Two-Hour Nasal Responses after a Single Dose of Ephedrine Nasal Spray in Healthy Males.

Background: Ephedrine is often used as nasal decongestant. Yet, the clinical study of intranasal ephedrine is scarce. In addition, the study tools may affect the measurement of the nasal patency. This problem has not been concerned. Objective: To investigate the nasal responses after using a single-dose of calibrated ephedrine nasal spray in Thai healthy male volunteers. The study also compared the differences between two methods of nasal patency measurement. Material and Method: Healthy males (n = 20) were recruited in a randomized, crossover, 2-day study. Each day was studied for anterior rhinomanometry (RN) or peak nasal inspiratory flow (PNIF). On test day, subjects were given ephedrine nasal spray, and measured by the specific tool for two hours. In addition, the visual analogue scale (VAS), cardiovascular (CVS) parameters, and adverse drug reactions were examined. Results: A single-dose ephedrine nasal spray significantly changed the nasal airway resistance (NAR), PNIF, and VAS at 5-minute. The NAR via RN was maximally decreased by 43.74±16.3% at 10-minute and returned to baseline at 90-minute. While, PNIF was maximally increased by 31.20±18.4% at 10-minute and returned to baseline at 60-minute. The nasal responses measured by two methods were significantly different at 5-, 15-, and 45-minute. VAS for nasal patency showed significant increases throughout the study period. CVS effects were negligible. Bitter taste was the most common adverse event reported. Conclusion: Ephedrine nasal spray is a fast-onset, short-acting decongestant. The decongestant effect of the drug varied by study tools. The variations appeared on the degree of nasal response and duration of action. The drug was generally safe.

Bioequivalence study of donepezil hydrochloride tablets in healthy male volunteers.

The objective of this study was to investigate the bioequivalence of two formulations of 5 mg donepezil HCL tablets: Tonizep as the test and Aricept as the reference. The two products were administered as a single oral dose according to a randomized two-phase crossover with a 3-week washout period in 20 healthy Thai Male volunteers. After drug administration, serial blood samples were collected over a period of 216 hours. Plasma donepezil concentrations were measured by high performance liquid chromatography with UV detection. Pharmacokinetic parameters were analyzed based on noncompartmental analysis. The logarithmically transformed data of AUC(0-∞) and C(max) were analyzed for 90% confidence intervals (CI) using ANOVA. The mean (90% CI) values for the ratio of AUC(0-∞) and C(max) values of the test product over those of the reference product were 1.08 (1.02-1.14) and 1.08 (0.99-1.17), respectively (within the bioequivalence range of 0.8-1.25). The median T(max) for the test product was similar to that of the reference product (2.0 hr), and the 90% CI for the T(max) difference between the two preparations was -0.19 to 0.29 hr and within the bioequivalence range of ± 20% of the T(max) of the reference formulation. Our study demonstrated the bioequivalence of the two preparations.

Role of SHIP-1 in the adaptive immune responses to aeroallergen in the airway.

BACKGROUND: Th2-dominated inflammatory response in the airway is an integral component in the pathogenesis of allergic asthma. Accumulating evidence supports the notion that the phosphoinositide 3-kinase (PI3K) pathway is involved in the process. We previously reported that SHIP-1, a negative regulator of the PI3K pathway, is essential in maintaining lung immunohomeostasis, potentially through regulation of innate immune cells. However, the function of SHIP-1 in adaptive immune response in the lung has not been defined. We sought to determine the role of SHIP-1 in adaptive immunity in response to aeroallergen stimulation in the airway. METHODOLOGY/PRINCIPAL FINDINGS: SHIP-1 knockout (SHIP-1-/-) mice on BALB/c background were immunized with ovalbumin (OVA) plus aluminum hydroxide, a strong Th2-inducing immunization, and challenged with OVA. Airway and lung inflammation, immunoglobulin response, Th2 cytokine production and lymphocyte response were analyzed and compared with wild type mice. Even though there was mild spontaneous inflammation in the lung at baseline, SHIP-1-/- mice showed altered responses, including less cell infiltration around the airways but more in the parenchyma, less mucus production, decreased Th2 cytokine production, and diminished serum OVA-specific IgE, IgG1, but not IgG2a. Naïve and OVA sensitized SHIP-1-/- T cells produced a lower amount of IL-4. In vitro differentiated SHIP-1-/- Th2 cells produced less IL-4 compared to wild type Th2 cells upon T cell receptor stimulation. CONCLUSIONS/SIGNIFICANCE: These findings indicate that, in contrast to its role as a negative regulator in the innate immune cells, SHIP-1 acts as a positive regulator in Th2 cells in the adaptive immune response to aeroallergen. Thus any potential manipulation of SHIP-1 activity should be adjusted according to the specific immune response.

Pharmacokinetics and bioequivalence study of the two 20-mg quinapril hydrochloride tablet formulations in healthy Thai male volunteers.

