Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies.

BACKGROUND AND OBJECTIVES: Fostamatinib is a spleen tyrosine kinase inhibitor that has been investigated as therapy for rheumatoid arthritis and immune thrombocytopenic purpura. The present studies assessed the potential for pharmacokinetic interaction between fostamatinib and the commonly prescribed medications oral contraceptive (OC), warfarin, and statins (rosuvastatin, simvastatin) in healthy subjects. METHODS: The OC study was a crossover study over two 28-day treatment periods (Microgynon(®) 30 plus placebo or fostamatinib). Concentrations of OC constituents (ethinyl estradiol/levonorgestrel) were measured. Effects on warfarin pharmacokinetics and pharmacodynamics were assessed (21-day study). Warfarin was administered on days 1 and 14, fostamatinib on days 8-20. The statin study was a two-period, fixed-sequence study of the effects of fostamatinib on exposure to rosuvastatin or simvastatin (single doses). Safety was assessed throughout. RESULTS: Fostamatinib co-administration with OC increased exposure to ethinyl estradiol [area under the plasma concentration-time curve at steady state (AUCss) 28% [confidence interval (CI 90%) 21-36]; maximum plasma concentration (Cmax) at steady state (Cmax,ss) 34% (CI 26-43)], but not levonorgestrel (AUCss 5%; Cmax,ss -3%), while exposure to luteinizing hormone and follicle-stimulating hormone decreased (≈ 20%). Fostamatinib did not affect the pharmacokinetics/pharmacodynamics of warfarin to a clinically relevant extent, but caused an upward trend in AUC for both R- and S-warfarin [18% (CI 13-23) and 13% (CI 7-19)]. Fostamatinib increased rosuvastatin AUC by 96% (CI 78-115) and Cmax by 88% (CI 69-110), and increased simvastatin acid AUC by 74% (CI 50-102) and Cmax by 83% (CI 57-113). CONCLUSION: Fostamatinib exhibits drug-drug interactions when co-administered with OC, simvastatin, or rosuvastatin, with the AUC of statins almost doubling. Fostamatinib did not exhibit a clinically relevant DDI on warfarin.

Platynosomum fastosum-induced chronic intrahepatic cholangitis and Spirometra spp. infections in feral cats from Grand Cayman.

The occurrence of platynosomiasis and intestinal sparganosis is described in feral cats from Grand Cayman, Cayman Islands. Spirometra spp. was observed within the intestine of 18.18% (10/55) of cats; 1.18% (1/55) of cats demonstrated gross and histological manifestation of parasitism by Platynosomum fastosum, but 14.5% (8/55) of cats had the characteristic pathological manifestations of P. fastosum-induced intrahepatic cholangitis without the concomitant presence of the intraductal trematode. Combined parasitism (Spirometra spp. and P. fastosum) was observed in 9.09% (5/55) of feral cats. Significant pathological findings were only associated with the hepatic fluke, P. fastosum, and were grossly characterized by moderate hepatomegaly with enlarged and dilated bile ducts. Examples of cestodes with morphological features characteristic of Spirometra spp. were observed within the small intestine without any associated pathological lesion. The histopathological evaluation of liver fragments revealed chronic intrahepatic cholangitis with and without the associated intraductal trematode, and was characterized by marked periductal fibrosis, adenomatous proliferation of bile duct epithelium, dilation of intrahepatic bile ducts and portal accumulations of inflammatory cells. The occurrence of the cestode in feral cats coupled with factors that are unique to Grand Cayman makes this island the ideal location for sporadic cases of human sparganosis.

Functional recovery following musculoskeletal injury in hospital workers.

