Elizabeth Rafeiro

Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU)

The Environmental Exposure Unit, an indoor pollen challenge system to test anti‐allergic medications, was used to compare the onset and duration of action and the efficacy of levocetirizine and desloratadine, two recently developed H1‐antagonists. In this double‐blind, placebo‐controlled, parallel‐group study, qualified subjects were randomised to once‐daily levocetirizine 5 mg (n = 141), desloratadine 5 mg (n = 140) or placebo (n = 92) and exposed to ragweed pollen on two consecutive days (7 h and 6 h). Symptoms were self‐rated every 30 min. On both days, levocetirizine produced a greater improvement in the major symptom complex score (primary efficacy variable) than desloratadine (p = 0.015); both were better than placebo (p < 0.001). Levocetirizine acted earlier (1 h vs. 3 h) and produced greater symptom relief at 24 h than desloratadine (p = 0.003). Levocetirizine also alleviated nasal obstruction better than desloratadine (p = 0.007) on day 1; and better than placebo (p = 0.014) after the second dose on day 2, which was not observed with desloratadine. Levocetirizine and desloratadine were safe and well tolerated.

A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis

BACKGROUND Decrements in cognitive performance are associated with the use of sedating antihistamines. Most, but not all, second-generation antihistamines have been found to be nonsedating. OBJECTIVE To examine the central nervous system (CNS) profile of a new second-generation antihistamine, desloratadine. METHODS Subjects with ragweed-induced allergic rhinitis (aged 18-60 years) who demonstrated a predetermined severity of symptoms after priming with ragweed pollen in the Environmental Exposure Unit were randomized to receive a single dose of desloratadine, 5 mg; diphenhydramine, 50 mg; or placebo. A comprehensive battery of repeatable, automated neuropsychological tests was administered to subjects before treatment (symptomatic baseline) and 90 minutes after taking study medication. RESULTS Both desloratadine (P = .04) and diphenhydramine (P < .01) alleviated the symptoms of allergic rhinitis compared with placebo, but treatment with diphenhydramine was associated with clinically meaningful decrements on all vigilance parameters (P < .05 for desloratadine-diphenhydramine contrasts). Also, subjects treated with diphenhydramine performed significantly worse than subjects given desloratadine or placebo across all cognitive domains evaluated. Most effect sizes for the mean desloratadine and diphenhydramine differences were between 0.4 and 0.8 (moderate to high). Stanford Sleepiness Scale scores also indicated significantly more somnolence with diphenhydramine vs desloratadine or placebo (P < .001). There were no significant differences on any of the cognitive parameters between subjects treated with desloratadine and those given placebo. CONCLUSIONS Desloratadine improved ragweed-induced allergic rhinitis symptoms without adversely affecting performance. Diphenhydramine improved allergic rhinitis symptoms but caused significant decrements in vigilance and cognitive functioning. Thus, efficacy of antihistamine treatment must be balanced against the associated effects on CNS functioning.

Effects of N-acetylcysteine and dithiothreitol on glutathione and protein thiol replenishment during acetaminophen-induced toxicity in isolated mouse hepatocytes

Isolated mouse hepatocytes were incubated with 1.0 mM acetaminophen (AA) for 1.5 h to initiate glutathione (GSH) and protein thiol (PSH) depletion and cell injury. Cells were subsequently washed to remove non-covalently bound AA and resuspended in medium containing N-acetylcysteine (NAC, 2.0 mM) or dithiothreitol (DTT, 1.5 mM). The effects of these agents on the replenishment of GSH and total PSH content were related to the development of cytotoxicity. When cells exposed to AA were resuspended in medium containing NAC or DTT, both agents replenished GSH and total PSH content to levels observed in untreated cells but only DTT was able to attenuate cytotoxicity. Addition of the GSH synthesis inhibitor, buthionine sulfoximine (BSO, 1.0 mM, 1.5 h), to cells in incubation medium containing AA, enhanced GSH and total PSH depletion and potentiated cytotoxicity. Resuspension of these cells in medium containing NAC did not alter the potentiating effects of BSO; GSH and PSH levels were not replenished and no cytoprotective effects were observed. However, when cells exposed to AA and BSO were resuspended in medium containing DTT, PSH content was replenished but GSH levels were not restored. In addition, DTT was able to delay the development of cytotoxicity. It appears that DTT, unlike NAC, has a GSH-independent mechanism of PSH replenishment. These observations suggest that while replenishment of GSH and total PSH content does not result in cytoprotection, the regeneration of critical PSH by DTT may play an important role in the maintenance of proper cell structure and/or function.

