5-fluorouracil (5-FU), a commonly utilized antitumor agent for the treatment of colon cancer, is linked to an increased risk of cardiovascular diseases. Antihistamines including astemizole (AST) have been reported to present cardiovascular toxicity; however, it remains unclear how 5-FU-mediated cardiotoxicity is affected by AST during the treatment of colon cancer. This study explored the role of AST in 5-FU-induced cardiotoxicity in colon cancer. 5-FU was used to induce cardiotoxicity in cardiomyocytes (HL-1 cells) and BALBc mice, creating in vitro and in vivo models of chemotherapeutic drug-induced cardiotoxicity. In the mice model, we found that the blocking of histamine signal by AST aggravated 5-FU-induced cardiac function injury and cardiac fibrosis. In HL-1 cardiomyocyte cells, the increases of apoptosis and generation of mitochondrial reactive oxygen species (mtROS) were evaluated after the combination treatment of AST and 5-FU. Proinflammatory M1-like-type macrophages were dominant in the AST and 5-FU combination group compared to control groups. The protein expression of prostaglandin-endoperoxide synthase 2 (Ptgs2) was assessed both in vitro and in vivo using Western blot analysis. Clinically, altered Ptgs2 was closely associated with adverse cardiovascular outcomes. Overall, the combination of AST and 5-FU significantly enhanced cardiotoxicity by inducing cardiomyocyte apoptosis, inflammation, and the expression of Ptgs2.

Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (PfNF54 IC50 = 0.012 μM; PfK1 IC50 = 0.040 μM) displaying high microsomal metabolic stability (HLM CLint < 11.6 μL·min-1·mg-1) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 × 50 mg·kg-1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.

Atypical kinetics of cytochrome P450 2J2: Epoxidation of arachidonic acid and reversible inhibition by xenobiotic inhibitors

A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexualgametocyticstages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of <0.1 μM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 ( PfNF54) strain while maintaining submicromolar potency against the multidrug-resistant strain, PfK1, with most showing low likelihood of cross-resistance with CQ. Selected analogues ( PfNF54-IC50 < 0.1 μM) were tested for cytotoxicity on Chinese hamster ovarian (CHO) cells and found to be highly selective (selectivity index > 100).Screeningof AST and its analogues against gametocytesrevealed their moderate activity (IC50: 1-5 μM) against late stage P.falciparum gametocytes, while the evaluation of activity against P.berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.

Immunosuppressive potential of astemizole against LPS activated T cell proliferation and cytokine secretion in RAW macrophages, zebrafish larvae and mouse splenocytes by modulating MAPK signaling pathway

Cholesterol plays a key role in membrane protein function and signaling in endothelial cells. Thus, disturbing cholesterol trafficking is an effective approach for inhibiting angiogenesis. We recently identified astemizole (AST), an antihistamine drug, as a cholesterol trafficking inhibitor from a phenotypic screen. In this study, we found that AST induced cholesterol accumulation in the lysosome by binding to the sterol-sensing domain of Niemann-Pick disease, type C1 (NPC1), a lysosomal surface protein responsible for cholesterol transport. Inhibition of cholesterol trafficking by AST led to the depletion of membrane cholesterol, causing SREBP1 nuclear localization. The depletion of membrane cholesterol resulted in dissociation of mammalian target of rapamycin (mTOR) from the lysosomal surface and inactivation of mTOR signaling. These effects were effectively rescued by addition of exogenous cholesterol. AST inhibited endothelial cell proliferation, migration and tube formation in a cholesterol-dependent manner. Furthermore, AST inhibited zebrafish angiogenesis in a cholesterol-dependent manner. Together, our data suggest that AST is a new class of NPC1 antagonist that inhibits cholesterol trafficking in endothelial cells and angiogenesis.

Three new alkaloids (1, 4 and 8), together with nine known analogues (2, 3, 5–7, and 9–12), were isolated from the marine-derived fungus Penicillium expansum Y32. Their structures including the absolute configurations were elucidated by spectroscopic and Mosher’s and Marfey’s methods, along with quantum electronic circular dichroism (ECD) calculations. Each of the compounds was evaluated for cardiovascular effects in a live zebrafish model. All of the compounds showed a significant mitigative effect on bradycardia caused by astemizole (ASM) in the heart rate experiments. Compounds 4–6 and 8–12 exhibited potent vasculogenetic activity in vasculogenesis experiments. This is the first study to report that these types of compounds show cardiovascular effects in zebrafish. The results suggest that these compounds could be promising candidates for cardiovascular disease lead compounds.