BACKGROUND: Hospital workers are at high risk of work-related musculoskeletal disorders (WRMSDs), but outcomes following such injuries have not been well studied longitudinally. AIMS: To ascertain functional recovery in hospital workers following incident WRMSDs and identify predictors of functional status. METHODS: Cases (incident WRMSD) and matched referents from two hospitals were studied at baseline and at 2 year follow-up for health status [SF-12 physical component summary (PCS)], lost workdays, self-rated work effectiveness and work status change (job change or work cessation). Predictors included WRMSD and baseline demographics, socio-economic status (SES), job-related strain and effort-reward imbalance. Logistic regression analysis tested longitudinal predictors of adverse functional status. RESULTS: The WRMSD-associated risk of poor (lowest quartile) PCS was attenuated from a baseline odds ratio (OR) of 5.2 [95% confidence interval (CI) 3.5-7.5] to a follow-up OR of 1.5 (95% CI 1.0-2.3) and was reduced further in multivariate modelling (OR = 1.4; 95% CI 0.9-2.2). At follow-up, WRMSD status did not predict significantly increased likelihood of lost workdays, decreased effectiveness or work status change. In multivariate modelling, lowest quintile SES predicted poor PCS (OR = 2.0; 95% CI 1.0-4.0) and work status change (OR = 2.5; 95% CI 1.1-5.8). High combined baseline job strain/effort-reward imbalance predicted poor PCS (OR = 1.7; 95% CI 1.1-2.7) and reduced work effectiveness (OR = 2.6; 95% CI 1.6-4.2) at follow-up. CONCLUSIONS: Baseline functional deficits associated with incident WRMSDs were largely resolved by 2 year follow-up. Nonetheless, lower SES and higher combined job strain/effort-reward imbalance predicted adverse outcomes, controlling for WRMSDs.

Co-administration of ketoconazole with H1-antagonists ebastine and loratadine in healthy subjects: pharmacokinetic and pharmacodynamic effects.

AIMS: Two studies were conducted to evaluate the effects of coadministration of ketoconazole with two nonsedating antihistamines, ebastine and loratadine, on the QTc interval and on the pharmacokinetics of the antihistamines. METHODS: In both studies healthy male subjects (55 in one study and 62 in the other) were assigned to receive 5 days of antihistamine (ebastine 20 mg qd in one study, and loratadine 10 mg qd in the other) or placebo alone using a predetermined randomization schedule, followed by 8 days of concomitant ketoconazole 450 mg qd/antihistamine or ketoconazole 400 mg qd/placebo. Serial ECGs and blood sampling for drug analysis were performed at baseline and on study days 5 (at the end of monotherapy) and 13 (at the end of combination therapy). QT intervals were corrected for heart rate using the formula QTc = QT/RR(alpha) with special emphasis on individualized alpha values derived from each subject's own QT/RR relationship at baseline. RESULTS: No significant changes in QTc interval from baseline were observed after 5 days administration of ebastine, loratadine or placebo. Ketoconazole/placebo increased the mean QTc (95% CI) by 6.96 (3.31-10.62) ms in the ebastine study and by 7.52 (4.15-10.89) ms in the loratadine study. Mean QTc was statistically significantly increased during both ebastine/ketoconazole administration (12.21 ms; 7.39-17.03 ms) and loratadine/ketoconazole administration (10.68 ms; 6.15-15.21 ms) but these changes were not statistically significantly different from the increases seen with placebo/ketoconazole (6.96 ms; 3.31-10.62 ms), P = 0.08 ebastine study, (7.52 ms; 4.15-10.89 ms), P = 0.26 loratadine study). After the addition of ketoconazole, the mean area under the plasma concentration-time curve (AUC) for ebastine increased by 42.5 fold, and that of its metabolite carebastine by 1.4 fold. The mean AUC for loratadine increased by 4.5 fold and that of its metabolite desloratadine by 1.9 fold following administration of ketoconazole. No subjects were withdrawn because of ECG changes or drug-related adverse events. CONCLUSIONS: Ketoconazole altered the pharmacokinetic profiles of both ebastine and loratadine although the effect was greater for the former drug. The coadministration of ebastine with ketoconazole resulted in a non significant mean increase of 5.25 ms (-0.65 to 11.15 ms) over ketoconazole with placebo (6.96 ms) while ketoconazole plus loratadine resulted in a nonsignificant mean increase of 3.16 ms (-2.73 to 8.68 ms) over ketoconazole plus placebo (7.52 ms). Changes in uncorrected QT intervals for both antihistamines were not statistically different from those observed with ketoconazole alone. The greater effect of ketoconazole on the pharmacokinetics of ebastine was not accompanied by a correspondingly greater pharmacodynamic effect on cardiac repolarization.

Deposition and pharmacokinetics of an HFA formulation of triamcinolone acetonide delivered by pressurized metered dose inhaler.

