New oral H1 antihistamines in children: facts and unmeet needs.

BACKGROUND: Second-generation antihistamines differ from first-generation ones because of their elevated specificity and affinity for peripheral H1-receptors and because of their lower penetration to the central nervous system, having fewer sedative effects as a result. Over the last few years, new compounds with different pharmacokinetic properties have been synthesized. More recent improvements of the molecules, generally in the form of active metabolites, led to the synthesis of new-generation antihistamines. METHODS: Recommendations on the minimum criteria that would have to be met for compounds to be classified as new-generation antihistamines have been recently established by a consensus statement. In the past, the pharmacokinetics and pharmacodynamics of H1 antihistamines have not been optimally investigated in the pediatric population, especially in infants and young children. RESULTS: The pharmacology of second-generation H1 antihistamines has been investigated relatively deeper than old antihistamines in children. In the pediatric population, clinical studies with new-generation antihistamines are still limited in number and, with rare exceptions, of brief duration. Comparative trials on the efficacy and safety between different compounds are also lacking. CONCLUSIONS: Properly designed, long-term trials with new-generation H1 antihistamines need to be performed in single age groups, in order to better define the effects of these drugs in all pediatric population.

Lack of tolerance to the protective effect of montelukast in exercise-induced bronchoconstriction in children.

The effect over time of regular treatment with montelukast (MNT) in inhibiting exercise-induced bronchoconstriction (EIB) has never been evaluated in children. The aim of the present study was to examine the preventive effect of MNT against EIB in children at different time-points over a 4-week treatment period. Thirty-two asthmatic children (aged 6-12 yrs) were enrolled in a double-blinded, randomised, parallel group design to receive a 4-week treatment with MNT (5 mg chewable tablets administered once daily in the evening) or placebo. Exercise challenge was performed at baseline and after 3, 7 and 28 days of treatment, 20-24 h after dosing. MNT was significantly more protective than placebo against EIB at each time. The mean percentage drop of forced expiratory volume in one second (FEV1) was 24.6, 13.6, 12.0 and 11.6 for MNT, and 24.4, 22.4, 21.8 and 21.0 for placebo, at baseline and after 3, 7 and 28 days, respectively. For each drug, no significant difference in the percentage drop of FEV1 was found between different days. Regular treatment with montelukast provided significant protection against exercise-induced bronchoconstriction in asthmatic children over a 4-week period with no tolerance to the bronchoprotective effect.

Biological effects of montelukast, a cysteinyl-leukotriene receptor-antagonist, on T lymphocytes.

BACKGROUND: Montelukast (MNT), a cysteinyl-leukotriene receptor (Cys-LTR) antagonist, has anti-inflammatory activity in the treatment of allergic diseases. If this effect is due only to blocking leukotrienes or also owing to inhibiting proliferation and survival of inflammatory cells, is actually unknown. OBJECTIVE: Testing the hypothesis that MNT could influence T lymphocyte functional behaviour in vitro. METHODS: Normal T lymphocytes were analysed for surface expression of Cys-LTR(1) and Cys-LTR(2) by means of monoclonal antibodies (mAbs), in the resting state and after activation with T helper type 2 cytokine or T cell receptor (TcR) stimulation. Proliferative activity, as well as IL-4 andIFN-gamma production, were simultaneously determined in samples exposed to molar concentrations of MNT from 10(-8) to 10(-5). Programmed cell death in cultured samples was evaluated by means of propidium iodide and fluorescein isothiocyanate-conjugated anti-Annexin V mAb staining. The complementary DNA microarray technique was adopted to identify gene products involved in apoptosis induction. RESULTS: Resting T cells expressed low levels of Cys-LTR. Upon anti-CD3 mAb activation, a progressive increase in Cys-LTR(1) and -LTR(2) expression was observed. Exposure to MNT reduced proliferative response to TcR engagement, increased IFN-gamma production and led to apoptosis at minimal concentrations of 10(-6) M. A progressive loss in BAD and B cell lymphoma/leukaemia-2 activities, and an increase in the expression of CD27, TRAF3, TRAIL, p53 and Fas genes were also observed. CONCLUSIONS: Biological effects of MNT delineate a complex picture of gene activation and repression, probably induced by Cys-LTR blockade. The induction of apoptosis in allergen-specific T cell population, as a final result, appears fundamental in the treatment of asthma.

Insulin supplement in type 2 diabetic patients with secondary failure to oral agents ameliorates hepatic and peripheral insulin sensitivity but not insulin secretion.