A novel HPLC–MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics

Astemizole (AST) is non-fluorescent in aqueous solution. This property makes its determination through direct fluorescence methods difficult. Reaction and supramolecular interaction mechanisms, between AST and palmatine (PAL) as they compete for occupancy of the cucurbit[7]uril (CB[7]) cavity, were studied using spectrofluorimetry, 1H NMR, and molecular modeling calculations. The association constants of the complexes formed between the host and the guest were determined. Based on the significant quenching of the supramolecular complex fluorescence intensity, a fluorescent probe method of high sensitivity and selectivity was developed to determine AST in its pharmaceutical dosage forms and in urine samples with good precision and accuracy. The linear range of the method was from 0.02 μg mL−1 to 2.2 μg mL−1. The detection limit was 0.007 μg mL−1. This shows that the proposed method has promising potential for therapeutic monitoring and pharmacokinetics and for clinical application.

We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-beta polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on paired helical filaments from brains of AD patients and surface plasmon resonance studies confirm these findings. The capacity of these drugs to penetrate the blood-brain barrier was evaluated: i) in vitro by parallel artificial membrane permeability assay followed by experimental Log P determinations; and ii) in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain of mice using HPLC/UV. Importantly, our studies indicate that the brain/blood concentration ratios for these compounds were suitable for their use as PET radiotracers. Since neurofibrillary tangles are positively correlated with cognitive impairment, we concluded that LNS and AST have a great potential in PET neuroimaing for in vivo early detection of AD and in reducing the formation of neurofibrillary tangles.

One titrimetric and two spectrophotometric methods, which are simple and sensitive, are described for the determination of astemizole (AST) in bulk drug and formulations. The methods use bromate-bromide mixture and two dyes, methyl orange and indigo carmine. In titrimetry (Method A), astemizole is treated with a known excess of bromate-bromide mixture in acid medium and after the bromination reaction is ensured to be complete, the residual bromine is back-titrated iodometrically. In spectrophotometric methods, the excess of bromine is estimated by treating it with a fixed amount of either methyl orange (Method B) or indigo carmine (Method C) and measuring the change in absorbance either at 520 or 610 nm. In all the methods, the amount of bromate reacted corresponds to the drug content. Titrimetric method is applicable over 4-16 mg range and the calculations are based on a 1:0.666 (AST: bromate) reacting ratio. In spectrophotometry, the calibration graph is found to be linear over 0.5-4.0 µg mL-1 (Method B) and 1.25 12.5 µg mL-1 (Method C) with molar absorptivity values of 6.6 x 10(4) L mol-1 cm-1 and 2.1 x 10(4) L mol-1 cm-1, respectively. The limits of detection and quantification are reported for methods B and C. The statistical evaluation of the methods was examined by determining intra-day and inter-day precision. The methods were applied to the determination of AST in tablets and syrups and the results were found to agree well with the label claim. The accuracy and reliability of the methods were further ascertained by parallel determination by a reference method and by calculating the Student's t-value and F-value at the 95% confidence level, and by recovery studies using standard addition technique.

Comparative effects of maternal prenatal and postnatal exposures to astemizole on reproductive parameters of rats

Astemizole and terfenadine were the prototypic nonsedating antihistamines, but they have the potential to cause cardiac arrhythmias by interfering with cardiac potassium channels and prolonging the QT interval. The risk is heightened because the levels of these drugs increase in the presence of inhibitors of cytochrome P450 3A4 (CYP3A4). Recently, diphenhydramine (DPH) (Benadryl and others), the prototypic H1-receptor antagonist, has been found to …

Janssen has announced that it is voluntarily withdrawing astemizole ['Hisminal'] from the market

Spectrophotometric determination of astemizole

Perinatal astemizole exposure in the rat throughout gestation: Long-term behavioral and anatomic effects associated with reproduction

641 Astemizole is not carcinogenic in mice and rats

The present study was performed to investigate the putative suppressive effects of H1-receptor antagonists (HRA) of the second generation (astemizole (AS), cetirizine (CT), loratadine (LO), oxatomide (OX) and terfenadine (TF)) on the mediator release from human basophils activated by two classical stimuli. Anti-IgE-mediated histamine release was inhibited in a dose-dependent fashion by TF (maximum inhibitory value: 33.8 +/- 7.6%, 100 microM, n = 7), whereas the other HRA exhibited weaker activity. The anti-IgE-induced LTC4 production was strongly suppressed by TF, LO and OX (92.4 +/- 6.3%, 90.8 +/- 6.0% and 88.5 +/- 5.6%, 100 microM, n = 4-5), while AS was less active (56.4 +/- 4.1%, 100 microM, n = 5). Histamine release induced by incubation with grass pollen antigen (0.01%) was inhibited by TF (40.7 +/- 4.1%, 50 microM, n = 4), but the other HRA showed only low activity. The present findings suggest that some HRA might exhibit direct inhibitory effects on activation of IgE-receptor bearing cells.

Reducing terfenadine or astemizole interactions

Reducing terfenadine or astemizole interactions