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.

Evaluation of the toxicity of guarana with in vitro bioassays.

A natural stimulant, Paullinia cupana, commonly called guarana, was tested for its ability to induce in vitro toxicity in Chinese hamster ovary (CHO) cells and bacterial cells (Photobacterium phosphoreum). The cytotoxic effects of aqueous guarana extracts were evaluated by three endpoint systems: neutral red (NR) uptake assay, total protein content [kenacid blue (KB)] assay, and tetrazolium (MTT) assay. The Microtox test was also used. Results indicated that the lowest concentration of guarana tested was not toxic and that the IC50 values calculated with the NR, KB, and MTT assays were lower than the highest concentration tested (40 mg/ml). There was no significant difference in cytotoxicity between the three test systems. The EC50 values obtained with the Microtox assay were consistent with these data. The present in vitro analysis suggests that the concentration of guarana is of critical importance in its cytotoxic activity and high doses could be harmful to human health.

Inhibitors in tea of intestinal absorption of phenylalanine in rats.

This work studies the effect of tea extract on the mucosal and serosal transport of phenylalanine, and attempts to identify the active ingredient(s) therein by studying the effect of known tea constituents like theophylline, caffeine and tannic acid. Tea and all the constituents tested inhibited the mucosal uptake of phenylalanine. The serosal transport was unaffected by caffeine and tannic acid, but inhibited by theophylline and high concentrations of tea. The in vitro activity of the intestinal Na+-K+ATPase was also assayed from a jejunal homogenate in presence of theophylline, caffeine, tannic acid and cAMP. All were found to inhibit significantly the enzyme. The in vitro activity of a purified Na+-K+ATPase was however stimulated by theophylline and caffeine, and inhibited only by tannic acid. It was concluded that the inhibitory effect of tea is exerted mainly through its constituents which inhibit the Na+-K+ pump directly (tannic acid) or indirectly (theophylline and caffeine), possible by elevating cAMP levels, dissipating thus the sodium gradient needed for the mucosal uptake of the amino acid.

Analysis of the potential carcinogenicity of coffee and its related compounds in a medium-term liver bioassay of rats.

The potential carcinogenicity of coffee and related compounds was examined using a medium-term liver bioassay based on the induction of glutathione S-transferase placental form (GST-P)-positive foci in F344 rats. A total of 230 males were initially injected with diethylnitrosamine (200 mg/kg body weight, ip) or saline as controls and 2 wk later were fed on diet or drinking water supplemented as follows for 6 wk: 5% regular instant coffee; 5% decaffeinated instant coffee; freshly brewed coffee, 8 g in 140 ml water; 0.1% caffeine, 0.2% methylglyoxal, 0.2% glyoxal; or 0.3% theophylline in the drinking water (w/v); and 0.4% theobromine in the diet (w/w). All rats were subjected to two-thirds partial hepatectomy at wk 3 and killed at wk 8. The resultant values for GST-P-positive hepatic focus induction were slightly increased with methylglyoxal and decreased with glyoxal and theobromine compared with the corresponding controls. Although the increase in number of foci for methylglyoxal was statistically significant at P < 0.05, the value was within the historical control levels. Regular and decaffeinated instant coffee as well as fresh-brewed coffee, caffeine and theophylline exerted no effects on focus development. Thus, the coffee-related compounds examined demonstrated no obvious enhancing potential, and it is therefore concluded that coffee and its main constituents are not carcinogenic for the rat liver.

[The synthesis and anti-inflammatory properties of 7-theophyllineacetic acid derivatives]. / Cercetari privind sinteza si proprietatile antiinflamatoare ale unor derivati ai acidului 7-teofilinilacetic.

Some esters of 7-theophyllinylacetic acid were synthetized, characterized physicochemically and tested for their anti-inflammatory properties. As compared to indomethacin, reference anti-inflammatory drug, all synthetized compounds were less toxic. The anti-inflammatory properties are influenced by the nature of the ester group radicals, the more active having ramified alchils.

