-
Structure (London, England : 1993) Mar 2021The hERG channel is a voltage-gated potassium channel involved in cardiac repolarization. Off-target hERG inhibition by drugs has become a critical issue in the...
The hERG channel is a voltage-gated potassium channel involved in cardiac repolarization. Off-target hERG inhibition by drugs has become a critical issue in the pharmaceutical industry. The three-dimensional structure of the hERG channel was recently reported at 3.8-Å resolution using cryogenic electron microscopy (cryo-EM). However, the drug inhibition mechanism remains unclear because of the scarce structural information regarding the drug- and potassium-bound hERG channels. In this study, we obtained the cryo-EM density map of potassium-bound hERG channel complexed with astemizole, a well-known hERG inhibitor that increases risk of potentially fatal arrhythmia, at 3.5-Å resolution. The structure suggested that astemizole inhibits potassium conduction by binding directly below the selectivity filter. Furthermore, we propose a possible binding model of astemizole to the hERG channel and provide insights into the unusual sensitivity of hERG to several drugs.
Topics: Astemizole; Binding Sites; Cryoelectron Microscopy; ERG1 Potassium Channel; HEK293 Cells; Humans; Molecular Docking Simulation; Potassium Channel Blockers; Protein Binding
PubMed: 33450182
DOI: 10.1016/j.str.2020.12.007 -
Journal For Immunotherapy of Cancer Jul 2023Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics...
BACKGROUND
Most immunotherapies approved for clinical use rely on the use of recombinant proteins and cell-based approaches, rendering their manufacturing expensive and logistics onerous. The identification of novel small molecule immunotherapeutic agents might overcome such limitations.
METHOD
For immunopharmacological screening campaigns, we built an artificial miniature immune system in which dendritic cells (DCs) derived from immature precursors present MHC (major histocompatibility complex) class I-restricted antigen to a T-cell hybridoma that then secretes interleukin-2 (IL-2).
RESULTS
The screening of three drug libraries relevant to known signaling pathways, FDA (Food and Drug Administration)-approved drugs and neuroendocrine factors yielded two major hits, astemizole and ikarugamycin. Mechanistically, ikarugamycin turned out to act on DCs to inhibit hexokinase 2, hence stimulating their antigen presenting potential. In contrast, astemizole acts as a histamine H1 receptor (H1R1) antagonist to activate T cells in a non-specific, DC-independent fashion. Astemizole induced the production of IL-2 and interferon-γ (IFN-γ) by CD4 and CD8 T cells both in vitro and in vivo. Both ikarugamycin and astemizole improved the anticancer activity of the immunogenic chemotherapeutic agent oxaliplatin in a T cell-dependent fashion. Of note, astemizole enhanced the CD8/Foxp3 ratio in the tumor immune infiltrate as well as IFN-γ production by local CD8 T lymphocytes. In patients with cancer, high H1R1 expression correlated with low infiltration by TH1 cells, as well as with signs of T-cell exhaustion. The combination of astemizole and oxaliplatin was able to cure the majority of mice bearing orthotopic non-small cell lung cancers (NSCLC), then inducing a state of protective long-term immune memory. The NSCLC-eradicating effect of astemizole plus oxaliplatin was lost on depletion of either CD4 or CD8 T cells, as well as on neutralization of IFN-γ.
CONCLUSIONS
These findings underscore the potential utility of this screening system for the identification of immunostimulatory drugs with anticancer effects.
Topics: United States; Mice; Animals; CD8-Positive T-Lymphocytes; Interleukin-2; Astemizole; Oxaliplatin; Immunity, Cellular; Histocompatibility Antigens Class I; Interferon-gamma
PubMed: 37419511
DOI: 10.1136/jitc-2023-006785 -
Postepy Dermatologii I Alergologii Jun 2014Histamine is a mediator, which increases the permeability of capillaries during the early phase of allergic reaction, causes smooth muscle contraction of bronchi and... (Review)
Review
Histamine is a mediator, which increases the permeability of capillaries during the early phase of allergic reaction, causes smooth muscle contraction of bronchi and stimulates mucous glands in the nasal cavity. Antihistamines are the basis of symptomatic treatment in the majority of allergic diseases, especially allergic rhinitis, allergic conjunctivitis, urticaria and anaphylaxis. The cardiotoxic effects of the two withdrawn drugs, terfenadine and astemizole, were manifested by prolonged QT intervals and triggering torsades de pointes (TdP) caused by blockade of the 'rapid' I Kr potassium channels. These phenomena, however, are not a class effect. This review deals with a new generation of antihistamine drugs in the context of QT interval prolongation risk.
PubMed: 25097491
DOI: 10.5114/pdia.2014.43191 -
British Journal of Clinical Pharmacology Aug 1998The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the... (Comparative Study)
Comparative Study Review
The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
Topics: Administration, Oral; Beverages; Biological Availability; Calcium Channel Blockers; Citrus; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Felodipine; Food-Drug Interactions; Humans; Intestine, Small; Mixed Function Oxygenases; Pharmacokinetics
PubMed: 9723817
DOI: 10.1046/j.1365-2125.1998.00764.x -
International Journal of Molecular... Dec 2021Apicomplexan parasites, such as , spp., spp., and spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the...
