BACKGROUND:MAP0004 is an investigational orally inhaled dihydroergotamine (DHE) delivered via a TEMPO(®) metered dose inhaler that was effective in the acute treatment of migraine in a large Phase 3 trial. Rapid and consistent absorption of DHE is important for efficacy in the acute treatment of migraine.METHODS:The pharmacokinetic parameters from four recent clinical studies, with doses including the proposed clinical dose of 1.0 mg nominal (0.65 mg emitted) MAP0004, were assessed for the consistency and speed of absorption of DHE.RESULTS:Across these studies, MAP0004 administration resulted in rapid DHE absorption, with a median time of maximum concentration (C(max)) of approximately 10 min. The C(max) and area under the curve from time zero to 2 hr associated with the MAP0004 1.0 mg nominal dose were also similar between the three studies with this dose. C(max) values after 1.0 mg MAP0004 administration were consistently lower than for 1.0 mg intravenous DHE administration, and C(max) appeared to correlate with incidence of nausea. In these studies, DHE absorption through the lung was fast, consistent, and not associated with any unique tolerability issues for this route of administration.CONCLUSIONS:These results provide evidence of the consistency of absorption that can be achieved with the use of an appropriate metered dose inhaler, which may translate into a predictable therapeutic response.

OBJECTIVE:MAP0004 is an investigational product which delivers dihydroergotamine (DHE) through the lung via a breath-synchronized metered dose inhaler. The objective of this study was to compare the acute effects of orally inhaled and intravenous (IV) DHE to placebo on maximum change and area under the curve for pulmonary arterial systolic pressure (PASP).RESEARCH DESIGN AND METHODS:A randomized, double-blind, placebo-controlled, 3-period, crossover study of 24 health adults. Trial registration NCT01089062. Study assessments included pharmacokinetics, electrocardiograms (ECG), and validated echocardiographic (Doppler)-derived measures of PASP by echocardiogram. The primary endpoint was the absolute change in calculated PASP using area under the curve, 0 to 2 hours (AUC(0-2h)).RESULTS:The change in PASP with IV DHE was significantly different than MAP0004 and placebo (AUC(0-2h)2857, 2624, and 2453 mmHg*min, respectively). After a second dose of MAP0004, AUC(0-4h) remained lower with MAP0004 than with a single dose of IV DHE. Adverse events were more common with IV DHE than with MAP0004 or placebo. None of the treatments produced clinically significant changes in PASP or other cardiac parameters. Changes in PASP were significantly smaller with MAP0004 compared with IV DHE.CONCLUSION:These results indicate the effects 1 mg of orally inhaled DHE on the cardiovascular system are less than with 1 mg of IV DHE, and that serial echocardiography can be a useful noninvasive means of assessing acute systemic effects.

BACKGROUND:MAP0004 is an orally inhaled investigational drug containing dihydroergotamine (DHE). Although DHE has been used for 60 years with no reported cardiac arrhythmias, a thorough QT study had not previously been performed with DHE.OBJECTIVE:The objective of this study was to assess the effects of MAP0004 on the QT interval as required for regulatory approval of a new product.METHODS:This randomized, double-blind, placebo-controlled, 3-period crossover study enrolled healthy volunteers. Subjects were assigned to receive, in randomized sequence, MAP0004 at a supratherapeutic dose (3-fold the clinically effective dose) (3.0 mg), moxifloxacin 400 mg, or inactive vehicle, each administered with 1 placebo capsule. Triplicate ECGs were performed continuously at baseline (day 0), before dosing, and over 24 hours after dosing in each treatment period. The effect on the QT interval was assessed using the Fridericia (QTcF) and individualized (QTcI) correction formulas.RESULTS:Fifty-four healthy adults (20 men, 34 women; mean age, 28 years) completed the trial and had measurable plasma levels of DHE after MAP0004 administration. The largest observed mean difference in QTcI between MAP0004 and placebo was 0.08 msec, and the largest 1-sided 95% upper confidence bound was 2.24 msec, both at 30 minutes after dosing. In contrast, moxifloxacin increased the mean QTcI between 9.57 and 11.28 msec relative to placebo, with a 1-sided lower 95% CL between 7.23 and 8.96 msec, confirming that the assay sensitivity was sufficient to detect MAP0004-related effects. Nausea (27.8%) was common following MAP0004 administration but apparently did not influence the QTc interval.CONCLUSIONS:A supratherapeutic dose of MAP0004 was not associated with prolonged QTc intervals. At the proposed clinical dose (1.0 mg), MAP0004 is unlikely to affect the QT interval. MAP0004 and its primary metabolite showed no evidence for prolongation of the QTc interval in healthy subjects according to the criteria required from regulatory agencies. ClinicalTrials.gov identifier: NCT01191723.

