Elizabeth A. Field

Developmental Toxicity of Boric Acid in Mice and Rats

Boric acid (BORA), an ingredient of many cosmetics, pharmaceuticals, and pesticides, was tested for developmental toxicity in timed-pregnant Swiss mice and Sprague-Dawley rats (n = 26-28/group). BORA (0, 0.1, 0.2, or 0.4% in feed) was provided throughout gestation to attain steady-state exposure as early as possible during prenatal development. Average doses (mg/kg/day) were 248, 452, or 1003 in mice, and 78, 163, or 330 in rats. To limit prenatal mortality, BORA (0.8% or 539 mg/kg/day) was provided to an additional group of rats on Gestational Days (GD) 6 to 15 only. On GD 17 (mice) or 20 (rats), fetuses were weighed and examined for malformations (external, visceral, skeletal). Mouse dams exhibited mild renal lesions (greater than or equal to 0.1%), increased water intake and relative kidney weight (0.4%), and decreased weight gain (0.4%) during treatment. There was a reduction of fetal body weight (greater than or equal to 0.2%) and an increased incidence of resorptions and malformed fetuses per litter (0.4%). Morphological changes included an increased incidence of short rib XIII (a malformation) and a decreased incidence of rudimentary or full rib(s) at lumbar I (an anatomical variation). Maternal rats exhibited increased liver and kidney weights at greater than or equal to 0.2%, altered water and/or food intake at greater than 0.2%, and decreased weight gain at greater than 0.4%. Average fetal body weight/litter was reduced at all doses. Prenatal mortality was increased only at 0.8%. The incidence of fetal malformations was significantly increased at greater than or equal to 0.2%. The most frequently observed malformations were enlarged lateral ventricles of the brain and agenesis or shortening of rib XIII. In rats, the no-observable-adverse-effect level (NOAEL) for maternal toxicity was 78 mg/kg (0.1%), while in mice the low dose of 248 mg/kg (0.1%) approached the maternal NOAEL with mild renal lesions in only 2 of 10 females. Embryo/fetal toxicity occurred in all groups of rats at greater than or equal to 78 mg/kg (greater than or equal to 0.1%) while the NOAEL for developmental toxicity in mice was 248 mg/kg (0.1%). Thus developmental toxicity occurred below maternally toxic levels in rats as well as in the presence of maternal toxicity in mice and rats.

Fluticasone propionate aqueous nasal spray compared with terfenadine tablets in the treatment of seasonal allergic rhinitis

BACKGROUND Comparative studies with topical corticosteroids and antihistamines for treatment of allergic rhinitis have not always demonstrated clear distinctions between the two on the basis of therapeutic efficacy. OBJECTIVE This study was designed to compare the efficacy and tolerability of fluticasone propionate aqueous nasal spray with those of terfenadine in the treatment of seasonal allergic rhinitis. METHODS Three hundred forty-eight patients with allergic rhinitis were given fluticasone propionate aqueous nasal spray (200 micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 4 weeks in a multicenter, randomized, double-blind, double-dummy, parallel-group study. RESULTS Clinician-rated total nasal symptom scores after 1, 2, 3, and 4 weeks of therapy and patient-rated total nasal symptom scores throughout treatment were significantly (p <0.05) lower in the fluticasone propionate group compared with the terfenadine group or the placebo group. Terfenadine was not statistically different from placebo on the basis of clinician-related nasal symptom scores, except for sneezing. Total nasal airflow, measured by rhinomanometry, significantly (p <0.05) improved in the fluticasone propionate group compared with the terfenadine group or the placebo group. More fluticasone propionate-treated patients compared with placebo-treated patients had reduced nasal mucosal eosinophil counts after 4 weeks of therapy (p <0.05). No serious or unusual drug-related adverse events were reported. Morning plasma cortisol concentrations after 4 weeks of therapy did not differ among groups. CONCLUSION Fluticasone propionate aqueous nasal spray is more effective than terfenadine tablets for treatment of seasonal allergic rhinitis.

Effect of fluticasone propionate aqueous nasal spray versus oral prednisone on the hypothalamic-pituitary-adrenal axis

BACKGROUND Fluticasone propionate is a glucocorticoid with negligible oral bioavailability and very low intranasal bioavailability that is used as an intranasal spray for the treatment of rhinitis. OBJECTIVE The purpose of this study was to evaluate the hypothalamic-pituitary-adrenal (HPA)axis effects of fluticasone propionate aqueous nasal spray (FP ANS) compared with oral prednisone and placebo by using a 6-hour cosyntropin infusion test. METHODS In a 4-week, randomized, double-blind, double-dummy, placebo-controlled parallel-group study, 105 adult patients with allergic rhinitis were randomly assigned to receive FP ANS 200 microg once daily, FP ANS 400 microg twice daily, oral prednisone 7.5 mg once daily, oral prednisone 15 mg once daily, or placebo. HPA-axis function was assessed at the screening visit and after 4 weeks of treatment by measuring morning plasma cortisol concentrations and poststimulation concentrations of plasma and urinary cortisol. RESULTS There was no evidence of altered HPA-axis response to cosyntropin by the end of treatment with FP ANS 200 microg once daily or FP ANS 400 microg twice daily when compared with placebo. In contrast, 4 weeks of treatment with oral prednisone 7.5 or 15 mg once daily was associated with significant (p < 0.05 vs placebo) reduction in HPA-axis function, as evidenced by lower plasma cortisol concentrations (area under the plasma concentration-time curve and peak concentrations) after cosyntropin stimulation and reduced mean 24-hour urinary cortisol excretion. FP ANS 400 microg twice daily and both prednisone regimens were associated with a significant (p < 0.05 vs placebo) reduction in mean morning plasma cortisol concentrations. CONCLUSION These results indicate that a 4-week course of FP ANS at four times the recommended dose does not suppress adrenal function in response to a 6-hour cosyntropin stimulation test.