Apicomplexan parasites, such as , spp., spp., and spp., cause significant morbidity and mortality. Existing treatments are problematic due to toxicity and the emergence of drug-resistant parasites. Because protozoan tubulin can be selectively disrupted by small molecules to inhibit parasite growth, we assembled an in vitro testing cascade to fully delineate effects of candidate tubulin-targeting drugs on and vertebrate host cells. Using this analysis, we evaluated clemastine, an antihistamine that has been previously shown to inhibit growth by competitively binding to the CCT/TRiC tubulin chaperone as a proof-of-concept. We concurrently analyzed astemizole, a distinct antihistamine that blocks heme detoxification in . Both drugs have EC values of ~2 µM and do not demonstrate cytotoxicity or vertebrate microtubule disruption at this concentration. Parasite subpellicular microtubules are shortened by treatment with either clemastine or astemizole but not after treatment with pyrimethamine, indicating that this effect is not a general response to antiparasitic drugs. Immunoblot quantification indicates that the total α-tubulin concentration of 0.02 pg/tachyzoite does not change with clemastine treatment. In conclusion, the testing cascade allows profiling of small-molecule effects on both parasite and vertebrate cell viability and microtubule integrity.
Topics: Animals; Antiparasitic Agents; Apicoplasts; Cells, Cultured; Clemastine; Histamine Antagonists; Humans; Microtubules; Parasites; Protozoan Proteins; Tubulin
PubMed: 35008492
DOI: 10.3390/ijms23010068 -
Environmental Health Perspectives Nov 1994
Topics: Animals; Astemizole; Carcinogens; Histamine H1 Antagonists; Hydroxyzine; Loratadine; Mice; Neoplasms, Experimental
PubMed: 9766947
DOI: No ID Found -
BMC Chemistry Feb 2021Imidazole is a five-membered heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds. It is also known as 1, 3-diazole.... (Review)
Review
Imidazole is a five-membered heterocyclic moiety that possesses three carbon, two nitrogen, four hydrogen atoms, and two double bonds. It is also known as 1, 3-diazole. It contains two nitrogen atoms, in which one nitrogen bear a hydrogen atom, and the other is called pyrrole type nitrogen. The imidazole name was reported by Arthur Rudolf Hantzsch (1857-1935) in 1887. 1, 3-diazole is an amphoteric in nature i.e. it shows both acidic and basic properties. It is a white or colorless solid that is highly soluble in water and other polar solvents. Due to the presence of a positive charge on either of two nitrogen atom, it shows two equivalent tautomeric forms. Imidazole was first named glyoxaline because the first synthesis has been made by glyoxal and ammonia. It is the basic core of some natural products such as histidine, purine, histamine and DNA based structures, etc. Among the different heterocyclic compounds, imidazole is better known due to its broad range of chemical and biological properties. Imidazole has become an important synthon in the development of new drugs. The derivatives of 1, 3-diazole show different biological activities such as antibacterial, antimycobacterial, anti-inflammatory, antitumor, antidiabetic, anti-allergic, antipyretic, antiviral, antioxidant, anti-amoebic, antihelmintic, antifungal and ulcerogenic activities, etc. as reported in the literature. There are different examples of commercially available drugs in the market which contains 1, 3-diazole ring such as clemizole (antihistaminic agent), etonitazene (analgesic), enviroxime (antiviral), astemizole (antihistaminic agent), omeprazole, pantoprazole (antiulcer), thiabendazole (antihelmintic), nocodazole (antinematodal), metronidazole, nitroso-imidazole (bactericidal), megazol (trypanocidal), azathioprine (anti rheumatoid arthritis), dacarbazine (Hodgkin's disease), tinidazole, ornidazole (antiprotozoal and antibacterial), etc. This present review summarized some pharmacological activities and various kinds of synthetic routes for imidazole and their derived products.
PubMed: 33602331
DOI: 10.1186/s13065-020-00730-1 -
Canadian Family Physician Medecin de... May 1999To review new treatments for allergic rhinitis. (Review)
Review
OBJECTIVE
To review new treatments for allergic rhinitis.
QUALITY OF EVIDENCE
Most studies supporting the principles in this paper are double-blind, placebo-controlled trials. Good evidence supports use of antihistamines, nasal steroid sprays, and immunotherapy. Fewer trials have been done on the new antileukotrienes.
MAIN MESSAGE
Allergic rhinitis causes significant morbidity, which can be successfully treated. Newer antihistamines, developed to replace terfenadine and astemizole which have potential side effects, include loratadine, cetirizine, and the newest, fexofenadine. Intranasal steroid sprays are also effective, particularly for people with nasal stuffiness. One study showed some growth retardation in children using beclomethasone over a prolonged period (1 year). The newer steroid sprays, such as fluticasone, budesonide, and mometasone furoate aqueous, however, have not been studied in the same way and are usually recommended for shorter periods. The newest group of medications showing real promise are the antileukotrienes, including zafirlukast and montelukast. Taken orally, these medications avoid the discomfort of nasal sprays and seem to have few side effects. Immunotherapy offers a new option: a short-course, preseasonal series of six to 11 injections that reduces the burden on patients for year-round therapy. Combinations of these therapies are also possible.