La presente invention concerne des compositions et des procedes de realisation d'un inhalateur-doseur pouvant debiter une quantite dosee d'une formulation comprenant un propulseur, a savoir l'hydrofluoroalcane, et des particules de dihydro-ergotamine mesylate, a raison de 0,1 mg a 4 mg de dihydro-ergotamine mesylate. En l'occurrence, les particules de dihydro-ergotamine mesylate presente une distribution cumulee des dimensions des particules de la substance medicamenteuse presentant un diametre volumetrique median d10 > 0,5 µm et un diametre volumetrique median d90 < 0,5 µm.

RationaleDry Eye syndrome affects approximately 9 million Americans and recent data (Ousler et al, Annals of Allergy, November 2004) indicate that some second generation antihistamines (including loratadine) have potential for ocular drying effects. Stimulation of muscarinic receptors is important for tear film production, and the ocular drying effects of commonly used OAs may be due to their off-target, antimuscarinic properties. To determine how frequently OAs are used by patients with highly symptomatic dry eye, we reviewed data from our large dry eye clinical trials.MethodsWe assessed OA use in three large U.S. Phase 3 dry eye trials in 1,725 moderate to severe patients with symptoms and signs of dry eye. We then compared demographic and disease severity factors between OA users and non-users.ResultsA total of 222/1,725 (13%) subjects were taking oral OAs prior to or concurrent with the study. They were fexofenadine (5%), loratadine (4%), cetirizine (3%), and diphenhydramine (2%). Comparing OA users and non-users at baseline, there was no difference in age, gender, corneal staining severity, Schirmer scores, or tear break-up times. The OA users did have significantly higher ocular itch scores (p = 0.005) than non-users. OA users had somewhat higher conjunctival staining scores than non-users (p = 0.062).ConclusionsOA use is common in patients with moderate to severe dry eye syndrome. OAs were apparently not effective in eliminating ocular itch symptoms, and their potential for worsening dry eye is apparently not well-appreciated. RationaleDry Eye syndrome affects approximately 9 million Americans and recent data (Ousler et al, Annals of Allergy, November 2004) indicate that some second generation antihistamines (including loratadine) have potential for ocular drying effects. Stimulation of muscarinic receptors is important for tear film production, and the ocular drying effects of commonly used OAs may be due to their off-target, antimuscarinic properties. To determine how frequently OAs are used by patients with highly symptomatic dry eye, we reviewed data from our large dry eye clinical trials. Dry Eye syndrome affects approximately 9 million Americans and recent data (Ousler et al, Annals of Allergy, November 2004) indicate that some second generation antihistamines (including loratadine) have potential for ocular drying effects. Stimulation of muscarinic receptors is important for tear film production, and the ocular drying effects of commonly used OAs may be due to their off-target, antimuscarinic properties. To determine how frequently OAs are used by patients with highly symptomatic dry eye, we reviewed data from our large dry eye clinical trials. MethodsWe assessed OA use in three large U.S. Phase 3 dry eye trials in 1,725 moderate to severe patients with symptoms and signs of dry eye. We then compared demographic and disease severity factors between OA users and non-users. We assessed OA use in three large U.S. Phase 3 dry eye trials in 1,725 moderate to severe patients with symptoms and signs of dry eye. We then compared demographic and disease severity factors between OA users and non-users. ResultsA total of 222/1,725 (13%) subjects were taking oral OAs prior to or concurrent with the study. They were fexofenadine (5%), loratadine (4%), cetirizine (3%), and diphenhydramine (2%). Comparing OA users and non-users at baseline, there was no difference in age, gender, corneal staining severity, Schirmer scores, or tear break-up times. The OA users did have significantly higher ocular itch scores (p = 0.005) than non-users. OA users had somewhat higher conjunctival staining scores than non-users (p = 0.062). A total of 222/1,725 (13%) subjects were taking oral OAs prior to or concurrent with the study. They were fexofenadine (5%), loratadine (4%), cetirizine (3%), and diphenhydramine (2%). Comparing OA users and non-users at baseline, there was no difference in age, gender, corneal staining severity, Schirmer scores, or tear break-up times. The OA users did have significantly higher ocular itch scores (p = 0.005) than non-users. OA users had somewhat higher conjunctival staining scores than non-users (p = 0.062). ConclusionsOA use is common in patients with moderate to severe dry eye syndrome. OAs were apparently not effective in eliminating ocular itch symptoms, and their potential for worsening dry eye is apparently not well-appreciated. OA use is common in patients with moderate to severe dry eye syndrome. OAs were apparently not effective in eliminating ocular itch symptoms, and their potential for worsening dry eye is apparently not well-appreciated.

