N-acetyltransferase 1 polymorphism increases cotinine levels in Caucasian children exposed to secondhand smoke: the CCAAPS birth cohort.

Cotinine is a proxy for secondhand smoke (SHS) exposure. Genetic variation along nicotine and cotinine metabolic pathways may alter the internal cotinine dose, leading to misinterpretations of exposure-health outcome associations. Caucasian children with available SHS exposure and hair cotinine data were genotyped for metabolism-related genes. SHS-exposed children had 2.4-fold higher hair cotinine (0.14±0.22 ng mg(-1)) than unexposed children (0.06±0.05 ng mg(-1), P<0.001). SHS-exposed children carrying the NAT1 minor allele had twofold higher hair cotinine (0.18 ng mg(-1) for heterozygotes and 0.17 ng mg(-1) for homozygotes) compared with major allele homozygotes (0.09 ng mg(-1), P=0.0009), even after adjustment for SHS dose. These findings support that NAT1 has a role in the metabolic pathway of nicotine/cotinine and/or their metabolites. The increased cotinine levels observed for those carrying the minor allele may lead to SHS exposure misclassification in studies utilizing cotinine as a biomarker. Additional studies are required to identify functional single-nucleotide polymorphism(s) (SNP(s)) in NAT1 and elucidate the biological consequences of the mutation(s).

Duration of day care attendance during infancy predicts asthma at the age of seven: the Cincinnati Childhood Allergy and Air Pollution Study.

BACKGROUND: Studies vary with respect to the reported effects of day care attendance on childhood asthma. OBJECTIVES: To evaluate the independent and combined effects of day care attendance and respiratory infections on the development of asthma at the age of seven in a prospective birth cohort. METHOD: At the age of seven, the study sample included 589 children with complete data of 762 enrolled at birth. Day care hours and number of respiratory infections were reported in follow-up questionnaires through age four. At 7 years of age, asthma was diagnosed in 95 children (16%), based on predefined symptoms criteria confirmed by either asthma FEV1 reversibility after bronchodilator or a positive methacholine test (PC20 ≤ 4 mg/mL). Logistic regression was used to investigate the relationships between asthma at the age of seven, cumulative hours of day care attendance and reported respiratory infections at ages 1-4. RESULTS: In the univariate analyses, day care attendance at 12 months was associated with an increased risk of asthma [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.1-3.0]. Both upper and lower respiratory infections at 12 months also increased the likelihood of asthma [OR = 2.4 (1.4-4.1); OR = 2.3 (1.5-3.7), respectively]. In the final multivariate logistic model, cumulative hours of day care attendance and number of lower respiratory infections at 12 months were associated with asthma [OR = 1.2 (1.1-1.5); OR = 1.4 (1.2-1.7), respectively]. However, a threshold of greater than 37.5 hours per week of day care attendance was associated with a lower risk of asthma [OR = 0.6 (0.4-0.9)]. CONCLUSION: Depending on duration of attendance, day care during infancy can either increase or reduce risk of asthma at the age of seven.

A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis.

Symptom and medication use are the key outcomes for assessing the efficacy of subcutaneous (SCIT) and sublingual allergen immunotherapy (SLIT). Our objective was to explore the similarities and differences between existing scoring mechanisms used in clinical trials of SLIT for seasonal allergens and characterize the impact that such differences may have on efficacy reporting. Randomized, double-blind, placebo-controlled clinical trials investigating the efficacy of SLIT for seasonal allergic rhinitis (2009-2013) were selected for review. Simulated and published data were used to demonstrate differences in scoring methods. Symptom and medication scoring methods across trials, although all designed to achieve the same objective, included important differences. The maximum daily symptom score (DSS) can vary widely depending on the number of symptoms assessed, and terminology of symptoms is not consistent. Similarly, daily medication scoring (DMS) methods differ greatly among studies and are dependent on medications allowed and weighting of scores assigned to each medication. When published DSS and DMS scores were used to calculate simulated daily combined scores (DCSs) based on various published methods, changes from placebo ranged from 19% to 29% when assuming all variables other than the DSS and DMS methods were equal. Variations in trial design, analysis, and seasonal characteristics also have effects on symptom and medication scoring outcomes. We identified multiple differences in trial scoring methods and design that make comparison among trials difficult. Symptom, medication, or combined scores cannot be indirectly compared among trials without taking the methods of scoring and other trial differences into account.

