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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., Competing Interests: Competing interests: OK is a co-founder of Samsara Therapeutics. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK’s wife, Laurence Zitvogel, has held research contracts with 9 Meters Biopharma, Daiichi Sankyo, Pilege, was on the Board of Directors of Transgene, is a co-founder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK’s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 ( Pf NF54 IC 50 = 0.012 μM; Pf K1 IC 50 = 0.040 μM) displaying high microsomal metabolic stability (HLM CL int < 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.

What Is Known and Objective: In order to expedite the availability of drugs to treat cancers in a cost-effective manner, repurposing of old drugs for oncological indications is gathering momentum. Revolutionary advances in pharmacology and genomics have demonstrated many old drugs to have activity at novel antioncogenic pharmacological targets. We decided to investigate whether prospective studies support the promises of nonclinical and retrospective clinical studies on repurposing three old drugs, namely metformin, valproate and astemizole., Methods: We conducted an extensive literature search through PubMed to gather representative nonclinical and retrospective clinical studies that investigated the potential repurposing of these three drugs for oncological indications. We then searched for prospective studies aimed at confirming the promises of retrospective data., Results and Discussion: While evidence from nonclinical and retrospective clinical studies with these drugs appears highly promising, large scale prospective studies are either lacking or have failed to substantiate this promise. We provide a brief discussion of some of the challenges in repurposing. Principal challenges and obstacles relate to heterogeneity of cancers studied without considering their molecular signatures, trials with small sample size and short duration, failure consider issues of ethnicity of study population and effective antioncogenic doses of the drug studied., What Is New and Conclusion: Well-designed prospective studies demonstrating efficacy are required for repurposing old drugs for oncology indications, just as they are for new chemical entities for any indication. Early and ongoing interactions with regulatory authorities are invaluable. We outline a tentative framework for a structured approach to repurposing old drugs for novel indications in oncology., (© 2018 John Wiley & Sons Ltd.)

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., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. In search for new NSCLC treatment options, we screened a cationic amphiphilic drug (CAD) library for cytotoxicity against NSCLC cells and identified several CAD antihistamines as inducers of lysosomal cell death. We then performed a cohort study on the effect of CAD antihistamine use on mortality of patients diagnosed with non-localized cancer in Denmark between 1995 and 2011. The use of the most commonly prescribed CAD antihistamine, loratadine, was associated with significantly reduced all-cause mortality among patients with non-localized NSCLC or any non-localized cancer when compared with use of non-CAD antihistamines and adjusted for potential confounders. Of the less frequently described CAD antihistamines, astemizole showed a similar significant association with reduced mortality as loratadine among patients with any non-localized cancer, and ebastine use showed a similar tendency. The association between CAD antihistamine use and reduced mortality was stronger among patients with records of concurrent chemotherapy than among those without such records. In line with this, sub-micromolar concentrations of loratadine, astemizole and ebastine sensitized NSCLC cells to chemotherapy and reverted multidrug resistance in NSCLC, breast and prostate cancer cells. Thus, CAD antihistamines may improve the efficacy of cancer chemotherapy., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The oncogenic ether-à-go-go-1 potassium channel (EAG1) activity and expression are necessary for cell cycle progression and tumorigenesis. The active vitamin D metabolite, calcitriol, and astemizole, a promising antineoplastic drug, target EAG1 by inhibiting its expression and blocking ion currents, respectively. We have previously shown a synergistic antiproliferative effect of calcitriol and astemizole in breast cancer cells in vitro, but the effect of this dual therapy in vivo has not been studied., Methods: In the present study, we explored the combined antineoplastic effect of both drugs in vivo using mice xenografted with the human breast cancer cell line T-47D and a primary breast cancer-derived cell culture (MBCDF). Tumor-bearing athymic female mice were treated with oral astemizole (50 mg/kg/day) and/or intraperitoneal injections of calcitriol (0.03 μg/g body weight twice a week) during 3 weeks. Tumor sizes were measured thrice weekly. For mechanistic insights, we studied EAG1 expression by qPCR and Western blot. The expression of Ki-67 and the relative tumor volume were used as indicators of therapeutic efficacy., Results: Compared to untreated controls, astemizole and calcitriol significantly reduced, while the coadministration of both drugs further suppressed, tumor growth (P < 0.05). In addition, the combined therapy significantly downregulated tumoral EAG1 and Ki-67 expression., Conclusions: The concomitant administration of calcitriol and astemizole inhibited tumor growth more efficiently than each drug alone, which may be explained by the blocking of EAG1. These results provide the bases for further studies aimed at testing EAG1-dual targeting in breast cancer tumors expressing both EAG1 and the vitamin D receptor.

Prion diseases such as Creutzfeldt-Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP-FRET-enabled high throughput assay (PrP-FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identified astemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the blood-brain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform.