In order to investigate the mechanism of amelioration of metabolic abnormalities with supplementary doses of insulin, islet B-cell function and insulin sensitivity were measured in 10 patients with Type 2 diabetes in secondary failure to oral agents. A small dose of ultralente insulin (0.26 +/- 0.07 U kg-ideal-body-weight-1) was added in the morning before breakfast. After 3 months insulin therapy and progressive improvement of metabolic control (HbA1 from 10.5 +/- 0.4 to 9.0 +/- 0.3% at the end of insulin treatment, p less than 0.001), basal C-peptide and incremental area during an oral glucose tolerance test were unchanged. In vivo peripheral insulin sensitivity (euglycaemic clamp with insulin infusion of 40, 160, and 600 mU m-2 min-1, respectively) was significantly improved (glucose requirement: to 4.7 +/- 1.0 from 3.0 +/- 0.6 mg kg-1 min-1, p less than 0.05 at first insulin level; to 10.8 +/- 0.5 from 9.3 +/- 0.7 mg kg-1 min-1, p less than 0.01 at second level; to 13.3 +/- 0.6 from 11.8 +/- 0.8 mg kg-1 min-1, p less than 0.025 at third level). Basal hepatic glucose production was also significantly reduced (from 4.3 +/- 0.4 to 3.3 +/- 0.3 mg kg-1 min-1, p less than 0.05), and residual glucose production further suppressed after insulin supplement (from 1.1 +/- 0.4 to 0.3 +/- 0.2 mg kg-1 min-1 after 120 min at 100 mU l-1 plasma insulin, p less than 0.05). Specific insulin binding to mononuclear leucocytes was unchanged (from 3.1 +/- 0.3 to 3.5 +/- 0.3%, NS).

Insulin secretion and insulin sensitivity defects are a common feature of mild, clinically homogeneous, recently diagnosed type II (non-insulin-dependent) diabetics.

Alteration in insulin secretion and reduced peripheral sensitivity to the hormone have been reported in type II diabetes. In this paper, a comparison is made of basal glucose production (3H-6 glucose), insulin secretion and insulin sensitivity in vivo (hyperglycemic clamp) and in vitro (binding to circulating monocytes) in 24 patients with recently diagnosed type II diabetes, matched for age and fasting glycemia and divided into non-obese (14 subjects) and moderately obese (10 subjects), and in 9 non-obese controls. The non-obese diabetics were slightly hyperinsulinemic during fasting (10.8 +/- 1.0 vs 4.8 +/- 0.8 microU/ml in controls, p less than 0.0005), with a significant reduction in early and late insulin secretion (14.0 +/- 1.5 vs 20.8 +/- 2.0 microU/ml, p less than 0.01 and 24.8 +/- 3.3 vs 34.7 +/- 2.14 microU/ml, p less than 0.025). The insulin sensitivity index MCR/I was significantly reduced (2.30 +/- 0.32 vs 4.14 +/- 0.40, p less than 0.005). Endogenous glucose production was significantly increased (107 +/- 10.2 vs 84 +/- 3.7 mg/m2 per min, p less than 0.025) and displayed a positive correlation with fasting glycemia (r = 0.51, p less than 0.05). Insulin binding to monocytes was significantly lower than in controls (2.36 +/- 0.22% vs 4.06 +/- 0.32%, p less than 0.0005). Moderately obese diabetics also were significantly hyperinsulinemic in the fasting state (18.1 +/- 2.8 microU/ml, p less than 0.0005 vs controls) but, typically, lacked the early secretory phase (20.6 +/- 3.6 microU/ml vs baseline, n.s.). A similar increase of hepatic glucose production (107 +/- 11.2 mg/m2 per min, p less than 0.025 vs controls, n.s. vs non-obese diabetics) and decrease of peripheral sensitivity to insulin (MCR/I = 1.78 +/- 0.31, p less than 0.0005 vs controls, n.s. vs non-obese diabetics) was found in moderately obese diabetics, as well as a significant reduction of insulin binding to insulated monocytes (2.62 +/- 0.4% p less than 0.01 vs controls, n.s. vs non-obese diabetics). These results confirm that common defects of both non-obese and moderately obese type II diabetics are: lack of early phase of glucose induced insulin secretion, increase in hepatic glucose production and decrease of peripheral insulin sensitivity together with reduction of insulin binding to circulating monocytes. The hypothesis of a unique defect as a cause of hyperglycemia in type II diabetes in early clinical phase is not borne out by the results of this study. Moderate obesity, even if able to reduce insulin sensitivity, seems to be less important in determining hyperglycemia.