Magnitude of efficacy measurements in grass allergy immunotherapy trials is highly dependent on pollen exposure.

BACKGROUND: The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment. METHODS: The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression. RESULTS: The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2)  = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season. CONCLUSIONS: In seasonal allergy trials with grass SLIT-tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results.

Vaccines for cytomegalovirus.

Cytomegalovirus (CMV) is a leading cause of congenital infection worldwide and therefore is recognized as an important target for vaccine development. Data from natural infections and work done with animal models, including models of congenital infection, provide the rationale for their development. CMV vaccine evaluations were begun in the mid-1970's with an attenuated live virus vaccine, Towne, but this vaccine has not consistently provided protection. Most recently, data from a trial with a subunit glycoprotein B (gB) vaccine administered with the adjuvant MF59 became available. This trial, conducted in post-partum women, demonstrated that the vaccine decreased CMV infections, increasing optimism that a protective CMV vaccine could be developed. Other approaches for CMV that have entered clinical trials include replicons, DNA vaccines, prime boost strategies, and chimeric live viruses. The replicon vaccine included gB and the T cell targets phosphoprotein (pp)65 and Immediate Early (IE)1 while the DNA vaccine was given with a new adjuvant and included gB and pp65. The optimal composition for a CMV vaccine remains to be defined but trials continue with the gB vaccine and others.

Abstracts from the North American Rhinology & Allergy Conference, February 3, 2011, Puerto Rico.

INTRODUCTION: To establish the efficacy of bepotastine besilate ophthalmic solution (bepotastine) 1.5%, a dual acting histamine H1 receptor antagonist approved for treatment of ocular itching associated with allergic conjunctivitis, compared to placebo in relieving ocular itching and redness for subjects with active allergic rhinoconjunctivitis. METHODS: A randomized, double-masked, placebo-controlled, confirmatory natural exposure study of bepotastine 1.5% and placebo was conducted during allergy season at 12 clinical sites throughout the U.S. Following a 7-day screening period, eligible subjects ≥12 years old were assigned in a 1:1 ratio to dosing OU b.i.d. either bepotastine 1.5% (n = 123) or placebo (n = 122). Subjects recorded instantaneous grades for their ocular symptoms prior to their next dose for 14 consecutive days. Clinically significant reduction in ocular sign or symptom grades between treatment groups required p ≤ 0.05 as determined by ANCOVA analysis. RESULTS: Significant clinical effectiveness with bepotastine 1.5% was demonstrated over the 2-week treatment period in comparison to placebo in the intent-to-treat population for reducing mean instantaneous grades for both ocular itching (p = 0.007) and redness (p = 0.001). Investigator rating of efficacy over the 2-week treatment period across response categories was also superior for bepotastine 1.5% compared to placebo (p = 0.024). Only one subject discontinued participation in the study due to an adverse event. CONCLUSIONS: These data support bepotastine 1.5% as an effective treatment for allergen-induced signs and symptoms in a clinical study designed to closely resemble the conditions under which patients with allergic rhinoconjunctivitis would require treatment.

Intent to accept and acceptance of herpes testing in adolescents and young adults.

OBJECTIVES: Understanding the intention-behaviour association with HSV-2 testing is important because it can inform interventions that might be needed to support an effective HSV-2 control programme. This study aims to understand attitudinal, symptomatic and historical precursors to intent to accept, and acceptance of, HSV-2 testing. METHODS: The sample included 900 individuals recruited from four sites located in two US cities. Participants completed self-report questionnaires. Expressed intent to accept HSV-2 testing was assessed with an item that asked about acceptance of a test with the same characteristics as the test offered later. The health behaviour outcome was acceptance of the HSV-2 test when it was offered. Predictors examined were STI history, genital symptoms, anxiety and STI-related stigma. RESULTS: Expressed intent significantly predicted test acceptance. However, a number of participants made testing decisions which were at odds with their stated intent. Genital symptoms and STI history significantly predicted both greater intent and test acceptance. STI stigma only predicted lower intent, whereas anxiety only predicted greater acceptance. Intent fully mediated the relationship between genital symptoms and test acceptance, but did not mediate the relationship between STI history and test acceptance. CONCLUSIONS: This study suggests that intent does not always predict behaviour, even when the two are measured within close temporal proximity. There are factors that may predict intent only or behaviour only, or may predict behaviour, but solely through influencing intent. Understanding how these various relationships work may be important to efforts designed to maximise acceptance of HSV-2 testing.

