Theophylline induced myocardial fibrosis in 25 mg kg(-1)/day and more treated groups: in which plasma concentrations of theophylline were more than 50 microg ml(-1). At doses of 100 mg kg(-1)(single) and 90 mg kg(-1)/day (repeated), theophylline caused tachypnea and excitement of movement. Each theophylline concentration in plasma was more than 194 microg ml(-1)in single 100 mg kg(-1)and 162 microg ml(-1)in repeated 90 mg kg(-1)/day injections, respectively. Death was observed at a dose of 200 mg kg(-1), in which the plasma concentration of theophylline was more than 264 microg ml(-1). Moreover, the recovery period from signs of toxic poisoning to normality in the 200 mg kg(-1)treated group was greater than that in the 150 mg kg(-1)and less treated groups. The results indicated that the in vivo toxicity of theophylline is highly dependent on plasma concentrations in rats which received single and also repeated doses of theophylline.

Theophylline toxicity in Thai children.

Theophylline is a useful drug in the treatment of respiratory diseases with bronchospasm but it has very narrow safety margin. The study was carried out in 44 admitted Thai children with plasma theophylline levels > 20 microg/ml to determine the association between blood levels and symptoms of theophylline toxicity. The prevalence of theophylline toxicity (plasma theophylline level > 20 microg/ml) in Thai children is about 11%. Thirty-four percent of the patients who had theophylline levels less than 30 microg/ml and 78% of those who had levels more than 30 microg/ml had symptoms of theophylline toxicity. The symptoms were related to the gastrointestinal tract (34%), cardiovascular system (18.2%), neurological system (6.8%) and metabolism (54.5%). The possible causes of theophylline toxicity were respiratory tract infection, theophylline overdosage, interaction with other drugs, impairment of liver function, congenital heart disease and theophylline usage in neonates. Theophylline is still a useful drug but should be used with caution. Theophylline levels should be checked in every child who receives theophylline.