Mortality-to-incidence ratio in cancer patients is extremely high, positioning cancer as a major cause of death worldwide. Despite hundreds of clinical trials for anti-cancer drugs that are currently in progress, most clinical trials for novel drug treatments fail to pass Phase I. However, previously developed drugs with novel anti-tumor properties offer a viable and cost-effective alternative to fight cancer. Histamine favors the proliferation of normal and malignant cells. Several anti-histamine drugs, including astemizole, can inhibit tumor cell proliferation. Astemizole has gained enormous interest since it also targets important proteins involved in cancer progression, namely, ether à-go-go 1 (Eag1) and Eag-related gene (Erg) potassium channels. Furthermore, Eag1 is thought to be an important marker and a therapeutic target for several different cancers. Astemizole inhibits Eag1 and Erg channel activity, and in cells expressing the Eag1 channel it decreases tumor cell proliferation in vitro and in vivo. It should be noted that some cardiovascular side effects have been reported for astemizole in a few rare cases. Nevertheless, astemizole stands as a very promising anti-cancer tool because it displays several anti-proliferative mechanisms, may serve as the basis to synthesize new anti-cancer agents, and has been previously administered clinically. In this review we will summarize the main findings relating to histamine and anti-histamines in cancer cell proliferation focusing on astemizole targets (Eag1 and Erg channels), and its anti-cancer effects in vitro and in vivo. We will also describe the side effects of astemizole and discuss proposals to overcome such effects in cancer patients. Finally, we will remark on the relevance of developing novel astemizole-related compounds.

A dual activity, conjugated approach has been taken to form hybrid molecules of two known antimalarial drugs, chloroquine (CQ) and the non-sedating H1 antagonist astemizole. A variety of linkers were investigated to conjugate the two agents into one molecule. Compounds 5-8 possessed improved in vitro activity against a CQ-resistant strain of Plasmodium falciparum, and examples 7 and 8 were active in vivo in mouse models of malaria.

Allergic rhinitis (AR) affects a large percentage of paediatric patients. With the wide array of available agents, it has become a challenge to choose the most appropriate treatment for patients. Second-generation antihistamines have become increasingly popular because of their comparable efficacy and lower incidence of adverse effects relative to their first-generation counterparts, and the safety and efficacy of this drug class are established in the adult population. Data on the use of the second-generation antihistamines oral cetirizine, levocetirizine, loratadine, desloratadine and fexofenadine, and the leukotriene receptor antagonist montelukast as well as azelastine nasal spray in infants and children are evaluated in this review. These agents have been found to be relatively safe and effective in reducing symptoms associated with AR in children. Alternative dosage forms such as liquids or oral disintegrating tablets are available for most agents, allowing ease of administration to most young children and infants; however, limited data are available regarding use in infants for most agents, except desloratadine, cetirizine and montelukast. Unlike their predecessors, such as astemizole and terfenadine, the newer second-generation antihistamines and montelukast appear to be well tolerated, with absence of cardiotoxicities. Comparative studies are limited to cetirizine versus ketotifen, oxatomide and/or montelukast. Although second-generation antihistamines and montelukast are deemed relatively safe for use in paediatric patients, there are some noteworthy drug interactions to consider when selecting an agent. Given the wide variety of available agents for treatment of AR in paediatric patients, the safety and efficacy data available for specific age groups, type of AR, dosage form availability and cost should be considered when selecting treatment for AR in infants and children.

Background: Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation., Methods: Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion., Results: Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism., Conclusion: These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.

Purpose: To compare the effects of astemizole, an antihistamine, versus placebo on the 1-year course of diabetic macular edema (DME) and to illustrate use of a modified ETDRS system for grading areas of retinal thickening and hard exudates that may be useful in clinical trials of treatments for this disorder., Methods: Between June 1994 and September 1997, at 2 clinics, 63 patients who had, in at least one eye (the study eye), DME that had not previously been treated with macular photocoagulation, and for which photocoagulation was not currently recommended by the investigator, were enrolled and randomly assigned to astemizole or placebo. Fifty-four of the 63 patients (86%, 26 in Clinic 1 and 28 in Clinic 2) completed 1 year of followup and had adequate 7-field stereoscopic film-based color fundus photographs of the study eye at the baseline and 1-year visits. DME was > 0.33 disc diameters (DD) from the center of the macula in 48% of study eyes and involved the center in 13%. Photographs were graded using the ETDRS protocol modified to allow estimates of areas of retinal thickening (RT) and hard exudate (HE) to be made on continuous scales in disc area (DA) units. Principal outcome measures were mean change in the square root of RT area (the average diameter of the area in DD), mean change in area of HE, and change in the degree to which RT involved or threatened the center of the macula., Results: At baseline, RT area in the 54 study eyes ranged from 0.09 to 4.0 DA (median 1.1). At the 1-year visit the square root of RT area (RTdd) had decreased by > or= 0.3 DD in 10 eyes, increased by >or = 0.3 DD in 19 and was about the same in 25. Mean change at 1 year was +0.09 DD (SD 0.57) for astemizole versus +0.19 DD (SD 0.48) for placebo, for a difference of -0.10 DD (95% CI -0.38, +0.19; p = 0.51). Adjustments for baseline and time-dependent risk factors did not change this result appreciably, although there was a trend towards a difference in favor of astemizole in the subgroup of patients with more severe retinopathy. Other morphologic outcomes paralleled change in RTdd. Change in RTdd did vary by clinic: -0.03 DD in Clinic 2, versus + 0.32 DD in Clinic 1, for a difference of -0.35 DD (95% CI -0.62, -0.07; p = 0.014). Clinic 1 is a tertiary retinal referral center in Pennsylvania and Clinic 2 a retinal clinic closely affiliated with a large diabetes clinic in Copenhagen. The unexpected clinic difference in outcome provided an opportunity for further analyses using the modified ETDRS system. In comparison to Clinic 1, Clinic 2 patients were more often male, were younger at diagnosis of diabetes, and had less severe retinopathy and better visual acuity, but these differences did not appear to explain the trend for lesser increase in RTdd., Conclusion: No effect of astemizole was found, but the confidence interval for the principal outcome, mean change in RTdd, included both a modest beneficial effect and a small harmful effect. This outcome measure did demonstrate a small difference in outcome by clinic, which could not be explained by baseline characteristics but may reflect differences in access to and/or continuity of care or other unmeasured differences associated with different referral patterns. Although optical coherence tomography may supplant photography as a measure of central RT, photographic assessments of change in RT and HE areas analyzed with the methods described herein may be useful outcomes in trials assessing treatment of early stages of DME. Application of these methods to other data sets is needed to confirm this conclusion.