P2Y(12) receptors participate in ADP-induced activation and aggregation of human platelets. INS50589, a selective P2Y(12) receptor antagonist, is being developed for use where controlled, reversible modulation of the platelet hemostatic function is needed. The tolerability, pharmacokinetics, and pharmacodynamics of INS50589 were tested in healthy human volunteers. Thirty-six subjects received intravenous infusions of placebo or INS50589 at 0.1-3 mg/kg/h for four hours. Platelet function, clotting parameters, bleeding time, safety assessments, and plasma concentrations of INS50589 and its major metabolite were monitored for 24 hours. Near-steady state plasma concentrations of INS50589 and effects on platelet function were achieved rapidly. The average maximal plasma concentration of INS50589 was linearly related to the dose administered. Intravenous INS50589 produced dose-dependent inhibition of platelet activation and aggregation in response to ADP in vitro until nearly full inhibition was achieved at the higher doses. Bleeding time was correspondingly increased, without any effect on activated clotting time, prothrombin time, or activated partial thromboplastin time. Platelet response to ADP had returned to at least 75% of the baseline value within 0.25-4 h after cessation of the intravenous infusion of INS50589, depending upon the dose and ADP challenge concentration. Infusions were well tolerated up to the highest dose tested. There was no evidence that the principal metabolite ( INS51088) contributed to these effects. INS50589 is a well-tolerated, reversible, competitive antagonist of ADP at the P2Y(12) human platelet receptor, and its potential therapeutic utility in various cardiovascular settings is discussed.

The aim of the present study was to investigate the possible interaction between intracellular Ca2+ and nitric oxide (NO) in rat pancreatic acinar cells, especially intracellular signaling events. (1) Nitric oxide donors SNP (0.1–100 μM) and NOR-3 (50–400 μM) induced Ca2+ oscillations in fluo-4-loaded acini, that appeared to be analogous to what we usually observe in acini stimulated with physiological secretagogues such as CCK-8 and this oscillations were abolished in the presence of carboxy-PTIO. (2) The NO donors-evoked Ca2+ oscillations were not abolished even in the absence of extracellular Ca2+ but totally disappeared when cells were pretreated with thapsigargin, a sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) inhibitor. (3) Inhibition of guanylate cyclase with 1 H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) attenuated Ca2+ oscillations evoked by SNP in the absence of extracellular Ca2+. (4) Inhibitors of phospholipase C activity, U73122 and the IP3R blocker xestospongin C, both abolished the SNP-induced Ca2+ response. (5) Furthermore, we found that both CCK-8 and carbachol (CCh) induced NO production in DAF-2-loaded acinar cells and that an inhibitor of NO synthase, NG-monomethyl-l-arginine (L-NMMA), significantly reduced CCK-8-induced Ca2+ oscillation. These results indicate that NO mobilizes Ca2+ from internal stores through activation of guanylate cyclase and resultant cGMP production. In addition, PLC activation of IP3 production is also suggested to be involved in Ca2+ mobilization via IP3 receptors. This suggests the presence of cross-talk between Ca2+ and NO in pancreatic acini and this cascade may, at least partially, participate in physiological secretagogue-evoked Ca2+ dynamics in pancreatic acinar cells.

The ophthalmic formulation of diquafosol tetrasodium (INS365), a P2Y(2) receptor agonist, is targeted to treat dry eye disease through rehydration of the ocular surface. Existing pharmacological therapies for dry eye disease are limited, therefore, approval of this medication is anticipated. This review summarises key findings during development and in clinical trials including clinical effectiveness and safety. The relevance of P2Y(2) receptor technology to dry eye disease and the disease process is discussed.