Amiodarone-induced disruption of hamster lung and liver mitochondrial function : lack of association with thiobarbituric acid-reactive substance production

Amiodarone (AM) is an efficacious antidysrhythmic agent that is limited clinically by numerous adverse effects. Of greatest concern is AM-induced pulmonary toxicity (AIPT) due to the potential for mortality. Mitochondrial alterations and free radicals have been implicated in the etiology of AM-induced toxicities, including AIPT. Isolated hamster lung and liver mitochondria were assessed for AM-induced effects on respiration, membrane potential, and lipid peroxidation. AM (50-400 microM) stimulated state 4 (resting) respiration at complexes I and II of tightly coupled lung mitochondria, with higher concentrations (200 and 400 microM) resulting in a subsequent inhibition. This biphasic effect of AM (200 microM) was also observed with isolated liver mitochondria. Only inhibition of respiration was observed with AM (50-400 microM) in less tightly coupled lung mitochondria. Based on safranine fluorescence, 200 microM AM decreased lung mitochondrial membrane potential (p < 0.05), while a concentration-dependent (50-200 microM) decrease of membrane potential was observed with liver mitochondria exposed to AM (p < 0.05). Formation of thiobarbituric acid-reactive substances (TBARS) was not altered by AM (50-400 microM) in incubations lasting up to 1 h. These results indicate that lipid peroxidation, as indicated by levels of TBARS, does not play a role in AM-induced alterations in mitochondrial respiration and membrane potential.

Quality of life indices may be predictive of placebo and medication response to treatment for allergic rhinitis

BACKGROUND Quality of life (QOL) is known to be an important clinical endpoint in determining medication efficacy; however, the predictive value of QOL indices for response to medication or placebo has not been tested. OBJECTIVE To determine whether a correlation between measures of QOL and response to medication/placebo exists in an evaluation of budesonide for allergic rhinitis. METHODS Two hundred nine participants completed the 36-item short-form health QOL survey at screening for entry into a study examining the onset of action of budesonide in an allergen challenge system. During the treatment phase, symptom assessments were recorded hourly after dosing of double-blind medication. Participants were determined to be responders or nonresponders to study medication. A responder was defined as a participant who rated medication effectiveness as fair to excellent with regard to symptom relief, for three consecutive hourly assessments during the study day or one whose total symptom score decreased by > or =25% for three consecutive hourly assessments. Baseline QOL scores were compared between responders and nonresponders. RESULTS Differences were noted among responders and nonresponders on the basis of whether budesonide or placebo was received. Ratings of general health perception, pain, physical function, and role limitation due to physical health were significantly lower among participants who responded to placebo, compared with placebo nonresponders. In addition, the overall physical health and 36-item short-form health survey averages were significantly lower. Differences between responders and nonresponders to budesonide did not reach statistical significance. CONCLUSIONS Lower baseline QOL scores were associated with a clinically significant response to placebo in a trial of treatment for allergic rhinitis. QOL may be a factor in participant response to medication in clinical studies and, hence, a predictor of outcome.

The controlled allergen challenge experience: comparison of allergic upper respiratory symptoms in the environmental exposure unit (EEU) and during seasonal exposure

Background Traditional assessment of seasonal allergic rhinitis (SAR) medication efficacy utilizes randomized controlled trials over 2-4 weeks in season. An additional study method employs single-dose responses using controlled allergen challenge such as the Environmental Exposure Unit (EEU). A comparison of allergic symptoms generated by controlled allergen challenge to those occurring in ragweed season symptoms has not been done. Methods 1821 subjects with known SAR to ragweed were mailed a survey during the third week of ragweed season, soliciting the nature and severity of SAR symptoms. Subjects participating in a subsequent controlled allergen challenge study using the EEU, were again asked to complete a similar survey that documented symptoms generated in this model. Those who completed both surveys comprised the primary analysis group. Results 550 subjects completed the ragweed season survey, 516 subjects completed the EEU survey, and 270 completed both. Symptoms generated by EEU exposure were similar to those elicited during ragweed season, with the exception of cough (68% vs. 27%, respectively, p <0.01). Subjects reported that symptoms were more severe in the EEU than those experienced on a typical ragweed season day, but less severe than those during peak ragweed season days. Conclusion Allergic upper respiratory tract symptoms produced during controlled ragweed pollen exposure in the EEU were similar in nature and degree to those experienced during ragweed season, supporting evidence that the EEU is a valid model for studying SAR. *This study was self-funded.