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The Western Journal of Medicine Dec 1994
Topics: Astemizole; Drug Information Services; Drug Interactions; Humans; Terfenadine; United States; United States Food and Drug Administration
PubMed: 7856171
DOI: No ID Found -
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 -
The Journal of Toxicological Sciences 2018In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and... (Comparative Study)
Comparative Study
Comparison of electropharmacological effects between terfenadine and its active derivative fexofenadine using a cross-over study in halothane-anesthetized dogs to analyze variability of pharmacodynamic and pharmacokinetic profiles of terfenadine and torsadogenic risk of fexofenadine.
In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.
Topics: Anesthesia; Animals; Arrhythmias, Cardiac; Blood Pressure; Cross-Over Studies; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Halothane; Heart Rate; Myocardial Contraction; Risk; Terfenadine
PubMed: 29540652
DOI: 10.2131/jts.43.183 -
Apoptosis : An International Journal on... Dec 2011Previously we found that terfenadine, an H1 histamine receptor antagonist, acts as a potent apoptosis inducer in melanoma cells through modulation of Ca(2+) homeostasis....
Previously we found that terfenadine, an H1 histamine receptor antagonist, acts as a potent apoptosis inducer in melanoma cells through modulation of Ca(2+) homeostasis. In this report, focusing our attention on the apoptotic mechanisms activated by terfenadine, we show that this drug can potentially activate distinct intrinsic signaling pathways depending on culture conditions. Serum-deprived conditions enhance the cytotoxic effect of terfenadine and caspase-4 and -2 are activated upstream of caspase-9. Moreover, although we found an increase in ROS levels, the apoptosis was ROS independent. Conversely, terfenadine treatment in complete medium induced ROS-dependent apoptosis. Caspase-4, -2, and -9 were simultaneously activated and p73 and Noxa induction were involved. ROS inhibition prevented p73 and Noxa expression but not p53 and p21 expression, suggesting a role for Noxa in p53-independent apoptosis in melanoma cells. Finally, we found that terfenadine induced autophagy, that can promote apoptosis. These findings demonstrate the great potential of terfenadine to kill melanoma cells through different cellular signaling pathways and could contribute to define new therapeutic strategies in melanoma.
Topics: Apoptosis; Autophagy; Caspases; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Melanoma; Reactive Oxygen Species; Signal Transduction; Terfenadine
PubMed: 21861192
DOI: 10.1007/s10495-011-0640-y -
British Journal of Pharmacology Sep 2019A second-generation antihistamine, terfenadine, is known to induce arrhythmia by blocking hERG channels. In this study, we have shown that terfenadine also inhibits the...
BACKGROUND AND PURPOSE
A second-generation antihistamine, terfenadine, is known to induce arrhythmia by blocking hERG channels. In this study, we have shown that terfenadine also inhibits the activity of G-protein-gated inwardly rectifying K (GIRK) channels, which regulate the excitability of neurons and cardiomyocytes. To clarify the underlying mechanism(s), we examined the effects of several antihistamines on GIRK channels and identified the structural determinant for the inhibition.
EXPERIMENTAL APPROACH
Electrophysiological recordings were made in Xenopus oocytes and rat atrial myocytes to analyse the effects of antihistamines on various GIRK subunits (K 3.x). Mutagenesis analyses identified the residues critical for inhibition by terfenadine and the regulation of ion selectivity. The potential docking site of terfenadine was analysed by molecular docking.
KEY RESULTS
GIRK channels containing K 3.1 subunits heterologously expressed in oocytes and native GIRK channels in atrial myocytes were inhibited by terfenadine and other non-sedating antihistamines. In K 3.1 subunits, mutation of Phe137, located in the centre of the pore helix, to the corresponding Ser in K 3.2 subunits reduced the inhibition by terfenadine. Introduction of an amino acid with a large side chain in K 3.2 subunits at Ser148 increased the inhibition. When this residue was mutated to a non-polar amino acid, the channel became permeable to Na . Phosphoinositide-mediated activity was also decreased by terfenadine.
CONCLUSION AND IMPLICATIONS
The Phe137 residue in K 3.1 subunits is critical for inhibition by terfenadine. This study provides novel insights into the regulation of GIRK channels by the pore helix and information for drug design.
Topics: Animals; Dose-Response Relationship, Drug; Female; G Protein-Coupled Inwardly-Rectifying Potassium Channels; Histamine Antagonists; Male; Molecular Docking Simulation; Mutation; Myocytes, Cardiac; Oocytes; Rats; Rats, Wistar; Structure-Activity Relationship; Xenopus laevis
PubMed: 31116876
DOI: 10.1111/bph.14717 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2021Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer...
