Safety considerations in the management of allergic diseases: focus on antihistamines.

OBJECTIVE: To conduct a systematic review of evidence supporting the safety profiles of frequently used oral H(1)-antihistamines (AHs) for the treatment of patients with histamine-release related allergic diseases, e.g. allergic rhinitis and urticaria, and to compare them to the safety profiles of other medications, mostly topical corticosteroids and leukotriene antagonists (LTRA). RESEARCH DESIGN AND METHODS: Systematic search of the published literature (PubMed) and of the regulatory authorities databases (EMA and FDA) for oral AHs. RESULTS: Similarly to histamine, antihistamines (AHs) have organ-specific efficacy and adverse effects. The peripheral H(1)-receptor (PrH1R) stimulation leads to allergic symptoms while the brain H(1)-receptor (BrH1R) blockade leads to somnolence, fatigue, increased appetite, decreased cognitive functions (impaired memory and learning), seizures, aggressive behaviour, etc. First-generation oral AHs (FGAHs) inhibit the effects of histamine not only peripherally but also in the brain, and additionally have potent antimuscarinic, anti-α-adrenergic and antiserotonin effects leading to symptoms such as visual disturbances (mydriasis, photophobia, and diplopia), dry mouth, tachycardia, constipation, urinary retention, agitation, and confusion. The somnolence caused by FGAHs interferes with the natural circadian sleep-wake cycle and therefore FGAHs are not suitable to be used as sleeping pills. Second-generation oral AHs (SGAHs) have proven better safety and tolerability profiles, much lower proportional impairment ratios, with at least similar if not better efficacy, than their predecessors. Only SGAHs, and especially those with a proven long-term (e.g., ≥12 months) clinical safety, should be prescribed for young children. Evidence exist that intranasally applied medications, like intranasal antihistamines, have the potential to reach the brain and cause somnolence. CONCLUSIONS: Second-generation oral antihistamines are the preferred first-line treatment option for allergic rhinitis and urticaria. Patients taking SGAHs report relatively little and mild adverse events even after long-term continuous treatments. An antihistamine should ideally possess high selectivity for the H(1)-receptor, high PrH1R occupancy and low to no BrH1R occupancy.

Efficacy of natural L-asparagine in the complex therapy for malignant tumors in experimental studies.

AIM: To study the influence of natural L-asparagine on the efficacy of cytostatic therapy for malignant tumors in experimental investigations. MATERIALS AND METHODS: Female C57B1/6 mice weighing 18-20 g were selected for the experiments. Lewis' lung carcinoma (LLC) and melanoma B16 cells were used in the study. Animals were inoculated with tumor cells intramuscularly. Solution of L-asparagine in a volume of 0.2 ml per mouse (in appropriate doses) was administered to the animals using gastric probe, daily, for 14 days. Cyclophosphane was administered intraperitoneally in total doses of 180 mg/kg and 90 mg/kg on days 3 and 7 after tumor implantation. The percentage of tumor growth inhibition was calculated and inhibition index and frequency of metastasis were assessed. RESULTS: It has been shown that despite low activity of L-asparagine with regard to primary tumor, the level of metastasis inhibition is rather high (up to 91% depending on experimental model, therapy regimen and follow-up period). The analysis of previously obtained data and our studies indicate that L-asparagine derived from burdock (Arctium lappa) root has not only its own antimetastatic activity but it is also able to increase antimetastatic activity of cyclophosphane partially reducing toxic effect of cyclophosphane on the organism without decreasing its antitumor and antimetastatic activities. CONCLUSION: L-asparagine derived from burdock (Arctium lappa) root can be effective in the complex anticancer therapy with the use of appropriate chemotherapy doses and regimens.

Improving SAR symptoms with levocetirizine: evaluating active and placebo effects in pollen challenge vs. natural exposure studies.

OBJECTIVE: Despite a plethora of published data on levocetirizine, no meta-analyses exist on the effect of study design, and covariates like age, gender, and baseline symptom severity on treatment response. The objective of this study was the efficacy of levocetirizine 5 mg tablets and matching placebo at reducing allergy symptoms in adult subjects with seasonal allergic rhinitis under various pollen exposure study conditions and by age, gender and baseline symptom severity. METHODS: This was a meta-analysis of original reports from randomized, double-blind, placebo-controlled studies. Clinical studies without detailed reports, open-label, non-randomized and non-controlled studies, or paediatric studies, were excluded. Study subjects were divided into an environmental exposure (EE) group or a natural exposure (NE) group. RESULTS: Data from 3640 subjects were analysed (n = 2174 for levocetirizine, n = 1466 for placebo). The overall results confirmed the efficacy of levocetirizine 5 mg, with an approximately 40% symptom score improvement from baseline, in both the EE and NE groups. While levocetirizine showed no gender- or age-related differences in efficacy, female subjects responded better to placebo in the EE, but not in the NE group; younger subjects (<30 years of age) responded less favourably to placebo compared with older subjects (≥ 50 years of age). Levocetirizine was consistently superior to placebo regardless of baseline symptom score levels. The highest significance levels between the active and placebo groups were observed in subjects sensitized to animal dander and grass. CONCLUSIONS: Differences between an oral antihistamine and placebo in clinical studies of allergic rhinitis might be due to a different response to placebo rather than to the active drug. Levocetirizine seems to have consistent efficacy regardless of age, gender, and baseline scores.