The aim of this study was to evaluate the effects of H(1) (antazoline and astemizole) or H(2) (cimetidine and famotidine) histamine receptor antagonists on the clonic phase, tonic seizures and morality of mice challenged with aminophylline to induce convulsions in mice. Moreover, the total plasma and brain concentrations of theophylline were evaluated. Astemizole (1 mg/kg) did not affect the threshold for aminophylline-induced seizures, but when administered at a dose of 2 mg/kg, it significantly reduced the CD(50) value of aminophylline from 249 mg/kg to 211 mg/kg (p < 0.01). The remaining histamine receptor antagonists studied i.e., antazoline (up to 1 mg/kg), cimetidine (up to 40 mg/kg) and famotidine (up to 10 mg/kg) had no impact on seizure susceptibility in aminophylline-induced convulsions. Furthermore, astemizole (2 mg/kg) decreased latency to the clonic phase of aminophylline-induced convulsions from 51.1 +/- 4.5 to 32.1 +/- 4.3 min (p < 0.01). It is noteworthy that astemizole, a novel H(1) receptor antagonist, did not alter the brain and plasma levels of theophylline, so the existence of pharmacokinetic interactions was excluded. Our results indicate that some interactions between methylxanthines and histamine receptor antagonists may be clinically important since these drugs are usually combined during the treatment of status asthmaticus.

Objective: To compare astemizole with other first or second generation antihistaminics in the treatment of allergic rhinitis or urticaria., Design: Systematic revision of clinical, controlled and randomized tests., Material and Methods: 36 controlled, randomized, clinical, double or simple blind tests were made in 6,446 patients; 4,513 of them were assigned to astemizole and 1,933 to other first or second generation antihistaminics. Analyzed outcomes: Rate of global success; global scoring improvement of rhinitis; ocular, nasal or pharingeal pruritus; watering; nasal obstruction; sneeze; urticaria; cutaneous response to histamine; time to get a satisfactory improvent; frequency of sedation and headache., Results: In connection to global success there were significant differences in favor of astemizole (OR 6.72, CI95% 5.36 to 8.41, p 0.0001); alike global scoring improvement of rhinitis (SMD -0.82, CI95% -1.70 to 0.06, p 0.04); rhinorrhea (SMD of -0.70, CI95% -1.47 to -0.03, p 0.02); nasal, pharingeal or ocular pruritus (SMD -0.64, CI95% -1.63 to 0.35, p 0.03); urticaria (SMD of -3.53, CI95% -4.11 to -2.94, p 0.0001), and reduction of cutaneous response to histamine (SMD -2.02, CI95% -2.47 to -1.57, p 0.0001). Differences for watering, nasal obstruction or sneeze were not observed. Finally, the safety area was analyzed considering the existence of sedation and headache; it was demonstrated less sedation (OR 0.23, CI95% 0.18 to 0.30, p 0.0001) and less headache (OR 0.58, CI95% 0.40 to 0.85, p 0.005) in the group treated with astemizole., Conclusions: The available evidence shows a therapeutic superiority of astemizole versus other antihistaminics in relation to the percentage of global success and the global scoring improvement of rhinitis, rhinorrhea, pruritus in general, urticaria symptoms and of the reduction of response to histamine, with a smaller frequency of headache or sedation.

Lichen nitidus is a rare chronic condition of unknown etiology. Generalized lichen nitidus is even rarer. We report here a 5-year-old girl who had multiple, asymptomatic, discrete, 1 to 2 mm flesh-colored, shiny, flat, papules on her face, upper limbs, and thighs with relative sparing of the trunk. Resolution of these papular lesions was followed by hyperpigmented macules in those areas. Histopathologic examination of a papular lesion revealed a localized granulomatous lymphohistiocytic infiltrate in an expanded dermal papilla with thinning of overlying epidermis and downward extension of the rete ridges at the lateral margin of the infiltrate, producing a typical "claw clutching a ball" picture, confirming our clinical diagnosis of lichen nitidus. The pigmented macules showed melanin pigmentation on histology. There was no response to oral astemizole treatment for 3 months. However, the lichen nitidus lesions resolved spontaneously without any further treatment over the next year, leaving behind a prominent pigmentary disturbance.