Terfenadine is a second-generation H1-antihistamine that despite potentially can produce severe side effects it has recently gained attention due to its anticancer properties. Lately, the subfamily 2 of inward rectifier potassium channels (Kir2) has been implicated in the progression of some tumoral processes. Hence, we characterized the effects of terfenadine on Kir2.x channels expressed in HEK-293 cells. Terfenadine inhibited Kir2.3 channels with a strikingly greater potency (IC50 = 1.06 ± 0.11 μmol L-1) compared to Kir2.1 channels (IC50 = 27.8 ± 4.8 μmol L-1). The Kir2.3(I213L) mutant, possessing a larger affinity for phosphatidylinositol 4,5-bisphosphate (PIP2) than the wild-type Kir2.3, was less sensitive to terfenadine inhibition (IC50 = 13.0 ± 2.9 μmol L-1). Additionally, the PIP2 intracellular application had largely reduced the inhibition of Kir2.1 channels by terfenadine. Our data support that Kir2.x channels are targets of terfena-dine by affecting their interaction with PIP2, which could be regarded as a mechanism of the antitumor properties of terfenadine.
Topics: HEK293 Cells; Histamine H1 Antagonists, Non-Sedating; Humans; Inhibitory Concentration 50; Potassium Channels, Inwardly Rectifying; Terfenadine
PubMed: 33151169
DOI: 10.2478/acph-2021-0017 -
Pharmaceuticals (Basel, Switzerland) Sep 2023is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for...
is a highly infectious protozoan that causes giardiasis, a gastrointestinal disease with short-term and long-lasting symptoms. The currently available drugs for giardiasis treatment have limitations such as side effects and drug resistance, requiring the search for new antigiardial compounds. Drug repurposing has emerged as a promising strategy to expedite the drug development process. In this study, we evaluated the cytotoxic effect of terfenadine on trophozoites. Our results showed that terfenadine inhibited the growth and cell viability of trophozoites in a time-dose-dependent manner. In addition, using scanning electron microscopy, we identified morphological damage; interestingly, an increased number of protrusions on membranes and tubulin dysregulation with concomitant dysregulation of were observed. Importantly, terfenadine showed low toxicity for Caco-2 cells, a human intestinal cell line. These findings highlight the potential of terfenadine as a repurposed drug for the treatment of giardiasis and warrant further investigation to elucidate its precise mechanism of action and evaluate its efficacy in future research.
PubMed: 37765140
DOI: 10.3390/ph16091332 -
Journal of the American Academy of... May 1998Two new systemic antifungal agents, terbinafine and itraconazole, have expanded the choices for treatment of onychomycosis. The pharmacokinetic and pharmacologic... (Comparative Study)
Comparative Study Review
BACKGROUND
Two new systemic antifungal agents, terbinafine and itraconazole, have expanded the choices for treatment of onychomycosis. The pharmacokinetic and pharmacologic properties provide the basis of their activity and are related to their efficacy and safety in dermatophyte infections.
OBJECTIVE
We describe the pharmacodynamics, pharmacokinetics, and pharmacology of terbinafine and itraconazole and the features that form a framework for comparing their efficacy. PHARMACODYNAMICS: Both terbinafine and itraconazole ultimately block ergosterol synthesis; terbinafine disrupts fungal cell wall synthesis earlier (squalene to squalene epoxide) than does itraconazole (lanosterol to ergosterol). In vitro, terbinafine exposure results in a toxic accumulation of squalene and decreased production of ergosterol. Minimal inhibitory concentrations (MICs) of terbinafine for dermatophytes are essentially equal to minimal fungicidal concentrations (MFCs). However, the MFCs of itraconazole are much higher than the MICs. PHARMACOLOGIC PROFILE: Both itraconazole and terbinafine penetrate keratinizing tissue; levels reached in nail plate exceed those in plasma. Therapeutic levels of the itraconazole persist in nails for up to 6 months after discontinuation of 3 months of therapy (200 mg/day) and during various pulsed cycles. After discontinuation of 1 month of therapy, terbinafine persists at therapeutic levels in the nail. Itraconazole has an affinity for mammalian cytochrome P-450 enzymes as well as for fungal P-450-dependent enzyme, and thus has the potential for clinically important interactions (e.g., astemizole, terfenadine, rifampin, oral contraceptives, H2 receptor antagonists, warfarin, cyclosporine). Terbinafine is not metabolized through this system and has little potential for drug-drug interactions.
CONCLUSION
The low MFCs exhibited by terbinafine for dermatophytes may be important in its clinical efficacy and low relapse rates. The safety profile of terbinafine directly reflects its mechanism of action.