Purpose: To investigate the safety and efficacy of diquafosol tetrasodium, a P2Y(2) receptor agonist that stimulates fluid and mucin secretion on the ocular surface, as a novel topical treatment of dry eye disease.Methods: Subjects with dry eye (n = 527) were evaluated in a randomized, double-masked, parallel-group trial comparing 24 weeks of treatment with 2 concentrations of diquafosol (1% and 2%) versus placebo instilled 4 times daily. Corneal staining, conjunctival staining, Schirmer tests, and subjective symptoms of dry eye were evaluated. Use of artificial tears was permitted as necessary.Results: Subjects treated with 2% diquafosol had significantly lower corneal staining scores compared with placebo at the 6-week, primary efficacy time point (P < 0.001), and superiority continued throughout the 24-week study. Reductions in corneal staining were observed as early as after 2 weeks of treatment, were maintained throughout the 24-week study, and were observed to worsen slightly (toward baseline) when diquafosol treatment was discontinued (week 25). Results for conjunctival staining were consistent with those observed for corneal staining. Schirmer scores at week 6 were significantly higher with diquafosol treatment than with placebo (P less than or equal to 0.030). The percentage of subjects with clearing of foreign body sensation (score of 0) was higher at week 6 in subjects treated with 2% diquafosol (21%) compared with placebo (15%), but the difference did not achieve significance (P = 0.193). Significant differences in favor of diquafosol were observed for clearing of foreign body sensation and for worst symptom in secondary data analyses.Conclusion: Diquafosol tetrasodium was well tolerated and was superior to placebo (vehicle) in reducing corneal staining and in relieving certain patient symptoms. Diquafosol has a favorable risk/benefit profile in a broad spectrum of patients with dry eye disease and is a novel topical treatment of dry eye.

Activation of P2Y2 receptors in various tissues results in secretion of ions, fluid and mucin. In situ hybridization experiments on fresh primate tissue confirm the presence of mRNA coding for the gene expression of the P2Y2 receptor in the conjunctiva and the meibomian gland. Topical ocular administration of nucleotides causes increased chloride and mucin secretion, as well as fluid transport. These pharmacologic findings lead to the hypothesis that P2Y2 receptor agonists may have therapeutic efficacy in diseases of impaired ocular hydration.

Third International Conference on the Lacrimal Gland, Tear Film and Dry Eye Syndromes: Basic Science and Clinical Relevance: Maui, Hawaii; November 15-18, 2000: Abstracts

Background: Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma, prospective, long-term, placebo-controlled trials characterizing their systemic safety with chronic use are lacking.Objective: This study was designed to prospectively evaluate the long-term safety of inhaled fluticasone propionate therapy.Methods: Fluticasone propionate powder, 500 mu g, or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind, parallel-groop study. Primary safety variables were measured at baseline and every 6 months thereafter Although evaluation of efficacy was not an objective of this study, pulmonary function testing was performed at monthly intervals.Results: Two years of treatment with fluticasone propionate had no significant effects on the skeletal system. No clinically significant changes were observed in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean change from baseline in lumbar spine (L-1 to L-4) bone density at week 104 was not significantly different between fluticasone propionate (-0.006 +/- 0.008 g/cm(2)) and placebo (-0.007 +/- 0.010 g/cm(2)). Markers of bone formation (serum osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly between treatment groups. The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations (P = .021) and 8-hour plasma cortisol area under the curve values (P = .020) at week 104. Drug-related adverse events were primarily topical effects of inhaled corticosteroids. Pulmonary function improved significantly during 2 years of fluticasone propionate treatment.Conclusion: Fluticasone propionate powder, 500 mu g twice daily for up to 2 years, was efficacious and well tolerated, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone density, or ophthalmic parameters in adults with mild asthma.

Dose-response relationships with inhaled corticosteroids in the treatment of asthma have been difficult to establish. A multicenter, double-blind, parallel-group study was conducted to evaluate the clinical efficacy and safety of low doses of inhaled fluticasone propionate (FP) in patients with mild to moderate asthma. Methacholine challenge testing was conducted in addition to measurement of traditional efficacy variables. After a single-blind screening period, 138 patients > or = 12 years of age were randomly assigned to receive placebo, FP 50 microg, or FP 100 microg, twice daily for 8 weeks. The results of methacholine challenge testing averaged over all visits favored FP 200 microg/day over placebo and FP 100 microg/day (p < 0.05); there were no significant differences between placebo and FP 100 microg/day. Mean changes from baseline to endpoint favored each dose of FP over placebo based on forced expiratory volume in 1 sec (FEV1), patient-measured peak expiratory flow (PEF), total symptom scores, and rescue bronchodilator use (p < 0.05); there were no differences in these parameters between the two doses of FP. The addition of methacholine challenge testing allowed definition of a dose-response relationship that was not apparent with traditional efficacy variables.