Novel formulations of asthma drugs contained in pressurized metered dose inhalers (pMDIs) are being developed containing hydrofluoroalkane (HFA) propellants. The objectives of this study were to assess the deposition in the lungs and oropharynx of triamcinolone acetonide (TAA; Azmacort, Aventis Pharma, Collegeville, PA) delivered by pMDI formulated with HFA-134a, together with the pharmacokinetic profile of TAA, and to determine the extent to which the Azmacort spacer improves targeting of TAA to the lungs. The deposition of TAA, labelled with 99mTc, was assessed by gamma scintigraphy in 10 patients with mild to moderate asthma (mean forced expiratory volume in one second [FEV1] 76% predicted), who received in randomized order three delivered (ex-device) doses of 75 microg TAA via pMDI coupled to an Azmacort spacer (TAA-spacer), and three delivered doses of 230 microg TAA via the same device, but with the spacer removed (TAA-no spacer). Mean lung deposition expressed as mass of drug was similar for each regimen (TAA-no spacer 175 microg; TAA-spacer 188 microg), but when expressed as percentage delivered dose, lung deposition was higher for TAA-spacer (53.8%) versus TAA-no spacer (26.0%), indicating superior drug targeting for TAA-spacer. The spacer reduced oropharyngeal deposition. The pharmacokinetic data showed higher plasma levels of drug for TAA-no spacer, resulting from higher oropharyngeal deposition. "Pharmacoscintigraphic" data showed proof of concept for a novel HFA delivery system for an inhaled corticosteroid based on pulmonary targeting of drug.

Effects of supratherapeutic doses of ebastine and terfenadine on the QT interval.

AIMS: The objective of this study was to compare the effects of high doses of ebastine with terfenadine and placebo on QTc. METHODS: Thirty-two subjects were randomly assigned to four treatments (ebastine 60 mg x day(-1), ebastine 100 mg x day(-1), terfenadine 360 mg x day(-1), placebo) administered for 7 days. Serial ECGs were performed at baseline and day 7 of each period. QT interval was analysed using both Bazett (QTcB) and Fridericia (QTcF) corrections. RESULTS: Ebastine 60 mg (+ 3.7 ms) did not cause a statistically significant change in QTcB compared with placebo (+ 1.4 ms). The mean QTcB for ebastine 100 mg was increased by + 10.3 ms which was significantly greater than placebo but was significantly less (P < 0.05) than with terfenadine 360 mg (+ 18.0 ms). There were no statistically significant differences in QTcF between ebastine 60 mg (-3.2 ms) or ebastine 100 mg (1.5 ms) and placebo (-2.1 ms); although terfenadine caused a 14.1 ms increase which was significantly different from the other three treatments. The increase in QTcB with ebastine most likely resulted from overcorrection of the small drug-induced increase in heart rate. CONCLUSIONS: Ebastine at doses up to five times the recommended therapeutic dose did not cause clinically relevant changes in QTc interval.

Effect of age and gender on the pharmacokinetics of ebastine after single and repeated dosing in healthy subjects.

OBJECTIVES: Ebastine is a potent and selective H1-receptor antagonist indicated for allergic rhinitis which undergoes extensive first pass metabolism by CYP3A4 to form an active metabolite, carebastine. The purpose of the study was to determine age- and gender-related differences in the pharmacokinetics of ebastine and carebastine. METHODS: The upper recommended oral dose of 20 mg once daily was administered to 12 healthy young (22 to 38 years) and 12 healthy elderly (50 to 92 years; 8 m and 4 f) subjects for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours following the initial dose on Day 1 and for 72 hours following the dose on Day 5 using a sensitive LC/MS/MS assay. The minimum quantifiable limit (MQL) for the assay was 0.05 ng/ml and 1.0 ng/ml for ebastine and carebastine, respectively. RESULTS: Mean area under the curve and Cmax values on Day 1 and Day 5 were similar for ebastine but approximately doubled for carebastine due to its longer half-life. Mean carebastine concentrations were approximately 10 to 20 fold higher than mean ebastine concentrations. For young subjects, the mean (%CV) ebastine t(1/2) was 5.76 (28.47) h and 20.38 (46.19) h on Day 1 and Day 5, respectively. Similarily, for young subjects, the mean (%CV) for carebastine t(1/2) was 7.03 (23.21) h and 26.12 (23.39) h on Day 1 and Day 5, respectively. This apparent prolongation of t(1/2) was probably due to lack of proper estimation of terminal half-life on Day 1 as fewer samples were collected for a shorter duration on Day 1. Using a multicomparison test for Cmin values, it was determined that steady state conditions were achieved by Day 5 for both age groups for ebastine and in young subjects for carebastine. The variability in ebastine pharmacokinetic parameters was higher than carebastine. A 50% increase in ebastine AUC(0-24) and Cmax values in elderly subjects, with no changes in t(1/2), could be explained by either increased absorption of ebastine in elderly subjects or due to a decrease in first pass metabolism. As ebastine shows a high first-pass effect, even a small change in this first pass can cause large changes in plasma exposure. The ebastine pharmacokinetic parameters for elderly subjects in this study lie between the values reported in young subjects in earlier studies. Hence, the apparent age-related pharmacokinetic difference for ebastine is probably due to the inherent variability in ebastine pharmacokinetics. There were no gender-related differences in either young or elderly subjects for mean AUC, Cmax, tmax and t(1/2) ebastine and carebastine values. Ebastine was absorbed rapidly with a median tmax of 1.25 to 2.25 h for both healthy young and elderly males and females on Day 1 and Day 5. There was a delayed appearance of carebastine as expressed by median tmax of 4.0 to 5.0 h, which did not change with age, gender or repeated administration. There were no clinically relevant differences between the groups of subjects with respect to adverse events or safety parameters. CONCLUSIONS: Thus, ebastine can be safely administered to elderly subjects with no clinically important age- or gender related differences in the pharmacokinetics of ebastine/carebastine.