Developmental toxicity evaluation of acrylamide in rats and mice

Acrylamide (ACRL), a widely used industrial chemical with neurotoxic effects, was evaluated for developmental toxicity. ACRL in distilled water was administered once daily by gavage on gestational days (gd) 6-17 to mice (0, 3, 15, or 45 mg/kg) and on gd 6-20 to rats (0, 2.5, 7.5, or 15 mg/kg). Following termination (gd 17, mice; gd 20, rats) fetuses were examined for external, visceral, and skeletal malformations. Maternal toxicity during treatment was observed at the highest dose as reduced body weight gain in both species and hindlimb splaying in treated mice only. Weight gain corrected for gravid uterine weight was also reduced in rats at 7.5 and 15 mg/kg/day. Embryo/fetal toxicity was not observed in rats, but fetal weight was reduced in mice administered 45 mg/kg/day. No increase in the incidence of malformations was observed in either species; however, the incidence of variations (predominately extra rib) increased with dose. In summary, administration of ACRL during organogenesis produced maternal and developmental toxicity at 45 mg/kg/day in mice and maternal, but not developmental, toxicity at doses greater than or equal to 7.5 mg/kg/day in rats.

The Efficacy of Fluticasone Propionate Aqueous Nasal Spray for Allergic Rhinitis and Its Relationship to Topical Effects

Fluticasone propionate aqueous nasal spray is an intranasal corticosteroid for the treatment of patients with allergic rhinitis. This double-masked, double-dummy, parallel-group study was conducted to confirm that the efficacy of fluticasone propionate nasal spray is attributable to topical rather than systemic effects. A total of 304 patients with documented seasonal allergic rhinitis were randomly assigned to receive fluticasone propionate nasal spray 200 micrograms once daily (n = 77), oral fluticasone propionate 5 mg once daily (n = 73), oral fluticasone propionate 10 mg once daily (n = 77), or placebo (n = 77) for 14 days. Plasma fluticasone propionate concentrations were determined at baseline and after 14 days of treatment (day 15). Nasal symptoms were recorded daily by patients and assessed weekly by clinicians. On day 15, more patients in the oral fluticasone propionate 5-mg or 10-mg groups, compared with patients in the fluticasone propionate nasal spray group or the placebo group, had detectable plasma fluticasone propionate concentrations, and mean concentrations were higher in the oral fluticasone propionate groups. Both clinician- and patient-rated total and individual nasal symptom scores for obstruction, rhinorrhea, sneezing, and itching were significantly lower in the fluticasone propionate nasal spray group compared with either of the oral fluticasone propionate groups or the placebo group. With few exceptions, oral fluticasone propionate (5 mg or 10 mg) was not significantly different from placebo on any measures of efficacy. These findings indicate that the efficacy of fluticasone propionate nasal spray (200 micrograms once daily) in the treatment of allergic rhinitis results from direct topical effects rather than from indirect effects after systemic absorption.

The effect of fluticasone propionate aqueous nasal spray on eosinophils and cytokines in nasal secretions of patients with ragweed allergic rhinitis.

Cytokines active on eosinophils are important in the pathogenesis of allergic diseases. A study was conducted to determine if nasal eosinophilia in allergic rhinitis is associated with an increase in eosinophil-active cytokines in nasal secretions and to compare the effects of fluticasone propionate aqueous nasal spray with astemizole and placebo on the levels of these cytokines. Forty-five patients with moderately severe ragweed allergic rhinitis were randomly assigned to receive 2 weeks of treatment with fluticasone propionate aqueous nasal spray 200 micrograms once daily, astemizole 10 mg once daily, or placebo. Nasal lavage was performed in July (preseason), August (peak season), September (after 2 weeks of treatment), and October (postseason). The number of eosinophils, the amount of eosinophil-derived neurotoxin (EDN), and the amount of eosinophil survival-enhancing activity were measured. Total mean nasal symptom scores, concentrations of nasal eosinophils and EDN, and eosinophil survival-enhancing cytokine activity in nasal secretions were significantly lower after 2 weeks of treatment with fluticasone propionate compared with astemizole or placebo. Survival-enhancing activity was detected in the nasal secretions of 25 patients. By blocking activity with monoclonal antibodies, specific cytokines were identified (granulocyte macrophage-colony stimulating factor, 3 samples; interleukin-3, 2 samples; interleukin-5, 5 samples). In conclusion, eosinophil-active cytokine concentrations parallel the nasal symptoms of patients with ragweed allergic rhinitis. Unlike astemizole, fluticasone propionate significantly lowers cytokine activity in nasal tissue, which may contribute to the therapeutic efficacy of the drug.

Good publication practice for pharmaceutical companies: why we need another set of guidelines

Peer-reviewed publication is an integral part of biomedical research; yet, although the conduct of trials sponsored by pharmaceutical companies is closely regulated by Good Clinical Practice (GCP), their reporting had, until now, no such framework. Journal editors have highlighted the problems that can arise if the relationship between sponsor companies and academic investigators is abused. In particular, they have drawn attention to the issues of non-publication of findings that do not support the sponsor’s marketing aims, and the need for investigators to have full access to the data [1] They have also raised concerns about the role played by