Antihistamines and their drug-drug interactions are reviewed in depth. The metabolism of "classic" or sedating antihistamines is coming to light through in vivo and in vitro studies. The polymorphic CYP 2D6 metabolic enzyme appears to be potently inhibited by many of these over-the-counter medications. The history of the discontinued "second-generation" antihistamines terfenadine and astemizole is reviewed to remind the reader why the understanding of the cytochrome P450 system became increasingly important when the cardiotoxicity of these drugs became apparent. The "third-generation" nonsedating antihistamines are also listed and compared. They have been exhaustively scrutinized for drug-drug interactions and cardiotoxicity, and they appear to have no serious drug-drug interactions at recommended doses.

Magnesium-deficient rats develop simultaneously a significant lowering of nociceptive threshold and a generalized inflammation. We investigated the relationship between these two phenomena by testing drugs that are able to suppress the inflammation in this model. In weaning rats fed a magnesium-depleted diet for ten days, the nociceptive threshold was assessed by the paw pressure test and the inflammation by a clinical score. A non-steroidal anti-inflammatory drug (piroxicam); antagonists of H1 and H2 receptors (astemizole and cimetidine. respectively); a glucocorticoid (dexamethasone); an inhibitor of mastocyte degranulation (cromoglycate); and estradiol benzoate were used to block the inflammatory response. Dexamethasone and estradiol significantly suppressed the inflammation (p < 0.001 vs control group). Cromoglycate showed a delayed anti-inflammatory effect (p < 0.01 vs control group on D10). The combination of astemizole and cimetidine partially blocked the inflammation process, whereas astemizole and piroxicam were without effect. Regardless of the effect of the test drugs on inflammation, no change in the time course of hyperalgesia was observed. These data support the view that hyperalgesia induced by the magnesium-depleted diet is not a consequence of the inflammatory process.

Second generation antihistamines have been employed in the treatment of seasonal allergic rhinitis for many years. However, their effects on two distinctive Mediterranean allergic conditions, viz. Parietaria pollinosis and cypress pollinosis, have been scarcely investigated, so far. A comparative efficacy and side effect trial of astemizole and terfenadine in the treatment of seasonal allergic rhinitis due to either Parietaria or cypress pollen was carried out in 27 adult patients, according to a double-blind, double-dummy parallel-group design. Airborne pollen monitoring allowed comparison of symptom scores with pollen counts. Seven patients (26%) withdrew, due to poor symptom control. In contrast, in a subset of 15 patients who completed the trial, treatment led to a substantial and statistically significant decline in symptom severity in both the astemizole and the terfenadine study group. However, no statistically significant inter-group differences could be detected., (Copyright 2001 Academic Press.)

Triamcinolone is a commonly used synthetic corticosteroid that has recently been tested in a large clinical trial for chronic obstructive pulmonary disease and shown to have some benefits. To our knowledge, there are no reviews of the pharmacotherapy of triamcinolone. This review has a brief overview of the pharmacology of triamcinolone, followed by a discussion of the clinical trials with triamcinolone. Triamcinolone is used in the treatment of respiratory inflammation, rheumatoid arthritis and a variety of other inflammatory conditions.

The impact of interventions designed to shift prescribing from loratadine to fexofenadine at HMOs was studied. Pharmacy claims data for a six-month preintervention period at four HMOs were analyzed to identify all new and refill prescriptions for loratadine, fexofenadine, astemizole, and cetirizine. The interventions consisted of a mandatory lockout of loratadine in favor of fexofenadine (at HMO A), a voluntary switch to fexofenadine promoted through letters to both physicians and members (HMO B), and a voluntary switch promoted through letters to physicians only (HMO C). There was no intervention at HMO D. Pharmacy claims data for the six months after each intervention program was implemented were analyzed to determine changes in the market share and prescribing of the study drugs. After the intervention programs were implemented, the market share of fexofenadine increased from 18.9% to 65.2% at HMO A, from 14.8% to 21.0% at HMO B, and from 20.7% to 23.8% at HMO C. Loratadine's market share decreased from 62.3% to 8.7% at HMO A, from 67.5% to 58.6% at HMO B, and from 70.5% to 65.3% at HMO C. HMOs A, B, and C each had greater shifts in market share for fexofenadine and loratadine than the control HMO. Changes in prescribing followed a similar pattern for the 25 physicians at each HMO who had most frequently prescribed loratadine during the preintervention period. The average cost per antihistamine prescription decreased 22.3% at HMO A. Prescription costs continued to rise at HMOs B, C, and D. Mandating the use of fexofenadine produced a significant increase in its market share, reduced the cost of nonsedating antihistamines, and successfully influenced prescribing behavior. Voluntary programs had a more modest impact on market share and did not stop increases in prescription costs.

An animal model of chronic allergic rhinitis was developed by repeated local booster sensitization into the nasal cavity in sensitized rats. The severity of allergic rhinitis was assessed by determining the extent of two markers of nasal allergic symptoms (sneezing and nasal rubbing) after antigen challenge. The number of incidents of sneezing and nasal rubbing was markedly increased during intranasal instillation of antigen in sensitized rats. The PCA titers were also markedly elevated by intranasal sensitization. Some histamine H(1)-receptor antagonists such as chlorpheniramine, ketotifen, astemizole and epinastine inhibited the increase in antigen-induced nasal symptoms in a dose-related manner. Nasal rubbing was more potently inhibited by H(1)-receptor antagonists than sneezing. In conclusion, we developed a chronic allergic rhinitis model showing nasal symptoms in rats, and this model may be useful for evaluating the effects of drugs on allergic rhinitis.