[The semisynthetic production of pharmacologically active flavone derivatives. I. The pharmaco-toxicological properties of theophylline-rutozide (TR 1722)]. / Cercetari privind obtinerea prin semisinteza a unor derivati flavonici farmacologic activi. I. Unele însusiri farmaco-toxicologice ale teofilin-rutozidului (TR 1722).

The pharmaco-toxicological properties of the compound theophylline-rutozide, termed conventionally TR-1722, are presented. Studied comparatively with aminophylline, it presents important advantages: soluble in water, the aqueous solutions have a pH close to the physiological one and are stable. It induces a weaker excitation on the central nervous system as compared to aminophylline, but its antihistaminic and anti-inflammatory properties are slightly increased. The physicochemical and pharmacological properties of TR 1722 recommend it for the patients with asthma and associated arterial hypertension or obstructive bronchopneumopathy associated with pulmonary hypertension.

The developmental toxicity of orally administered theophylline in rats and mice.

Theophylline (THEO), a widely prescribed anti-asthmatic, was evaluated for developmental toxicity. It was administered continuously on Gestational Days 6 through 15 to pregnant Sprague-Dawley (CD) rats in the feed (0, 0.15, 0.30, or 0.40%) and to pregnant Swiss (CD-1) mice in the drinking water (0, 0.075, 0.15, or 0.20%). Estimated intake of THEO for rats was 0, 124, 218, or 259 mg/kg/day, while for mice it was 0, 282, 372, or 396 mg/kg/day. In rats, maternal weight gain parameters (weight gain during gestation and treatment, as well as corrected weight gain) decreased at 0.40%. While food consumption was lower only in the 0.40% treatment group, water consumption was higher in all treated groups. There was a dose-related decreasing trend in gravid uterine weight. The number of live fetuses per litter decreased at 0.40% and the average male and female fetal weight per litter decreased at 0.30 and 0.40%. There was no increase in malformations. In mice, maternal corrected body weight and weight gain during gestation decreased at 0.15 and 0.20%, and weight gain during treatment and gravid uterine weight decreased at 0.20%. Water consumption was reduced by as much as 30-45% of controls at 0.15 and 0.20%, respectively, while food consumption did not change with THEO treatment. There was an increase in percentage resorptions per litter and a decrease in the average male and female fetal weight per litter at 0.15 and 0.20%. An increasing trend was noted for percentage malformed fetuses per litter, and percentage litters with externally malformed fetuses were slightly increased in the mid- and high-dose groups. However, these increases were not statistically significant. In summary, there were developmental effects seen in rats at a dose (0.30%) that did not produce overt maternal toxicity, but the adverse developmental effects in mice were observed at doses that caused reduced maternal water consumption and body weight gain. It is possible that water deprivation contributed to the effects seen in mice after THEO treatment. For maternal toxicity, no observable adverse effect levels (NOAELs) were 218 mg/kg for rats and 282 mg/kg for mice. NOAELs for developmental toxicity were 124 mg/kg for rats and 282 mg/kg for mice. These NOAELs are approximately 10- to 30-fold greater than doses required to maintain humans on serum THEO concentrations that are clinically useful.

Systemic effect of ipecac on acute toxicity of phenobarbital and theophylline in rats.

The emetic agent ipecac is widely used for the initial treatment of acute oral drug overdose. Its emetic and gastric evacuative efficacies have been studied extensively but its potential for pharmacologic interactions with various drugs and other possible poisons has not been explored. The purpose of this investigation was to determine if ipecac can alter the acute toxicity of two widely used drugs that act on the central nervous system, phenobarbital and theophylline. Ipecac syrup, 5 ml/kg, was administered by gavage to male Lewis rats either 1 hr before or 15 or 30 min after the start of an iv infusion of phenobarbital or theophylline. Control animals received the syrup vehicle only. Ipecac elicited vomiting-like behavior (frequent, wide opening of the mouth) for more than 1 hr. The drug infusion was stopped immediately after onset of the loss of righting reflex (phenobarbital) or maximal seizures (theophylline). Samples of cerebrospinal fluid, blood (for serum), and the brain were obtained at that time for analysis of drug concentrations. There were no significant differences between control and ipecac-treated animals with respect to the dose requirements and drug concentrations in cerebrospinal fluid, serum, and brain at the respective pharmacologic endpoint. It is concluded that ipecac has no apparent effect on the acute toxicity of phenobarbital and theophylline in rats.

Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice.

Theophylline, a methylated xanthine closely resembling caffeine and theobromine, is a widely used pharmaceutical agent for the treatment of respiratory disorders and certain acute cardiovascular conditions. The National Toxicology Program has conducted 13-week subchronic toxicity studies in F344 rats and B6C3F1 mice (10 animals/group) following administration of theophylline via the diet or by gavage. Administration of theophylline in the feed (0, 1000, 2000, and 4000 ppm) resulted in no mortality or body weight effects in F344 rats, but did induce periarteritis of the arteries adjacent to mesenteric lymph nodes and the pancreas, particularly arterioles in the latter. Also observed in rats dosed with theophylline via the diet was an increased severity of chronic nephropathy in males, especially at the high dose. Administration of theophylline at the same concentrations in the feed to B6C3F1 mice resulted in no mortality, but terminal body weights were significantly decreased in all dosed groups. An increased incidence of hepatocellular glycogen depletion was observed in male and female mice, and this change is believed to represent a physiological alteration exacerbated by the administration of theophylline. Administration of theophylline by gavage to F344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the early death of one high-dose male and female and significantly decreased or increased terminal body weights of high-dose males and females, respectively. Similar to the results of the dosed-feed study, male and female rats receiving theophylline by gavage demonstrated a dose-related increase in the incidence and severity of perivascular inflammation of mesenteric arteries. Gavage administration of theophylline to B6C3F1 mice (0, 75, 150, and 300 mg/kg) resulted in the early death of all high-dose females and 3/10 high-dose males and significant depression of terminal body weights in high- and mid-dose males and low-dose females. As in the dosed-feed study, the primary histopathologic change in the mouse subchronic gavage study was hepatocellular glycogen depletion, although in this case it was seen only in females. In summary, the major target organs for orally administered theophylline in 13-week subchronic toxicity studies appear to be the mesenteric arteries in F344 rats and the liver in B6C3F1 mice. On the basis of organ weight changes and/or minor histopathologic effects, many other tissues were also affected, particularly the kidneys in dosed-feed male rats and the uterus in gavage-dosed female rats.

(RS), (R)(-) and (S)(+) derivatives of 2-N-arylalkylamino-1-butanol having antiarrhythmic properties.

A series of theophyllinyl-7'-ethyl derivatives of (RS), (R)(-) and (S)(+) 2-aminobutanol were synthesized and tested in various models of experimental arrhythmia for their preventive and curative properties; (R)(-) 2-N-theophyllinyl-7'-ethyl amino-1-butanol (1a) and (R)(-) theophyllinyl-7'-ethyl-2-N-methylamino-1-butanol (3a) hydrochlorides showed interesting antiarrhythmic properties. The levorotatory compounds of R configuration showed stronger protective and also therapeutic effect in different experimental arrhythmias.

Theophylline toxicity.

The adverse effects of theophylline were recognized soon after its introduction into clinical medicine. Reports of major toxic reactions to theophylline, particularly in children, discouraged its use and led to homeopathic dosing recommendations that had little therapeutic effect. Concomitant with the renaissance in theophylline use during the past decade, reports of theophylline toxicity have increased. The epidemiology of theophylline intoxication has changed in recent years, and today most instances of serious toxicity are due to intentional overdosage, as in a suicide attempt. The adverse effects of theophylline involve the gastrointestinal, nervous, cardiovascular, and urinary systems. In addition, significant metabolic derangements are noted in patients with severe intoxication. Treatment of theophylline intoxication involves attention to fluid and electrolyte balance and initiation of measures to remove theophylline from the body (gastric lavage or emesis, repeated charcoal administration by mouth, and charcoal hemoperfusion in serious cases).