In vitro and in vivo techniques used in drug development for evaluation of dose delivery of inhaled corticosteroids.

Oral inhaled corticosteroids are important in the treatment of asthma since their delivery is targeted directly to the lung, which is the site of action. Triamcinolone acetonide (TAA) is an effective and safe corticosteroid that is marketed as a metered-dose inhaler (MDI) with an integrated spacer (Azmacort) for the treatment of asthma. Due to the phasing out of chlorofluorocarbon (CFC) propellants, Azmacort has been reformulated with a non-CFC propellant. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation of oral inhaled MDIs requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies to ensure clinical comparability for both efficacy and safety. This paper describes a chronological series of studies designed to support the reformulation of Azmacort. These included in vitro studies to estimate respirable fraction, in vivo pulmonary deposition studies, in vivo pharmacokinetic-pharmacodynamic studies to estimate the systemic effects of each formulation, and final clinical studies in adult and pediatric patients to confirm the clinical comparability of the new formulation of Azmacort. The results of these studies, performed at various stages during the development of new formulations, were critical in guiding the reformulation efforts for Azmacort.

Absence of pharmacokinetic interaction between orally co-administered naproxen sodium and diphenhydramine hydrochloride.

The potential for a pharmacokinetic interaction between naproxen and diphenhydramine was examined in a randomized three-way crossover design with a 1-week washout between dosing. Single oral doses of 220 mg of naproxen sodium and 50 mg of diphenhydramine hydrochloride were given separately and together to 30 healthy male and female subjects. Heparinized blood samples obtained for 48 h postdose were assayed for plasma naproxen and diphenhydramine concentrations using validated high-performance liquid chromatography (HPLC) and gas chromatography (GC) assay methods, respectively. The area under the plasma concentration-time curve (AUC), maximum plasma concentrations (C(max)), time of C(max) (T(max)) and terminal exponential half-life (t(1/2,z)), were analysed for significant treatment differences by analysis of variance (ANOVA). Based on absence of significant treatment effects on AUC and C(max), single-dose oral co-administration of 220 mg of naproxen sodium with 50 mg of diphenhydramine hydrochloride does not alter the pharmacokinetics of either naproxen or diphenhydramine. Significant treatment differences seen for naproxen T(max) (0.3 h, males only) and diphenhydramine t(1/2,z) (0.8 h, females only) were minor and are unlikely to have therapeutic consequences. Thus, efficacy and safety of concomitant naproxen and diphenhydramine should not be altered due to a pharmacokinetic interaction.

A review of the cardiac systemic side-effects of antihistamines: ebastine.