New-generation H1-blockers may possess antiallergic properties, and their effect may differ, depending on the target organ. A double-blind, placebo-controlled, parallel-group study was carried out during the pollen season to compare the clinical effect on nasal and conjunctival symptoms of astemizole (10 mg o.d.) and loratadine (10 mg o.d.) with their effect on skin-test reactivity to allergen and histamine. Thirty-eight patients (12-56 years of age) were studied. Nasal and ocular symptoms were recorded daily from days 4 to 7. Skin prick tests with serial concentrations of allergens and one concentration of histamine were carried out before and at the end of the 7-day treatment period. Parallel-line bioassay, analysis of variance, and covariance were used to analyze skin test data. Loratadine and astemizole significantly decreased symptoms from baseline (P < 0.004 and P < 0.006). Skin-test reactivity to allergen and histamine was more profoundly decreased by astemizole than loratadine. The histamine covariant was more important in the allergen effect of astemizole than in that of loratadine. Two H1-blockers having the same clinical effect on nasal and ocular symptoms during the pollen season have totally different effects on skin-test reactivity. Skin-test reactivity to allergen or histamine is not predictive of the clinical efficacy of H1-blockers during seasonal allergic rhinitis.

Nonsedating H1 antihistamines such as terfenadine, loratadine, and astemizole are widely prescribed for the treatment of allergic rhinitis. The comparative efficacy of these agents has not been thoroughly studied. We studied 14 subjects in an open-label four-way crossover trial. Patients were recruited from an outpatient allergy clinic. Inclusion criteria were documented rhinitis symptoms for at least 2 years before the study and skin-test positivity in response to perennial allergens. Each subject underwent sequential 2-week trials of each of four H1 antihistamines: terfenadine, loratadine, astemizole, and chlorpheniramine. No placebo was included. Outcome measures were subjective rhinitis symptom scores, overall efficacy scores, and concomitant pseudoephedrine use. In addition, nasal-examination scores were obtained by way of physician assessment at the end of each 2-week trial, and side effects were tabulated. Nasal-examination scores for each of the four H1 antihistamines were significantly better than the baseline scores (p < 0.05). No statistically significant differences in rhinitis symptom scores, overall efficacy scores, or concomitant pseudoephedrine use were noted. We detected no clinically significant differences in efficacy among terfenadine, loratadine, astemizole, and chlorpheniramine in the treatment of perennial allergic rhinitis.

Astemizole (Hismanal), an antihistamine agent, has been reported to be associated with ventricular arrhythmias. In this paper we present a case of QT prolongation and torsades de pointes (TdP) in a 77-year-old woman who had been taking astemizole (10 mg/day) for 6 months because of allergic skin disease. At the time of admission, the serum concentration of astemizole and its metabolites was markedly elevated at 15.85 ng/ml, approximately 3 times the normal level. The patient was also taking cimetidine, a known inhibitor of cytochrome P-450 enzymatic activity, and during her admission was diagnosed as having vasospastic angina. To the best of our knowledge, this is the first report of astemizole-induced QT prolongation and TdP in Japan.

To clarify the mechanisms of enhanced cardiotoxic effects of astemizole in ischemic hearts, we examined the effects of astemizole on ventricular activation, effective refractory periods (ERPs), RT intervals, and incidence of programmed electrical stimulation (PES)-induced ventricular arrhythmias in the dog heart after myocardial infarction. Myocardial infarction was produced by the two-stage ligation of left anterior descending coronary artery in dogs. At 7 days after ligation, bipolar electrodes were sutured on the ventricular surface of the infarcted and the normal zones for applying an electrical stimulation or recording the ventricular activation. Ventricular-activation delay was measured in a premature excitation, which was produced by a stimulation at a coupling interval between 300 and 140 ms on the ventricular surface of the normal zone. The ERP and the RT interval were determined during atrial pacing. The ventricular-activation delay increased after astemizole at doses of 0.3-3 mg/kg in the infarcted zone and at 3 mg/kg in the normal zone. Astemizole at doses of 0.3-3 mg/kg significantly prolonged the ERP to a greater extent in the infarcted zone than in the normal zone, and thus a dispersion of ERP between normal and infarcted zones increased. The RT interval in the normal zone significantly increased after astemizole to a greater extent at a long coupling interval. The RT interval in the infarcted zone also increased after astemizole at doses of 0.1-3 mg/kg to a greater extent than that in the normal zone. Astemizole at doses of 0.3-3 mg/kg increased the incidence of PES-induced ventricular arrhythmias. In conclusion, enhanced cardiotoxic effects of astemizole in ischemic hearts may be caused by increased activation delay in the ischemic regions and increased ERP dispersion in the ventricle.