Percutaneous reactivity to natural rubber latex proteins persists in health-care workers following avoidance of natural rubber latex.

BACKGROUND: Long-term avoidance of natural rubber latex [Hevea brasiliensis (Hev b)] is currently recommended for health-care workers (HCWs) with established natural rubber latex (NRL) allergy. Percutaneous sensitivity to eight Hev b NRL allergens was evaluated in HCWs in 2000. To date, no studies have evaluated the longitudinal effects of NRL avoidance on percutaneous sensitivity to NRL allergens. OBJECTIVE: The aims of this study were to evaluate changes in percutaneous reactivity to non-ammoniated latex (NAL) and NRL allergens in HCWs 5 years after a recommendation to avoid NRL and to evaluate factors that predict the persistence of in vivo sensitivity to NAL and NRL allergens. METHODS: Skin prick testing was performed with NAL, seven NRL allergens (Hev b 1, 2, 3, 4, 6.01, 7.01, and 13), and recombinant Hev b 5 (rHev b 5) in 34 HCWs who were initially evaluated in 2000 for occupationally related NRL allergy. Serial 10-fold dilutions of NAL and NRL allergens were employed in skin testing. Sera from the HCWs were assayed for latex and enhanced latex (rHev b 5-enriched allergosorbent)-specific IgE antibodies using the ImmunoCAP assay. RESULTS: The prevalence of work-related symptoms significantly decreased between 2000 and 2005 with avoidance of NRL (P<0.05). A >/=100-fold reduction in percutaneous sensitivity to Hev b 2 and Hev b 7 was less likely in those with prior history of systemic reactions to NRL (P=0.0053), reported history of reaction to cross-reactive foods (P=0.014), continued local reactions to NRL gloves (P<0.0001), or high NRL glove exposure since the initial study (P=0.0075). The diagnostic sensitivity and specificity of the latex-specific IgE serology was 54% and 87.5%, respectively, in comparison with NAL skin tests. The addition of rHev b 5 to the ImmunoCAP (enhanced latex) allergosorbent altered the diagnostic sensitivity and specificity of the ImmunoCAP to 77% and 75%, respectively. CONCLUSION: While symptoms may resolve quickly with NRL avoidance therapy, detectable IgE indicating continued sensitization remains beyond 5 years, and thus continued avoidance of NRL should be recommended.

Diisocyanate conjugate and immunoassay characteristics influence detection of specific antibodies in HDI-exposed workers.

BACKGROUND: The structural characteristics of diisocyanate chemical protein antigens vary depending upon the methods of production, and may influence diisocyanate antigen immunoassays. The impact of different antigen preparation methods on immunoassay sensitivity, specificity, and predictive value for identifying workers with diisocyanate asthma (DA) has not been systematically evaluated. OBJECTIVE: Evaluate the influence of preparation methodology of hexamethylene diisocyanate human serum albumin (HDI-HSA) conjugates on the performance of specific antibody assays for identifying workers with confirmed HDI asthma. METHODS: Asthmatic reactions to HDI exposure were assessed in 80 autobody shop workers by specific inhalation challenge (SIC). HDI-specific IgE and IgG in serum were measured by RAST and ELISA with seven different HDI-HSA conjugates prepared in liquid phase with monomeric or polymeric HDI, or vapour-phase monomeric HDI. The HDI : HSA substitution ratios were determined by mass spectrometry. RESULTS: DA was confirmed by SIC in 23 subjects. The maximal sensitivity for detecting specific IgE among workers with positive SIC results was higher with RAST and with polymeric vs. monomeric HDI-albumin conjugates (21.7% vs. 8.7%) with a generally high specificity (>or=95%). HDI-HSA specific IgG antibody was also detected in 22-43% of HDI asthmatics depending upon the conjugate used. The specificity of specific IgG varied from 88% to 96%, and it was higher for monomeric (vs. polymeric) HDI-albumin conjugates with low (vs. high) substitution ratios. CONCLUSION: The test performance of specific IgE and IgG immunoassays for identifying a positive SIC response varied with different HDI-HSA conjugates. Standard test antigens and common immunoassays must be used to minimize inter-laboratory variability.

House dust (1-3)-beta-D-glucan and wheezing in infants.