OBJECTIVE: To determine the pharmacokinetics and bioequivalence of two 20-mg quinapril hydrochloride tablet preparations; Quinaril (The Biolab Ltd, Bangkok, Thailand) as the test and Accupril as the reference. MATERIAL AND METHOD: The present study was a single dose, randomized two-period crossover design conducted in 24 healthy volunteers under fasting conditions with a 7-day washout period. Serial plasma concentrations of quinapril and its active metabolite quinaprilat up to 24 h after dosing were determined by HPLC with UV detection. The pharmacokinetic parameters were analyzed by noncompartmental analysis and the ANOVA was carried out using logarithmically transformed data of the AUC and C as well as untransformed T(max). RESULTS: There were no significant differences between the two preparations regarding the T(max) of quinapril and quinaprilat and their median T(max) were 0.5 h and 1.4 - 1.5 h, respectively. The half-life of quinapril (1.2 h) was faster than quinaprilat (1.8-1.9 h) although the volume of distribution (Vd/F) of quinapril (1.1 L/kg) was larger than quinaprilat (0.3 L/kg), however, its clearance rate (CL/F) was faster when compared to quinaprilat (20-26 ml/min/kg vs. 1.7 ml/min/kg). The mean (90% CI) for the ratios Reference/Test of quinapril were 0.99 (0.89-1.10), 0.99 (0.90-1.09) and 1.01 (0.90-1.14), respectively for AUC(0-24), AUC(0-infinity) and C(max). Similarly, the corresponding values for quinaprilat were 0.95 (0.90-1.01), 0.95 (0.90-1.01) and 1.03 (1.00-1.07), respectively. These values were within the bioequivalence range of 0.80 - 1.25, thus, demonstrated the bioequivalence of the two preparations. CONCLUSION: The results of the present study indicated that the two quinapril HCL preparations are bioequivalent and it can be assumed that they are therapeutically equivalent and exchangeable in clinical practice.

TLR-dependent IL-4 production by invariant Valpha14+Jalpha18+ NKT cells to initiate contact sensitivity in vivo.

LPS stimulated B-1 cell polyclonal in vivo IgM responses depend on IL-4 release by invariant Valpha14+Jalpha18+ NKT (iNKT) cells. The IgM Abs can recruit effector T cells to mediate contact sensitivity. LPS activates the B-1 cell response just 1 day later, and depends on CD1d, iNKT cells, IL-4, TLR4, and MyD88. LPS in vivo and in vitro stimulates rapid preferential production of IL-4 in hepatic iNKT cells within 2 h. TLR4 were demonstrated in iNKT cells by flow cytometry and functional studies. Thus, innate microbial stimulation via TLR can activate iNKT cell and B-1 cell collaboration. The result is polyclonal IgM Ab responses capable of recruiting Ag-specific T cells into tissues. This may be involved in the promotion of autoimmunity by infectious agents.

Alpha-galactosylceramide-induced iNKT cells suppress experimental allergic asthma in sensitized mice: role of IFN-gamma.

Allergic asthma is a multifaceted syndrome consisting of eosinophil-rich airway inflammation, bronchospasm, and airway hyper-responsiveness (AHR). Using a mouse model of allergic asthma, we previously reported that invariant NKT (iNKT) cells increase the severity of this disease. Herein, we demonstrate that a single i.v. injection of alpha-galactosylceramide (alpha-GalCer), 1 h before the first airway allergen challenge of OVA-sensitized mice, abrogates elicitation of AHR, airway eosinophilia, IL-4 and IL-5 production in bronchoalveolar lavage fluid, and specific anti-OVA IgE antibodies. Further, alpha-GalCer administered intranasally also strongly inhibited the major symptoms of asthma in sensitized and challenged mice. Alpha-GalCer treatment induces iNKT cell accumulation in the lungs, and shifts their cytokine profile from pro-asthmatic IL-4 to a protective IFN-gamma production. The role of IFN-gamma from iNKT cells in protection was shown by adoptive transfer of sorted iNKT cells from OVA-sensitized and alpha-GalCer-treated mice which protected immunized recipients from manifesting asthma by an IFN-gamma-dependent pathway. Our findings demonstrate for the first time that alpha-GalCer administered locally inhibits asthma symptoms, even in predisposed asthmatic mice, through an iNKT cell- and IFN-gamma-dependent pathway.

Comparative efficacy of wheal-and-flare suppression among various non-sedating antihistamines and the pharmacologic insights to their efficacy.

BACKGROUND AND OBJECTIVE: Non-sedating antihistamines (loratadine, fexofenadine, and cetirizine) have been widely used in Thailand. This study examined the time-of-onset and compared the 95% inhibitory effect of these agents on histamine-induced cutaneous reaction so as to understand the diversity of their efficacy. PATIENTS AND METHOD: Thirty-one atopic patients were randomized into 4 treatment groups, placebo (n = 7), loratadine (n = 8), fexofenadine (n = 8), and cetirizine (n = 8). They were pricked with histamine every 30 min for 4 hrs. The percentage change of the wheal/flare area was calculated. RESULTS: All active treatments showed wheal suppression superior to placebo after 210 min for loratadine (P = 0.04); 90 min for fexofenadine (P = 0.009); and 60 min for cetirizine (P = 0.02), while flare suppression was significantly marked after 150 min (P = 0.0008) for loratadine; 90 min for fexofenadine (P = 0.0001), and 60 min for cetirizine (P = 0.006). All drugs except loratadine demonstrated a 95% suppression of wheal superior to the placebo (P = 0.001 for fexofenadine; P = 0.0001 for cetirizine). Only fexofenadine exhibited a 95% suppression of flare statistically superior to placebo (P = 0.02). Discrepancies among the effects of these 3 antihistamines were also detected. DISCUSSION AND CONCLUSION: All antihistamines tested repressed the wheal-and-flare area superbly over the placebo within 4 hours. Cetirizine exerted the fastest onset, and it also appeared to be the most efficacious inhibitor. The heterogeneity of their efficacy probably stems from their diverse physicochemical properties, which have also been discussed.