Because of serious cardiovascular events, warnings against concomitant use of certain medications with the use of antihistamine (HismanalR have been published and added to product labeling. Quinine, the optical isomer to quinidine, is included in these warnings. We present the case of a patient with only mild electrolyte disturbances who experienced an episode of torsades de pointes after a single dose of quinine while taking astemizole.

Background: Terfenadine, astemizole, cetirizine, and loratadine are compared in their abilities to produce relief of symptoms of allergic rhinitis., Objective: The aim of this study was to compare the onset of action and efficacy of the study medications., Methods: 111 ragweed-sensitive subjects were primed with pollen in the Environmental Exposure Unit. Study entry required adequate symptoms over a 3 hour exposure to 5000 +/- 300 grains/m3 of ragweed pollen. On the test day, subjects were given a single dose of either terfenadine 60 mg (22), astemizole 10 mg (22), cetirizine 10 mg (23), loratadine 10 mg (22), or placebo (22) when sufficiently symptomatic after a 60-minute exposure. Allergen levels were maintained and symptoms recorded every 30 minutes., Results: Proportions of subjects with clinically important relief were cetirizine, 69.6%; terfenadine, 54.5%; loratadine, 50.0%; astemizole, 40.9%; and placebo, 31.8% but differences weren't significant between treatment groups (P = .119). Survival curves for times to onset of clinically important relief for the four treatment groups were not different (P = .119). Subjects realizing definitive relief were cetirizine, 65.2%; terfenadine, 45.5%; loratadine, 31.8%; placebo, 27.3%; and astemizole, 22.7% (P = .023). Survival analysis of onset time for definitive relief found significant differences (P = .010). The ranking was cetirizine --> terfenadine --> loratadine --> astemizole (quickest to slowest). Global evaluation based on subject willingness to take the medication again yielded percentages: cetirizine, 82.6%; terfenadine, 66.7%; astemizole, 63.6%; loratadine, 40.9%; and placebo, 36.4% (P = .036)., Conclusion: Cetirizine and terfenadine continuously ranked higher in terms of onset of action and efficacy, while loratadine and astemizole ranked lower. Significance was detected in definitive relief and relative efficacy.

The efficacy and safety of the two antihistamines, astemizole and loratadine, were compared in a double-blind study of 84 patients with perennial allergic rhinitis. Patients were randomized to receive orally either astemizole 10 mg once daily (n = 40) or loratadine 10 mg once daily (n = 44) for 1 week. No other antirhinitis medication was allowed during the study. By day 7 the mean daily symptom scores, recorded on diary cards, were lower in patients receiving astemizole than in those receiving loratadine for runny nose, itchy nose and sneezing, although not for blocked nose, and treatment differences only reached statistical significance for runny nose. After 7 days, 53.75% of patients on astemizole and 38.6% on loratadine were free of symptoms, and 87% of patients on astemizole described the treatment as good or excellent compared with 62% on loratadine. The present results suggest that astemizole may be more effective than loratadine in controlling symptoms of perennial allergic rhinitis.

Episodic cluster headache is a well-recognized entity usually starting in the second decade of life. Uncommonly, the first typical symptoms may present in the first decade of life, but are rarely recognized as such during childhood. We report a 12-year-old girl who presented with a 1-year history of bouts of right-sided hemicrania with ipsilateral, clearly demarcated, redness and itching of the skin of the face, lasting from 15 minutes to 2 hours per day. The episodes recurred up to several times daily for a few days and were followed by remissions lasting up to 2 months. Thorough investigations failed to prove any definite cause. Antihistamine prophylaxis, first with astemizole and then with loratadine, proved to be very effective. During the follow-up period of more than 3 years, such a prophylactic regimen provided excellent relief, with only two relapses due to noncompliance. We suggest that in a sequential treatment trial for cluster headache during childhood, antihistamines should have their place, especially in those cases where clinical evidence may suggest histamine involvement.

They were studied 48 children of 3 to 8 years old, of two sex (30 male and 18 female), that attended the external service of otolaryngology of the Hospital of the ISSSTE of Nuevo Laredo, Tamaulipas (Mexico) and the private practice of the Allergy Clinic and Otolaringol in Nuevo Laredo, Tamaulipas, of the month of November of 1995 to April of 1996. Some of the side effects observed in the patients treated in the group A (carbinoxamine-P) were: mild sedation and in some instances hyperexcitability and irritability. However, it was not necessary to discontinue the medication or to modify the dose. In the group B (astemizole-P) was observed only excitement and irritability in some instances by hypersensitivity to the pseudoephedrine. It is very important to consider that the adequate and timely treatment in a patient with otitis serous media will permit to avoid sequels that they can cause, in the long run, a meaningful impact in the language and intellectual development of the child.

Allergic rhinitis afflicts close to 40% of the nation's population and costs more than $1.8 billion a year. The toll exacted by this disorder has been greatly alleviated by nonsedating second-generation antihistamines loratadine, terfenadine, and astemizole. The three agents effectively reduce symptoms without the sometimes intolerable adverse effects of older drugs, but they are not completely equivalent. For example, terfenadine requires twice/day dosing, whereas the others can be given once/day. Astemizole has a slow onset and extremely prolonged duration of action. Both terfenadine and astemizole may have cardiotoxic effects (e.g., torsades de pointes) when serum concentrations rise due to overdosing or drug interactions. Cetirizine, a recently approved second-generation antihistamine, has sedative and anticholinergic effects, although to a lesser degree than the first-generation antihistamines.