BACKGROUND: (1-3)-Beta-D-glucan is a fungal cell wall component, suspected to cause respiratory symptoms in adults. However, very little is known on the possible health effects of (1-3)-beta-D-glucan during infancy. We examined the association between (1-3)-beta-D-glucan exposure and the prevalence of allergen sensitization and wheezing during the first year of life in a birth cohort of 574 infants born to atopic parents. Endotoxin exposure was included as a possible confounder. METHODS: (1-3)-Beta-D-glucan and endotoxin exposures were measured in settled dust collected from infants' primary activity rooms. The primary outcomes at approximately age one included parental reports of recurrent wheezing and allergen sensitization evaluated by skin prick testing to a panel of 15 aeroallergens as well as milk and egg white. RESULTS: Exposure to high (1-3)-beta-D-glucan concentration (within fourth quartile) was associated with reduced likelihood of both recurrent wheezing [adjusted OR (aOR) = 0.39, 95% CI = 0.16-0.93] and recurrent wheezing combined with allergen sensitization (aOR = 0.13, 95% CI = 0.03-0.61). Similar trends were found between (1-3)-beta-D-glucan concentrations and allergen sensitization (aOR = 0.57, 95% CI = 0.30-1.10). In contrast, recurrent wheezing with or without allergen sensitization was positively associated with low (1-3)-beta-D-glucan exposure within the first quartile (aOR = 3.04, 95% CI = 1.25-7.38; aOR = 4.89, 95% CI = 1.02-23.57). There were no significant associations between endotoxin exposure and the studied health outcomes. CONCLUSIONS: This is the first study to report that indoor exposure to high levels of (1-3)-beta-D-glucan (concentration >60 microg/g) is associated with decreased risk for recurrent wheezing among infants born to atopic parents. This effect was more pronounced in the subgroup of allergen-sensitized infants.

Allergen concentration in natural rubber latex.

BACKGROUND: Hevea brasiliensis latex serum is commonly used as the in vivo and in vitro reference antigen for latex allergy diagnosis as it contains the full complement of latex allergens. OBJECTIVE: This study quantifies the concentrations of the significant allergens in latex serum and examines its suitability as an antigen source in latex allergy diagnosis and immunotherapy. METHODS: The serum phase was extracted from centrifuged latex that was repeatedly freeze-thawed or glycerinated. Quantitation of latex allergens was performed by two-site immunoenzymetric assays. The abundance of RNA transcripts of the latex allergens was estimated from the number of their clones in an Expressed Sequence Tags library. RESULTS: The latex allergens, Hev b 1, 2, 3, 4, 5, 6, 7 and 13, were detected in freeze-thawed and glycerinated latex serum at levels ranging from 75 (Hev b 6) to 0.06 nmol/mg total proteins (Hev b 4). Hev b 6 content in the latex was up to a thousand times higher than the other seven latex allergens, depending on source and/or preparation procedure. Allergen concentration was reflected in the abundance of mRNA transcripts. When used as the antigen, latex serum may bias the outcome of latex allergy diagnostic tests towards sensitization to Hev b 6. Tests that make use of latex serum may fail to detect latex-specific IgE reactivity in subjects who are sensitized only to allergens that are present at low concentrations. CONCLUSION: Latex allergy diagnostics and immunotherapy that use whole latex serum as the antigen source may not be optimal because of the marked imbalance of its constituent allergens.

The psychosocial impact of serological diagnosis of asymptomatic herpes simplex virus type 2 infection.

OBJECTIVES: To evaluate the impact of a positive herpes simplex virus type 2 (HSV-2) serological test on psychosocial functioning among people with no known history of genital herpes. METHODS: Individuals (age 14-30 years) without a history of genital herpes were recruited from an urban university setting and sexually transmitted diseases (STD), primary care, and adolescent clinics. Participants completed a questionnaire addressing psychological functioning, psychosocial adjustment, and perceived quality of sex and were offered free HSV-2 antibody testing. 33 HSV-2 positive people and 60 HSV-2 negative people demographically matched from the same source of recruitment were re-evaluated at a 3 month follow up visit. HSV-2 positive participants also completed a genital herpes quality of life (GHQOL) measure. RESULTS: Of the 33 who were HSV-2 seropositive, four did not recall their diagnosis. In comparing those who were HSV-2 positive with those who were negative, repeated measures analysis of variance indicated there were no significant differences over time on any of the measures. None the less, many HSV-2 positive individuals indicated that the diagnosis had a notable impact on their quality of life. Also, among the HSV-2 positive people, lower GHQOL at the 3 month follow up was predicted by higher interpersonal sensitivity (r = -0.44, p<0.05), lower social support (r = 0.40, p<0.05), and quality of sex (r = 0.62, p<0.01) at baseline. CONCLUSIONS: A diagnosis of asymptomatic HSV-2 infection does not appear to cause significant lasting psychological difficulties. Those for whom the diagnosis had the greatest impact were interpersonally vulnerable before the diagnosis. These results suggest that assessment of interpersonal distress may be important to include as part of pretest and post-test counselling.