CONCLUSIONS
With new medications and immunotherapy options, family physicians can offer effective treatment to patients with allergic rhinitis.
Topics: Administration, Topical; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Child; Controlled Clinical Trials as Topic; Double-Blind Method; Glucocorticoids; Histamine Antagonists; Humans; Immunotherapy; Leukotriene Antagonists; Middle Aged; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Time Factors
PubMed: 10349070
DOI: No ID Found -
Biologics : Targets & Therapy 2016Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. HCC is usually asymptomatic at potential curative stages, and it has very poor prognosis if... (Review)
Review
Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. HCC is usually asymptomatic at potential curative stages, and it has very poor prognosis if detected later. Thus, the identification of early biomarkers and novel therapies is essential to improve HCC patient survival. Ion channels have been proposed as potential tumor markers and therapeutic targets for several cancers including HCC. Especially, the ether à-go-go-1 (Eag1) voltage-gated potassium channel has been suggested as an early marker for HCC. Eag1 is overexpressed during HCC development from the cirrhotic and the preneoplastic lesions preceding HCC in a rat model. The channel is also overexpressed in human HCC. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including Eag1. Actually, in vivo studies have shown that astemizole may have clinical utility for HCC prevention and treatment. Here, we will review first some general aspects of HCC including the current biomarkers and therapies, and then we will focus on Eag1 channels as promising tools in the early diagnosis of HCC.
PubMed: 27703327
DOI: 10.2147/BTT.S87402 -
The Cochrane Database of Systematic... Jul 2008Clozapine is widely used for people with schizophrenia. Although agranulocytosis, weight gain, and cardiac problems are serious problems associated with its use,... (Review)
Review
BACKGROUND
Clozapine is widely used for people with schizophrenia. Although agranulocytosis, weight gain, and cardiac problems are serious problems associated with its use, hypersalivation, sometimes of a gross and socially unacceptable quantity, is also common (30-80%).
OBJECTIVES
To determine the clinical effects of pharmacological interventions for clozapine-induced hypersalivation.
SEARCH STRATEGY
We searched the Cochrane Schizophrenia Group Trials Register (March 2007), inspected references of all identified studies for further trials, contacted relevant pharmaceutical companies, drug approval agencies and authors of trials.
SELECTION CRITERIA
We included randomised controlled trials comparing pharmacological interventions, at any dose and by any route of administration, for clozapine-induced hypersalivation.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For dichotomous data (homogenous) we calculated relative risk (RR) with 95% confidence intervals (CI) and numbers needed to treat (NNT) on an intention-to-treat basis. We calculated weighted mean difference (WMD) for continuous data.
MAIN RESULTS
Of the 15 trials identified, 14 were conducted in China and 14 in hospitals. The quality of reporting was poor with no studies clearly describing allocation concealment and much data were missing or unusable. All results are vulnerable to considerable bias. Most frequently the primary outcome was the diameter of the wet patch on the pillow. Antimuscarinics (astemizole, diphenhydramine, propantheline, doxepin) were the most commonly evaluated drugs. For the outcome of 'no clinically important improvement' astemizole and diphenhydramine were more effective than placebo (astemizole: n=97, 2 RCTs, RR 0.61 CI 0.47 to 0.81 NNT 3 CI 2 to 5; diphenhydramine: n=131, 2 RCTs, RR 0.43 CI 0.31 to 0.58, NNT 2 CI 1.5 to 2.5), but the doses of astemizole used were those that can cause toxicity. Data involving propantheline were heterogeneous (I2= 86.6%), but both studies showed benefit over placebo. Adverse effects were poorly recorded. Of the other interventions, oryzanol (rice bran oil and rice embryo oil extract) showed benefit over the antimuscarinic doxepin in terms of 'no clinically important change' (n=104, 1 RCT, RR 0.45 CI 0.27 to 0.75, NNT 4 CI 2 to 7). The Chinese medicine suo quo wan (comprises spicebush root, Chinese yam and bitter cardamom) showed benefit over doxepin (n=70, 1 RCT, RR 'no clinically important change' 0.31 CI 0.16 to 0.59, NNT 3 CI 1.5 to 3.7).
AUTHORS' CONCLUSIONS
There are currently insufficient data to confidently inform clinical practice. The limitations of these studies are plentiful and the risk of bias is high. These trials, however, are invaluable guides for current and future study design. Well conducted randomised trials are possible. Some may be underway. Current practice outside of well designed randomised trials should be clearly justified.
Topics: Antipsychotic Agents; Clozapine; Drugs, Chinese Herbal; Muscarinic Antagonists; Phenylpropionates; Randomized Controlled Trials as Topic; Sialorrhea
PubMed: 18646130
DOI: 10.1002/14651858.CD005579.pub2