Astemizole toxicity

CYP3A4 is involved in the metabolism of 80%-90% of all currently available drugs (Table 2). Its presence accounts for the majority of the cytochrome enzymes in the liver. It has attracted attention from both physicians and pharmaceutical companies, as there have been incidences of fatal drug interactions, which have resulted in the withdrawal of these drugs from the market (terfena-dine in 1997, astemizole in 1999, and cisapride in 2000). Combinations ofpotent CYP3A4 inhibitors and substrates can drive drug levels to the toxic range. The... 

Interactions Erythromycin and clarithromycin inhibit the hepatic metabolism of theophylline, warfarin, terfenadine, astemizole, carbamazepine and cyclosporine which can lead to toxic accumulations of these drugs. An interaction with digoxin may occur in some patients. In this case, the antibiotic eliminates a species of intestinal flora that ordinarily inactivates digoxin, thus leading to greater reabsorption of digoxin from the enterohepatic circulation. 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrolides, especially clarithromycin (48-51), typically resulting in prolongation of the QT interval and cardiac dysrhythmias (torsade de pointes) (52). 

Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrohdes, especially clarithromycin (87-89,116), typically resnlting in prolongation of the QT interval and cardiac dysrhjdhmias (torsade de pointes) (111). The potential interaction of azithromycin with terfenadine has been evaluated in a randomized, placebo-controlled study in 24 patients who took terfenadine plus azithromycin or terfenadine pins placebo (90). However, azithromycin did not alter the pharmacokinetics of the active carboxylate metabolite of terfenadine or the effect of terfenadine on the QTc interval. 

The toxicity of astemizole also appears to be remarkably low. An acute toxicity study in rats found that at 25,000 times the antihistaminic dose (2,560 mg/kg) the drug produced some transient sedation but no lethality up to 2 weeks after administration—an extreme safety margin. This raises the possibility that antihistamines may have intrinsic antiasthmatic activity, but at such doses that the toxicity of the first-generation drugs precluded such a use at safe doses. 

Ketoconazole has been associated with hepatic toxicity, hence necessitating liver function tests before, during, and after termination of the therapy. Ketoconazole reduces the serum level of testosterone, which returns to normal levels after discontinuation of therapy. It increases the plasma levels, bioavailability, or actions of oral anticoagulants, astemizole, terfenidine, corticosteroids, and cyclosporine, but decreases that of theophylline. 

Terfenadine (Seldane) or astemizole (Hismanal) given with macrolides might cause toxicity to the heart. The patient is also at risk for hemorrhage if the patient takes both warfarin (Coumadin) and marolides within the same time period. The patient may also experience increased theophylline levels which can lead to toxicity when theophylline is given along with zanthines such as aminophylline and caffeine. 

In vitro studies have shown that ketoconazole inhibits the metabolism of astemizole. Ketoconazole, and to a lesser extent itraconazole and miconazole, also appear to reduce the metabolism of terfenadine by inhibition of the cytochrome P450 isoenzyme CYP3A. " High serum levels of astemizole and terfenadine (but not its metabolites) block cardiac potassium channels leading to prolongation of the QT interval, which may precipitate the development of torsade de pointes arrhythmia (see Table 15.2 , (p.583)). The risk of cardiac arrhythmias with other non-sedating antihistamines appears to be non-existent or very much lower (see Table 15.2 , (p.583)), so any pharmacokinetic interactions do not result in clinically relevant cardiac toxicity. In fact, studies have shown that desloratadine at nine times the recommended dose, fexofenadine in overdose, and mizolastine at four times the recommended dose do not affect the QT interval. However, some questions remain about loratadine and ebastine. Additionally, some studies have reported that ketoconazole alone is associated with a small increase in QT interval, and at least one case of torsade de pointes has been reported for ketoconazole alone. Therefore the cardiac effects of ketoconazole may be additive with those of the antihistamines, and this may be important for ebastine and loratadine. 

Major Applications Sensors, lithographic plates, optical recording media, photoreceptor, inks, indication system for product exceeding threshold temperature,lubricants, textiles, food stor-age,i3 determination of amiodarone, " astemizole, bromhexine,i6 clomipramine, deutiforin, domperidone, fluoroquinolone, roxithromycin, terfenadine, thiabendazole, antihistamines Safety/Toxicity Biodegradation and toxicity ... 

Matrix-assisted laser desorption/ionization-tandem mass spectrometric method (MALDI-MS/MS) has proven to be a reliable tool for direct measurement of the disposition of small molecules in animal tissue sections. As example, MALDI-MS/MS imaging system was employed for visualizing the spatial distribution of astemizole and its primary metabolite in rat brain tissues. Astemizole is a second-generation antihistamine, a block peripheral HI receptor, which was introduced to provide comparable therapeutic benefit but was withdrawn in most countries due to toxicity risks. Astemizole was observed to be heterogeneously distributed to most parts of brain tissue slices including cortex, hippocampus, hypothalamic, thalamus, and ventricle regions while its major metabolite, desmethylastemizole, was only found around ventricle sites. We have shown that astemizole alone is likely to be responsible for the central nervous system (CNS) side effects when its exposures became elevated. 

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