A rotavirus vaccine for infants: the Asian experience.

INTRODUCTION: Severe rotavirus gastroenteritis in children causes significant morbidity worldwide and substantial deaths in developing countries. Hence, a live attenuated vaccine Rotarix was developed with human strain RIX4414 of G1P1A P[8] specificity. RIX4414 trials in infants have begun in developed and developing countries worldwide. An overview of RIX4414 in developed and developing countries and prospects with this vaccine in Asia are presented. METHODS: Completed RIX4414 trials have been reviewed. RESULTS: Two oral doses of RIX4414 were well tolerated with a reactogenicity profile similar to placebo. RIX4414 was also highly immunogenic, e.g., in a dose-ranging study conducted in Singapore, 98.8% to 100% of infants had a vaccine take after 2 doses. RIX4414 did not affect the immune response of simultaneously administered routine infant vaccines. RIX4414 significantly reduced severe rotavirus gastroenteritis in settings where multiple serotypes including the emerging G9 type co-circulated. CONCLUSION: These encouraging results warrant further evaluation of the vaccine worldwide and especially in developing countries with the highest need. Therefore, evaluation of the Rotarix vaccine is continuing in large phase III trials in Asia and worldwide.

Attitudes about human papillomavirus vaccine among family physicians.

STUDY OBJECTIVE: Human papillomavirus (HPV) vaccines will soon be available for clinical use, and the effectiveness of vaccine delivery programs will depend largely upon whether providers recommend the vaccine. The objectives of this study were to examine family physicians' attitudes about HPV immunization and to identify predictors of intention to recommend immunization. DESIGN: Cross-sectional survey instrument assessing provider and practice characteristics, knowledge about HPV, attitudes about HPV vaccination, and intention to administer two hypothetical HPV vaccines. PARTICIPANTS: Surveys were mailed to a national random sample of 1,000 American Academy of Family Physicians (AAFP) members. MAIN OUTCOME MEASURE: Intention to administer two hypothetical HPV vaccines (a cervical cancer/genital wart vaccine and a cervical cancer vaccine) to boys and girls of different ages. RESULTS: One hundred fifty-five surveys (15.5%) were returned and 145 were used in the final sample. Participants reported higher intention to recommend both hypothetical HPV vaccines to girls vs. boys (P < 0.0001) and to older vs. younger adolescents (P < 0.0001). They were more likely to recommend a cervical cancer/genital wart vaccine than a cervical cancer vaccine to boys and girls (P < 0.001). Variables independently associated with intention (P < 0.05) included: female gender of provider, knowledge about HPV, belief that organizations such as the AAFP would endorse vaccination, and fewer perceived barriers to vaccination. CONCLUSIONS: Female gender, knowledge about HPV, and attitudes about vaccination were independently associated with family physicians' intention to recommend HPV vaccines. Vaccination initiatives directed toward family physicians should focus on modifiable predictors of intention to vaccinate, such as HPV knowledge and attitudes about vaccination.

Acceptability of human papillomavirus self testing in female adolescents.