Topics: Antifungal Agents; Arthrodermataceae; Candida; Dermatomycoses; Dose-Response Relationship, Drug; Ergosterol; Humans; Itraconazole; Metabolic Clearance Rate; Nails; Naphthalenes; Terbinafine
PubMed: 9594936
DOI: 10.1016/s0190-9622(98)70483-9 -
Cellular Physiology and Biochemistry :... 2017Suicidal erythrocyte death or eryptosis contributes to or even accounts for anemia in a wide variety of clinical conditions, such as iron deficiency, dehydration,... (Review)
Review
Suicidal erythrocyte death or eryptosis contributes to or even accounts for anemia in a wide variety of clinical conditions, such as iron deficiency, dehydration, hyperphosphatemia, vitamin D excess, chronic kidney disease (CKD), hemolytic-uremic syndrome, diabetes, hepatic failure, malignancy, arteriitis, sepsis, fever, malaria, sickle-cell disease, beta-thalassemia, Hb-C and G6PD-deficiency, Wilsons disease, as well as advanced age. Moreover, eryptosis is triggered by a myriad of xenobiotics and endogenous substances including cytotoxic drugs and uremic toxins. Eryptosis is characterized by cell membrane scrambling with phosphatidylserine exposure to the erythrocyte surface. Triggers of eryptosis include oxidative stress, hyperosmotic shock, and energy depletion. Signalling involved in the regulation of eryptosis includes Ca2+ entry, ceramide, caspases, calpain, p38 kinase, protein kinase C, Janus-activated kinase 3, casein kinase 1α, cyclin-dependent kinase 4, AMP-activated kinase, p21-activated kinase 2, cGMP-dependent protein kinase, mitogen- and stress-activated kinase MSK1/2, and ill-defined tyrosine kinases. Inhibitors of eryptosis may prevent anaemia in clinical conditions associated with enhanced eryptosis and stimulators of eryptosis may favourably influence the clinical course of malaria. Additional experimentation is required to uncover further clinical conditions with enhanced eryptosis, as well as further signalling pathways, further stimulators, and further inhibitors of eryptosis. Thus, a detailed description of the methods employed in the analysis of eryptosis may help those, who enter this exciting research area. The present synopsis describes the experimental procedures required for the analysis of phosphatidylserine exposure at the cell surface with annexin-V, cell volume with forward scatter, cytosolic Ca2+ activity ([Ca2+]i) with Fluo3, oxidative stress with 2',7'-dichlorodihydrofuorescein diacetate (DCFDA), glutathione (GSH) with mercury orange 1(4-chloromercuryphenyl-azo-2-naphthol), lipid peroxidation with BODIPY 581/591 C11 fluorescence, and ceramide abundance with specific antibodies. The contribution of kinases and caspases is defined with the use of the respective inhibitors. It is hoped that the present detailed description of materials and methods required for the analysis of eryptosis encourages further scientists to enter this highly relevant research area.
Topics: Calcium; Cell Size; Cytosol; Eryptosis; Erythrocytes; Flow Cytometry; Glutathione; Humans; Lipid Peroxidation; Oxidative Stress; Phosphatidylserines; Protein Kinases
PubMed: 28922657
DOI: 10.1159/000480469 -
Current Drug Metabolism 2019Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450... (Review)
Review
BACKGROUND
Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. Information for major drug-metabolizing cytochrome P450 (P450) enzymes is now available that supports the use of this primate species as an animal model for drug development. Here, we collect and provide an overview of information on the activities of common marmoset hepatic and intestinal microsomes with respect to 28 typical human P450 probe oxidations.
RESULTS
Marmoset P450 2D6/8-dependent R-metoprolol O-demethylation activities in hepatic microsomes were significantly correlated with those of midazolam 1'- and 4-hydroxylations, testosterone 6β-hydroxylation, and progesterone 6β-hydroxylation, which are probe reactions for marmoset P450 3A4/5/90. In marmosets, the oxidation activities of hepatic microsomes and intestinal microsomes were roughly comparable for midazolam and terfenadine. Overall, multiple forms of marmoset P450 enzymes in livers and intestines had generally similar substrate recognition functionalities to those of human and/or cynomolgus monkey P450 enzymes.
CONCLUSION
The marmoset could be a model animal for humans with respect to the first-pass extraction of terfenadine and related substrates. These findings provide a foundation for understanding individual pharmacokinetic and toxicological results in nonhuman primates as preclinical models and will help to further support understanding of the molecular mechanisms of human P450 function.
Topics: Animals; Callithrix; Humans; Intestinal Mucosa; Liver; Microsomes; Models, Animal; Oxidation-Reduction; Pharmaceutical Preparations
PubMed: 30280664
DOI: 10.2174/1389200219666181003143312