The effects of E-4716 on chemical mediators were compared with those of classical antihistaminics and other second generation (nonsedating) drugs normally used in the therapy of allergic reactions, such as astemizole, terfenadine and ebastine, in a series of in vitro and in vivo tests. In vitro, antihistaminic activity was demonstrated in a test on isolated organs and a binding test on histamine receptors, with no anticholinergic activity observed. A high antihistaminic activity was also shown in in vivo tests on chemical mediators release by compound 48/80, histamine-induced bronchospasm in anesthetized guinea pigs and histamine-induced cutaneous reaction in beagle dogs. The antiallergic activity was studied in passive cutaneous anaphylaxis test using ovalbumin antibodies. Astemizole and E-4716 had similar activities with ED50 values of 0.8 and 0.5 mg/kg, respectively, whereas terfenadine (ED50 = 4.5) was less active. E-4716 also inhibited the vascular permeability response in histamine-stimulated conjunctivitis model after topical ocular administration (ED50 = 0.002, 0.0002, 0.015 and 1.2% at 30 min and 6, 12 and 24 h, respectively). E-4716 had a high and selective antihistaminic and antiallergic activity by all routes of administration (oral, i.v., i.p., topical ocular and inhalation). These results, combined with its low toxicity and lack of central effects, indicate that E-4716 has excellent potential for therapeutic use.

Although uncommon, torsades de pointes (TdP) associated with astemizole and/or erythromycin use have been reported previously. We describe a 30-year-old woman who had congenital prolongation of QT interval and TdP occurred after taking astemizole and erythromycin. Temporary cardiac pacing was successful in suppressing TdP. Prolongation of QT interval had good response to oral propranolol.

Background: Astemizole, an H1-histamine-receptor antagonist prescribed for seasonal allergic rhinitis, has a slow onset of action and a strong suppressive effect on the wheal and flare reaction, which interferes with skin testing results. The newer antihistamine cetirizine appears to have a rapid onset of action and a low potential to interfere with posttreatment skin testing results., Objective: To compare the efficacy, safety, and skin test inhibition of astemizole and cetirizine in the treatment of seasonal allergic rhinitis., Methods: In a double-blind, parallel-group study conducted at six sites during ragweed pollination season, 263 subjects were randomized to receive 10 mg of astemizole, 5 mg of cetirizine, or 10 mg of cetirizine daily for 2 weeks. The subjects rated seven allergic rhinitis symptoms daily, the subjects and investigators provided global assessments of the responses to the treatments, and the subjects rated their satisfaction with the treatments. Thirty-nine subjects at one study site underwent quantitative skin testing before and after treatment., Results: As measured by reduction from baseline in total symptom severity score, which was the primary efficacy measure in the study, all three treatments significantly relieved the symptoms of allergic rhinitis (P less than .05). This finding was supported by the global ratings and the subject satisfaction ratings. There were no significant differences among the three treatments for reduction from baseline in total symptom severity score. The mean subject satisfaction score with 10 mg of cetirizine was significantly greater than that with astemizole (P less than .05). In the skin tests performed 3, 7, and 14 days after the end of antihistamine treatment, the subjects who had received the cetirizine doses had significantly greater mean sum of wheal and mean sum of erythema values than those who had received the astemizole dose (P less than .05). Sensitivity to ragweed pollen extract returned to 90% of baseline within three days of the end of cetirizine treatment. Both drugs were well tolerated and their adverse event profiles were similar., Conclusions: Astemizole and cetirizine are effective and well tolerated in alleviating the symptoms of ragweed-induced allergic rhinitis. Cetirizine inhibits skin test results to a much lesser extent than does astemizole. Physicians may wish to consider the potential for skin test inhibition when selecting an antihistamine for patients with allergic rhinitis.

The efficacy and side effects of once-daily astemizole-D, a combination of 10 mg astemizole and 240 mg pseudoephedrine, were compared with those of twice-daily brompheniramine-D, a combination of 12 mg brompheniramine and 50 mg phenylpropanolamine (Lunerin), in 64 patients with seasonal allergic rhinitis caused by birch pollen. Efficacy was monitored by patient's diary scores, investigator assessments of nasal and eye symptoms and need of rescue medication during the 4-week study period. Both astemizole-D and brompheniramine-D reduced nasal and eye symptoms of allergy. There were no significant differences between the treatment groups regarding obstruction, but brompheniramine-D alleviated symptoms of rhinorrhoea and itchy eyes significantly more than astemizole-D. On the other hand, the patients in the brompheniramine-D group reported dry mouth, tiredness and drowsiness more often than those in the astemizole-D group. The results indicate that the two drugs are effective in the treatment of seasonal allergic rhinitis, but astemizole-D is better tolerated than brompheniramine-D.