OBJECTIVES: To develop scales assessing acceptability of human papillomavirus (HPV) testing in adolescents, to compare acceptability of self to clinician testing, and to identify adolescent characteristics associated with acceptability. METHODS: Female adolescents 14-21 years of age attending a hospital based teen health centre self collected vaginal samples and a clinician, using a speculum, collected cervicovaginal samples for HPV DNA. Acceptability of and preferences for self and clinician testing were assessed at baseline and 2 week visits. RESULTS: The mean age of the 121 participants was 17.8 years and 82% were black. The acceptability scales demonstrated good internal consistency, reliability, test-retest reliability, and factorial validity. Scores were significantly lower for self testing than clinician testing on the acceptability scale and three subscales measuring trust of the test result, confidence in one's ability to collect a specimen, and perceived effects of testing (p < 0.01). Of those who reported a preference, 73% preferred clinician to self testing. Acceptability scores for both self and clinician testing increased significantly pre-examination to post-examination (p < 0.01). Multivariable analyses demonstrated that race was independently associated with pre-examination and post-examination acceptability of self testing, and that sexual behaviours and gynaecological experiences were associated with specific acceptability subscales. CONCLUSIONS: This sample of adolescents found clinician testing for HPV to be more acceptable than self testing and preferred clinician to self testing. If self testing for HPV is offered in the future, clinicians should not assume that adolescent patients will prefer self testing. Instead, they should educate adolescents about available testing options and discuss any concerns regarding self collection technique or accuracy of test results.

Gender-specific predictors of genital herpes vaccine acceptance in a college population.

Vaccines represent one promising method for reducing the sexually transmitted disease (STD) epidemic. This study evaluated whether influences on the decision to accept a genital herpes vaccine differed by gender. In all, 518 college students completed a questionnaire on sexual history, health beliefs, and acceptance of a potential genital herpes vaccine. Each predictor variable plus a gender interaction term were analysed in separate logistic regression models. Follow-up analyses were performed by gender for outcomes that displayed significant interactions. Results indicated that a prior history of an STD and increased perception of risk for acquiring genital herpes were significant predictors of vaccine acceptance for men, while younger age and concerns about vaccine safety were significant predictors for women. Endorsement of a vaccine strategy targeting sexually experienced people was an influential factor for both genders, but was a much stronger one for women. Results suggest that gender-specific strategies may be crucial to genital herpes vaccine acceptance.

Treatment with intranasal fluticasone propionate significantly improves ocular symptoms in patients with seasonal allergic rhinitis.

BACKGROUND: If monotherapy with an intranasal corticosteroid can alleviate both nasal and ocular symptoms of allergic rhinitis, treatment may be simplified and costs may be reduced. OBJECTIVE: The purpose of this study was to evaluate the efficacy of once-daily fluticasone propionate (FP) aqueous nasal spray 200 microg compared with vehicle placebo and oral loratadine (LOR) 10 mg in reducing ocular symptoms associated with seasonal allergic rhinitis. METHODS: A total of 471 patients received vehicle placebo, LOR, or FP in this multi-centre, double-blind, double-dummy, randomized study. Patients were > or =12 years old with a history of seasonal allergic rhinitis and a positive skin test for a relevant allergen. During the baseline and treatment periods, patients rated the severity of eye itching, tearing, and redness via visual analogue scales that ranged from 0 (no symptoms) to 100 (most severe symptoms). The three ocular ratings were added to derive the total ocular symptom score (TOSS). Patients with a TOSS > or =120 on at least 4 of the 7 days before the randomization visit were enrolled. The primary outcome was the difference between FP and vehicle placebo in the mean change from baseline in the reflective TOSS overall (averaged over the 28-day treatment period). A difference between FP and vehicle placebo of 25.5 was considered clinically significant. RESULTS: The overall mean change from baseline in the TOSS was significantly greater in the FP group compared with vehicle placebo (clinically significant difference of 28.8; P<0.001) and compared with LOR (difference of 16.2; P=0.028). Overall mean (SEM) changes were -59.9 (5.4) for the placebo group, -72.5 (5.4) for the LOR group, and -88.7 (5.3) for the FP group. The FP treatment group also showed significantly greater overall mean changes in ocular itching, tearing, and redness compared with vehicle placebo (P<0.001) and compared with LOR (P< or =0.045). CONCLUSION: Patients treated with intranasal FP had clinically and statistically significant decreases in ocular symptom scores compared with vehicle placebo. Data also suggest that FP reduced ocular symptoms more than or comparable with oral LOR. Patients experiencing ocular symptoms associated with allergic rhinitis may benefit from monotherapy with intranasal FP.

Evaluations of unformulated and formulated dendrimer-based microbicide candidates in mouse and guinea pig models of genital herpes.