The cardiac safety of ebastine, a long-acting, non-sedating antihistamine, has been thoroughly assessed in phase I-III clinical studies. Ebastine alone at the recommended doses of 10 mg and 20 mg has no clinically relevant effect on QTc interval in adults and in special patient populations (elderly, children or subjects with hepatic or renal impairment). Ebastine administered at 60 and 100 mg/day (3-5 times the maximum recommended dose) for 1 week had statistically significantly smaller effects (3.7 and 10.3 msec, respectively) on the QTc interval than terfenadine (18 msec) at three times the recommended dose (360 mg/day). The mean QTc interval prolongation observed with ebastine 100 mg/day was small and not clinically meaningful, although the results were statistically significant vs. placebo. The effect of ebastine 60 mg/day was not statistically different from placebo. Steady-state drug interaction studies demonstrated that the co-administration of ebastine 20 mg with ketoconazole or erythromycin produced significant increases in systemic exposure for ebastine, which were accompanied by small increases in QTc (approximately 10 msec above ketoconazole or erythromycin alone). Results from individual studies suggest that, when coadministered with ketoconazole, ebastine produces similar changes in QTc interval measurements compared to loratadine and cetirizine. Pooled data from clinical efficacy trials of ebastine 1-30 mg/day administered for 2-3 weeks showed no clinically relevant cardiac effects as assessed by serial electrocardiographs and Holter monitoring. The overall cardiac safety profile based on currently available information suggests that ebastine, like loratadine and cetirizine, has a lower potential for causing adverse cardiovascular effects than terfenadine.

Injuries from construction falls. Functional limitations and return to work.

Finding a measure that distinguishes well between the severity levels of less serious injuries such as those found in occupational settings has been problematic. In this study of 255 construction workers who sustained nonfatal falls at work, two measures of injury severity were used--the Injury Severity Score (ISS) and the disability index of the Stanford Health Assessment Questionnaire (HAQ), a functional limitation measure. The HAQ scores were more normally distributed than the ISS and provided useful information about the degree to which workers were disabled from falls during their first week of recovery. The mean HAQ score was 1.46 (SD = 0.75) on a scale of 0 to 3, with higher numbers representing more limited functioning. With regard to individual tasks, participants reported having the most difficulty performing heavy chores (mean = 1.89; SD = 1.02), dressing themselves (mean = 1.54; SD = 1.05), and bending to pick up clothing from the floor (mean = 1.40; SD = 1.02). The HAQ scores were significantly and moderately correlated with days lost from work (r = .52; p < .001). Unexpectedly, 97 workers reported that they were able to return to light or modified duty following their falls.

Injury severity associated with nonfatal construction falls.

This study evaluated injury severity in a group of construction workers who sustained nonfatal falls at work. The sample consisted of 255 adults who were identified from Doctor's First Reports (DFRs) submitted to the California Department of Industrial Relations. For those that fell from heights (n = 195), the mean height of fall was 9.2 feet (SD = 7.1). The mean number of lost work days was 44.3 days (SD = 58.6) and the median was 10 days. Two measures of injury severity were used--the Injury Severity Score and the disability section of the Health Assessment Questionnaire (HAQ). Seventeen participants (7%; 95% CI, 4-10%) were deemed permanently disabled. A simultaneous multiple regression model, using five independent variables, explained approximately 21% of the variance in HAQ scores. Nonunion status and safety climate scores indicating increased risk were positively correlated with higher functional limitation as measured by HAQ scores, as were greater heights and impact on concrete surface. Higher scores on both injury severity measures were significantly and moderately associated with a greater number of days lost from work. These findings suggest that injury severity and permanent disability associated with falls in construction are notable, and identify key target areas for intervention and prevention.

Surveillance and investigation of homicides at work: California fatality assessment and control evaluation program.

The authors describe California's Fatality Assessment and Control Evaluation program, a state-based surveillance and investigation program for traumatic occupational fatalities. FACE has identified occupational homicides as a priority for targeted prevention efforts to reduce the incidence of work-related fatalities.

Predictors of carbon monoxide and hydrogen cyanide exposure in smoke inhalation patients.

