Jodan D. Ratz

Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU)

The Environmental Exposure Unit, an indoor pollen challenge system to test anti‐allergic medications, was used to compare the onset and duration of action and the efficacy of levocetirizine and desloratadine, two recently developed H1‐antagonists. In this double‐blind, placebo‐controlled, parallel‐group study, qualified subjects were randomised to once‐daily levocetirizine 5 mg (n = 141), desloratadine 5 mg (n = 140) or placebo (n = 92) and exposed to ragweed pollen on two consecutive days (7 h and 6 h). Symptoms were self‐rated every 30 min. On both days, levocetirizine produced a greater improvement in the major symptom complex score (primary efficacy variable) than desloratadine (p = 0.015); both were better than placebo (p < 0.001). Levocetirizine acted earlier (1 h vs. 3 h) and produced greater symptom relief at 24 h than desloratadine (p = 0.003). Levocetirizine also alleviated nasal obstruction better than desloratadine (p = 0.007) on day 1; and better than placebo (p = 0.014) after the second dose on day 2, which was not observed with desloratadine. Levocetirizine and desloratadine were safe and well tolerated.

Efficacy of levocetirizine compared with montelukast in subjects with ragweed-induced seasonal allergic rhinitis in the Environmental Exposure Unit.

Levocetirizine dihydrochloride, a potent H1-receptor antagonist, and montelukast sodium, a selective leukotriene receptor antagonist, have been approved for the treatment of seasonal allergic rhinitis (SAR), but target two different pathways that cause SAR symptoms. The study objective was to compare the efficacy of levocetirizine (LCTZ), 5 mg, and montelukast (MLKT), 10 mg, in reducing SAR symptoms in ragweed-sensitive adults exposed to ragweed pollen in the Environmental Exposure Unit (EEU). This randomized, double-blind, placebo-controlled, parallel-group study of 418 adult subjects with SAR to ragweed compared the efficacy of LCTZ, MLKT, and placebo administered once daily (11:00 A.M.) for 2 consecutive days in the EEU. There were three evaluation periods: period I, 0-5 hours after first dose; period II, 22.5-24 hours after first dose; and period III, 0-4.5 hours after second dose. The primary efficacy variable was the Major Symptom Complex (MSC) score (six symptoms) over period I. Both active drugs significantly improved the MSC score compared with placebo in all periods. The adjusted mean MSC score difference between LCTZ and MLKT was -0.93 (p = 0.100) in period I, -3.11 (p < 0.001) in period II, -2.42 (p < 0.001) in period III, and -1.88 (p < 0.001) over the total treatment period. The same trends were observed for the Total Symptom Complex score (10 symptoms) and most individual symptoms. Subject-reported global satisfaction was greater for LCTZ compared with MLKT and placebo. All treatments had a favorable safety profile. LCTZ, 5 mg, was more effective than MLKT, 10 mg, in subjects with SAR and had better subject-reported global satisfaction.

Neuroprotection against ischemic brain injury conferred by a novel nitrate ester

Nitrates exhibit a selectivity of action in different tissue types not fully recognized: in particular, the neuromodulatory and cardiovascular properties can be dissociated. A novel nitrate showed relatively weak systemic effects, but in the middle cerebral artery occlusion rat model of focal ischemia, reduced the cerebral infarct by 60-70% when administered 4 h after the onset of ischemia.

Onset of action of loratadine/montelukast in seasonal allergic rhinitis subjects exposed to ragweed pollen in the Environmental Exposure Unit.

Onset of action is recognized as an important pharmacologic property of allergic rhinitis (AR) medications. This study was designed to evaluate the onset of action of loratadine/montelukast (L/M; 10 mg/10 mg) versus placebo in subjects with ragweed-induced seasonal AR (SAR). A single-center, double-blind, parallel-group study of ragweed-sensitive AR subjects (n = 310) was performed in the Environmental Exposure Unit (EEU). Subjects were exposed to ragweed pollen in the EEU and symptoms were recorded at 30, 60, 90, and 120 minutes before a single dose of L/M or placebo. After dosing, symptoms were recorded for 4 hours, at 15-minute intervals for the first 2 hours and at 30-minute intervals for the final 2 hours. The primary end point was time to onset of action of L/M, defined as the first time point at which the mean change from baseline in total symptom score (TSS) for L/M became and remained significantly better than placebo. Secondary end points included nasal congestion scores and peak nasal inspiratory flow (PNIF). The onset of action of L/M for TSS was 1 hour and 15 minutes (p = 0.005 versus placebo). L/M reduced nasal congestion as indicated by significant improvements in both the nasal congestion score (p = 0.011) and the PNIF measurements (p = 0.007) within 1 hour and 15 minutes postdose. The incidence of treatment-emergent adverse events was similar between groups. The onset of action after treatment with L/M was 1 hour and 15 minutes for TSS, as well as nasal congestion. L/M was well tolerated.

Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate

We have shown previously that the D‐ and L‐ enantiomers of isoidide dinitrate (D‐IIDN and L‐IIDN) exhibit a potency difference for relaxation and cyclic GMP accumulation in isolated rat aorta and that this is related to preferential biotransformation of the more potent enantiomer (D‐IIDN). The objective of the current study was to examine the effect of the flavoprotein inhibitor, diphenyleneiodonium sulphate (DPI), on the enantioselectivity of IIDN action. In isolated rat aortic strip preparations, exposure to 0.3 μM DPI resulted in a 3.6 fold increase in the EC50 value for D‐IIDN‐induced relaxation, but had no effect on L‐IIDN‐induced relaxation. Incubation of aortic strips with 2 μM D‐ or L‐IIDN for 5 min resulted in significantly more D‐isoidide mononitrate formed (5.0±1.5 pmol mg  protein−1) than L‐isoidide mononitrate (2.1±0.7 pmol mg protein−1) and this difference was abolished by pretreatment of tissues with 0.3 μM DPI. DPI had no effect on glutathione S‐transferase (GST) activity or GSH‐dependent biotransformation of D‐ or L‐IIDN in the 105,000×g supernatant fraction of rat aorta. Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 μM DPI significantly inhibited D‐IIDN‐induced cyclic GMP accumulation, but had no effect on L‐IIDN‐induced cyclic GMP accumulation. In the intact animal, 2 mg kg−1 DPI significantly inhibited the pharmacokinetic and haemodynamic properties of D‐IIDN, but had no effect L‐IIDN. These data suggest that the basis for the potency difference for relaxation by the two enantiomers is preferential biotransformation of D‐IIDN to NO, by an enzyme that is inhibited by DPI. Given that DPI binds to and inhibits NADPH‐cytochrome P450 reductase, the data are consistent with a role for the cytochromes P450‐NADPH‐cytochrome P450 reductase system in this enantioselective biotransformation process.