Prevention of sexually transmitted infections is a priority in developed and developing countries. One approach to prevention is the use of topical microbicides, and one promising approach is the use of dendrimers, highly branched macromolecules synthesized from a polyfunctional core. Three new dendrimer products developed to provide stable and cost-efficient microbicides were initially evaluated in vitro for anti-herpes simplex virus activity and then in vivo by using a mouse model of genital herpes. From these experiments one product, SPL7013, was chosen for further evaluation to define the dose and duration of protection. Unformulated SPL7013 provided significant protection from genital herpes disease and infection at concentrations as low as 1 mg/ml and for at least 1 h following topical (intravaginal) administration of 10 mg/ml. This compound was then formulated into three vehicles and further evaluated in mouse and guinea pig models of genital herpes infection. In the murine evaluations each of the formulations provided significant protection at concentrations of 10 and 50 mg/ml. Formulated compounds provided protection for at least 1 h at a concentration of 10 mg/ml. From these experiments formulation 2V was chosen for dose ranging experiments using the guinea pig model of genital herpes. The guinea pig evaluations suggested that doses of 30 to 50 mg/ml were required for optimal protection. From these studies a lead compound and formulation (2V of SPL7013) was chosen for ongoing evaluations in primate models of simian immunodeficiency virus and Chlamydia trachomatis infection.

Comparison of mometasone furoate administered by metered dose inhaler with beclomethasone dipropionate.

This study compared the efficacy and safety of mometasone furoate (MF) administered by metered dose inhaler (MDI) 56, 200 or 500 pg b.i.d., with beclomethasone dipropionate (BDP) 168 microg b.i.d. and placebo. Adult patients (n=395), with moderate persistent asthma (FEV1 50-90% of predicted normal), previously maintained on inhaled corticosteroids, were enrolled at 16 centres in a four-week, randomised, double-blind, double-dummy, multicentre, dose-ranging trial. At endpoint, FEV1 was significantly improved (p<0.01) with MF-MDI 56, 200 and 500 microg b.i.d., as well as with BDP (6%, 13%, 14% and 4%, respectively), compared with placebo (-12%). Mean change in FVC, FEF2575%, and a.m. and p.m. peak expiratory flow rate (PEFR) were also significantly improved for all active treatment groups at endpoint compared with placebo. Asthma symptoms and quality of life (SF-36) related to physical functioning improved with active treatments relative to placebo. All doses of MF-MDI were well tolerated. Treatment with MF-MDI 200 pg b.i.d. was superior to BDP MDI 168 microg b.i.d. or MF-MDI 56 microg b.i.d., with no additional benefit derived from a higher MF-MDI 500 microg b.i.d. dose. MF-MDI was well tolerated, with superior efficacy compared with BDP MDI in these patients with moderate persistent asthma.

Double-blind, randomized, placebo-controlled study of topical 5% acyclovir-1% hydrocortisone cream (ME-609) for treatment of UV radiation-induced herpes labialis.

Immunopathology is recognized as an important component of infectious disease manifestations, and corticosteroids have been used as an adjunct to antimicrobial therapy for a variety of conditions. Antiviral therapy of herpes labialis has been shown to result in only a small reduction in the time to healing and the duration of pain. To determine if topical application of a combination product containing 5% acyclovir and 1% hydrocortisone (ME-609) could provide benefit to herpes labialis patients, 380 immunocompetent adults with a history of herpes labialis were exposed to experimental UV radiation (UVR) to induce a recurrence. On day 2, just before the appearance of the majority of lesions ("delayed" lesions), subjects were randomized to receive active medication or vehicle control six times per day for 5 days. Overall, 120 of 380 patients developed delayed classical lesions, of whom 50 of 190 (26%) had been treated with ME-609 and 70 of 190 (37%) had received placebo (a reduction of 29% [P = 0.02]). Healing time, measured as the time to normal skin, was reduced by treatment with ME-609 (9.0 days for treated patients versus 10.1 days for the controls [P = 0.04]). There was a trend toward a reduction in the maximum lesion size in the ME-609 recipients compared to that in the controls (43 versus 60 mm(2), respectively [P = 0.07]). The treatment had no effect on lesion pain, but ME-609 treatment reduced the number of patients with moderate or severe tenderness. Compared to treatment with a placebo, treatment with the combination antiviral-immunomodulatory cream provided benefit to patients with experimental UVR-induced herpes labialis, reducing classical lesion incidence, healing time, lesion size, and lesion tenderness. ME-609 is a novel product that merits further evaluation as a treatment for cold sores.