Background: Few clinical trials have directly compared the efficacy of antihistamines with topical nasal corticosteroids., Objective: The study was performed to compare the efficacy and safety of triamcinolone acetonide nasal spray at a dose of 110 micro g in each nostril once daily with 10 mg of oral astemizole once daily for the treatment of seasonal allergic rhinitis., Methods: A multicenter, double-blind, parallel-group study was conducted in 239 patients who were randomized to receive either triamcinolone acetonide or astemizole. A 5-day, drug-free, lead-in period was followed by 4 weeks of double-blind treatment. One hundred four patients treated with triamcinolone acetonide and 105 patients treated with astemizole could be evaluated., Results: Overall, triamcinolone acetonide was more effective than astemizole in reducing total nasal symptoms, nasal stuffiness, nasal itching, and sneezing (p

The efficacy of the second generation antihistamine ebastine has been investigated in the treatment and prevention of seasonal allergic rhinitis (SAR). In a double-blind randomised study, patients treated with a single daily dose of ebastine 10mg (n = 116) for 2 weeks showed a significant improvement in symptoms of SAR compared with those treated with placebo (n = 85). Sneezing, rhinorrhoea, tears and conjunctival irritation were all significantly improved, but not blocked nose. The overall efficacy of treatment was judged to be significantly superior in the ebastine group. There was no increase in bodyweight at the end of the study in either of the groups. There was no increase bodyweight at the end of the study in either of the groups. The percentage of patients reporting adverse events were headache, somnolence, nausea, dry mouth, stomach upset and increased appetite. The efficacy of ebastine 10 mg/day (n = 111) was similar to that of astemizole 10 mg/day (n = 106) over a 4-month period in preventing the symptoms of SAR in the open randomised study. The efficacy of both drugs in preventing the onset of sneezing, rhinorrhoea, blocked nose and tears was significant, when symptoms were compared with those during the previous year. At the end of the study, the astemizole-treated patients had a significant increase in bodyweight, which was not observed in the ebastine group. The percentage of patients reporting adverse events was significantly greater in the astemizole group (34.9% versus 20.7%; p = 0.02). Thus, ebastine is a useful alternative treatment for seasonal allergic rhinitis. It has also shown efficacy comparable to that of astemizole in the prevention of onset of symptoms of this allergic condition, and appears to be better tolerated than this agent.

Lichen nitidus (LN) is an uncommon skin disorder. We observed 3 patients with an association of lichen nitidus and atopic dermatitis (AD), which to the best of our knowledge has not been previously reported in the literature. It remains to be evaluated whether the association of LN and AD is fortuitous or not.

This multicentre double-blind, placebo controlled study had a practical objective, based on the expectation that many patients with seasonal allergic rhinitis will be prescribed oral antihistamine monotherapy by their primary care physician, whereas allergy specialists are more likely to prescribe combination therapy including antiinflammatories. The specific question was, "Will the addition of nedocromil sodium 1% nasal spray to astemizole tablets improve control of symptoms of seasonal allergic rhinitis induced by ragweed pollen, as compared to astemizole therapy alone?'. Following a one-week baseline, planned to coincide with the start of the local ragweed pollen season, patients (aged 12-64) were randomly assigned to four weeks' double-blind test treatment with either nedocromil sodium 1% nasal spray four times daily (QID) + astemizole (n = 146) or placebo nasal spray + astemizole (n = 148) or double-dummy (nasal spray + capsules) placebo (n = 71). Patient diary cards were kept throughout the five weeks, and clinic visits were made before and after baseline and after one and four weeks' treatment. During the 10-day peak pollen period, the diary card rhinitis symptom summary score (0-4 severity scale) was significantly reduced in patients receiving either astemizole alone (p < 0.001) or the combination therapy (p < 0.001) as compared with placebo. Direct comparison of the active treatments further showed that symptoms were significantly less severe (p < 0.01) with the combined therapy than with astemizole alone, and this despite significantly greater reliance on permitted rescue medications (p < 0.05 for pseudoephedrine usage) in the astemizole group. Clinical assessments of rhinitis made during the peak pollen visit, after the first week of test treatment, were also significantly (p < 0.05 - p < 0.01) in favour of combined therapy with nedocromil sodium 1% nasal spray + astemizole rather than astemizole alone, and at the same time this preference was confirmed by physician (p = 0.011) and patient (p = 0.003) opinions of symptom control. In conclusion, this antiinflammatory + antihistamine treatment proved superior to antihistamine alone for effective management of allergic rhinitis. The combined therapy worked quickly and was well-tolerated, with no serious adverse events or untoward effects on blood or urine variables.

A group of 36 children aged from 1 10/12 to 11 years was the subject of clinical and laboratory examinations. It was found that there is a close relationship between food hypersensitivity to milk and symptoms of the skin (81%), upper (61%) and lower (55%) respiratory tract, digestive tract (47%) and central nervous system (14%). These symptoms occured in isolated or associated forms on the different organs or systems. An elimination diet and pharmacological treatment with Astemizol were used in all children from the investigated group. Complete relief of symptoms was observed in 39% of children; 44% of examined patients had a regression of symptoms of 1 and/or 2 organs. Side effects of treatment with Astemizol were observed in the form of excessive appetite (22%), body weight gain (3%), vomiting (3%), diarrhoea (3%), bleeding from the nose (3%), sleepiness (5%). Due to the good therapeutic effect and insignificant side effects, the supporting pharmacological treatment with Astemizol was found useful in children with hypersensitivity to cow's milk.