OBJECTIVE: A prospective study of civilian (nonfirefighter) smoke inhalation patients was carried out to test the hypotheses that: 1) absorption of carbon monoxide and hydrogen cyanide from smoke can be predicted by clinical examination and historical data; and, more specifically 2) a history of exposure to burning synthetic polymers is an important predictor of systemic cyanide levels. METHODS: The study was conducted over a three-year period at six urban hospitals. Patients with or without burns who were exposed to smoke within five hours of hospital arrival were sampled for carboxyhemoglobin, whole blood cyanide, urine cotinine and urine creatinine. Controls consisted of a smaller group of smoking status-matched, nonsmoke-exposed burn patients. ANALYSIS: Historical information was obtained on SMOKING status, FIRETYPE (structural vs other), MATERIAL burned (natural vs synthetic) and LAGTIME (from exposure to sampling). A smoke inhalation SCORE (0-10) was assigned to each case, based on physical examination findings and changes on chest X ray, and carboxyhemoglobin and cyanide levels were entered into various multivariate linear regression models. RESULTS: A total of 40 cases and 9 controls were recruited, ranging in age from 15 to 92 years. Thirty-four cases were discharged alive and six expired in-hospital. Observed carboxyhemoglobin levels ranged from 1.2% to 41.6% in cases (mean 8.6%), and from 0.5 to 7.3% in controls (mean 2.9%). Observed cyanide levels ranged from nondetectable (< 0.05 micrograms/mL) to 2.79 micrograms/mL in cases (mean 0.25 micrograms/mL), and from nondetectable to 0.11 micrograms/mL in controls (mean 0.03 micrograms/mL). Among cases, linear regression models explained up to 35% of the observed variance in carboxyhemoglobin levels (p < 0.001) and up to 48% of the variance in cyanide levels (p = 0.0001). CONCLUSIONS: SCORE was the strongest predictor of both carboxyhemoglobin and cyanide levels; LAGTIME also explained significant variance for [log-transformed] carboxyhemoglobin. Historical factors, such as FIRETYPE, MATERIAL, and SMOKING status, did not explain significant variance in most of the statistical models employed.

Work disability in adults with cystic fibrosis.

Greater numbers of persons with cystic fibrosis (CF) reach adulthood and, therefore, actively participate in the labor force. In this study, we estimated labor force participation rates and determined risk factors for work disability among persons with CF. We recruited 49 (73%) of 67 adults followed at one of two hospital-based CF centers. We ascertained employment history and CF-attributed work disability by structured questionnaire. Independently, we reviewed medical records for demographics and illness severity indicators. We analyzed potential risk factors for work disability by logistic regression analysis. All of those studied reported past or present labor force participation, consistent with high work motivation. Complete cessation of work attributed to CF was reported by 17 (35%; 95% CI, 21 to 49%). Although 23 (47%; 95% CI, 32 to 60%) of those surveyed stated that CF had affected career choice, only nine respondents had ever received career counselling and 16 had ever discussed job choice with their physicians. After adjusting for standard measures of disease severity by multiple logistic regression, age, adult diagnosis of CF, female gender, and single marital status, analyzed as a group, provided significant additional explanatory power to a predictive model of disability risk (model chi square [4 d.f.] = 11.5, p < 0.05). Health care professionals who design interventions targeted at work disability among persons with CF should address demographic factors as well as illness severity and should assess the vocational needs of persons with CF and the potential benefit of career counselling.

The effect of RP 59227, a platelet-activating factor antagonist, against antigen challenge and eosinophil and neutrophil chemotaxis in asthmatics.

STUDY OBJECTIVES: Platelet-activating factor (PAF), an inflammatory mediator, induces microvascular leak, eosinophil chemotaxis, and possibly increases non-specific bronchial hyperresponsiveness in humans. PAF antagonists may have clinical benefits in asthma. DESIGN: We determined the safety and efficacy of a 240 mg oral dose of RP-59227 in attenuating the early and late phase antigen challenge in eight asthmatics, using a double-blind, placebo-controlled, crossover design. Also determined was the effect of the ex vivo addition of PAF following placebo or drug and the level of neutrophil (NCA) and eosinophil chemotactic activity (ECA) in the serum immediately, and 4 h after antigen challenge with either drug or placebo. RESULTS: There was not a significant difference in the maximum percent fall in FEV1 during the early and late phase on screening or placebo days or drug RP-59227 days. There was a significant inhibitory effect (p < 0.05) in peak ECA and NCA in blood after RP-59227. The addition of PAF to ex vivo serum was less effective in inducing chemotaxis to eosinophils following RP-59227 (p < 0.05). CONCLUSIONS: RP-59227 attenuated the release of NCA and ECA after antigen challenge, and reduced the effect of exogenously added PAF in inducing eosinophil chemotaxis but did not protect against the antigen-induced early or late phase response.

HIV/AIDS training for health care providers working with women at risk.

Diagnosis of HIV/AIDS in women is frequently inadequate. Often women are not assessed for risk behaviors that put them at risk for HIV infection. Viral transmission is preventable through behavioral changes. Past experience has demonstrated that one effective method to educate women at risk is to train direct care providers who work with women. Highly skilled providers with expertise in prevention education strategies can facilitate and support behavioral changes in women at risk for HIV transmission.