Anticancer effects of ikarugamycin and astemizole identified in a screen for stimulators of cellular immune responses.

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.

Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model.

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

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead.

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.

Astemizole Inhibits mTOR Signaling and Angiogenesis by Blocking Cholesterol Trafficking.

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.

Repurposing Cationic Amphiphilic Antihistamines for Cancer Treatment.

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.

In vivo dual targeting of the oncogenic Ether-à-go-go-1 potassium channel by calcitriol and astemizole results in enhanced antineoplastic effects in breast tumors.

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.

Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents.

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.

Astemizole: an old anti-histamine as a new promising anti-cancer drug.

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.

Treatment of allergic rhinitis in infants and children: efficacy and safety of second-generation antihistamines and the leukotriene receptor antagonist montelukast.

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.

Chloroquine-astemizole hybrids with potent in vitro and in vivo antiplasmodial activity.

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.

Effect of tecastemizole on pulmonary and cutaneous allergic inflammatory responses.

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.

An extension of the Early Treatment Diabetic Retinopathy Study (ETDRS) system for grading of diabetic macular edema in the Astemizole Retinopathy Trial.

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.

Effect of histamine receptor antagonists on aminophylline-induced seizures and lethality in mice.

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.

[Efficacy and safety of astemizole in the treatment of allergic rhinitis and urticaria: a systematic review with meta-analysis]. / Eficacia e inocuidad del astemizol en el tratamiento de la rinitis alérgica y la urticaria: revisión sistemática con metaanálisis.

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.

Generalized lichen nitidus.

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.

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.

Assessment of the relationship between hyperalgesia and peripheral inflammation in magnesium-deficient rats.

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 in the treatment of seasonal allergic rhinitis due to Parietaria and cypress pollen.

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.

Triamcinolone: new and old indications.

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.