Francis M. Cuss

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log10 of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04–0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.

Th2 cytokines and asthma. The role of interleukin-5 in allergic eosinophilic disease.

Interleukin-5 is produced by a number of cell types, and is responsible for the maturation and release of eosinophils in the bone marrow. In humans, interleukin-5 is a very selective cytokine as a result of the restricted expression of the interleukin-5 receptor on eosinophils and basophils. Eosinophils are a prominent feature in the pulmonary inflammation that is associated with allergic airway diseases, suggesting that inhibition of interleukin-5 is a viable treatment. The present review addresses the data that relate interleukin-5 to pulmonary inflammation and function in animal models, and the use of neutralizing anti-interleukin-5 monoclonal antibodies for the treatment of asthma in humans.

Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle.

1 In human airways synthetic human sequence calcitonin gene‐related peptide (hCGRP), a novel peptide produced by alternative processing of mRNA from the calcitonin gene, caused concentration‐dependent contraction of human bronchi (EC50 4.9 × 10−9 m) and was significantly more potent than substance P or carbachol. 2 The contractile response was unaffected by atropine (2 × 10−6 m), propranolol (10−6 m), indomethacin (10−5 m), tetrodotoxin (3 × 10−6 m), chlorpheniramine (10−4 m), cimetidine (10−5 m), or FPL55712 (10−4 m) suggesting a direct effect of CGRP on airways smooth muscle. 3 CGRP was detected in human airways by radioimmunoassay with highest concentrations in cartilaginous airways. 4 CGRP was localised by immunocytochemistry to both nerves and ganglia in human airways. 5 CGRP, is a potent constrictor of human airways and may have important effects on airway function and be implicated in the pathogenesis of bronchial hyper‐responsiveness and asthma.

Biology of interleukin-5 and its relevance to allergic disease

While bronchoconstriction associated with an acute attack is the most prominent feature of asthma, chronic inflammation is the underlying cause (1, 2, 3). Therefore, considerable attention has been focused on the role of chronic pulmonary inflammation in the pathophysiology of asthma, especially as it relates to ongoing airway hyperreactivity. Pulmonary inflammation is characterized by edema, decreased mucociliary clearance, epithelial damage, increased neuronal responsiveness, and bronchoalveolar eosinophilia (2). There are small numbers of eosinophils in the lung tissue of normal subjects, but they accumulate noticeably in the lungs of patients with asthma (2). Eosinophils are produced in the bone marrow from myeloid precursors in response to cytokine activation, and are released from the bone marrow by an appropriate stimulus. Once in the circulation, they rapidly accumulate in tissue, both in the human and in animal models ( 1, 4). Activated eosinophils synthesize and release lipid mediators that can cause edema, bronchoconstriction, and chemotaxis (1). They also secrete enzymes and proteins that can lyse epithelial tissue and are found in the lungs of patients with asthma ( 5 ) . Furthermore, the role of the eosinophil as a protective agent against parasitic infection is somewhat limited (6). Therefore, the eosinophil is an ideal target for selectively inhibiting the tissue damage that accompanies pulmonary inflammation during asthma, without inducing the immunosuppressive consequences that would arise from inhibiting the actions of other inflammatory cells. relevance to

Nociceptin inhibits cough in the guinea‐pig by activation of ORL1 receptors

We studied the central and peripheral antitussive effect of ORL1 receptor activation with nociceptin/orphanin FQ in conscious guinea‐pigs. In guinea‐pig cough studies, nociceptin/orphanin FQ (10, 30, and 90 μg) given directly into the CNS by an intracerebroventricular (i.c.v.) route inhibited cough elicited by capsaicin exposure by approximately 23, 29 and 52%, respectively. The antitussive activity of nociceptin/orphanin FQ (90 μg, i.c.v.) was blocked by the selective ORL1 antagonist [Phe1γ(CH2‐NH)Gly2]nociceptin‐(1‐13)‐NH2 (180 μg, i.c.v.) and J113397 (10 mg kg−1, i.p.) but not by the opioid antagonist, naltrexone (3 mg kg−1, i.p.). Furthermore, intravenous (i.v.) nociceptin/orphanin FQ (1.0 and 3.0 mg kg−1) also inhibited cough approximately by 25 and 42%, respectively. These findings indicate that selective ORL1 agonists display the potential to inhibit cough by both a central and peripheral mechanism, and potentially represent a novel therapeutic approach for the treatment of cough.

Bioavailability and Metabolism of Mometasone Furoate following Administration by Metered‐Dose and Dry‐Powder Inhalers in Healthy Human Volunteers

These studies were conducted to assess the systemic bioavailability of mometasone furoate (MF) administered by both the dry‐powder inhaler (DPI) and the metered‐dose inhaler with an alternate propellant (MDI‐AP). The pharmacokinetics of single doses (400 μg) of MF administered by intravenous (IV) and inhalation routes was assessed in a randomized, three‐way crossover study involving 24 healthy volunteers. In a separate study, 6 healthy subjects were administered a single dose of tritiated (3H‐) MF by DPI, and the radioactivity in blood, urine, feces, and expired air was determined. Following IV administration, MF was detected in all subjects for at least 8 hours postdose. The half‐life (t1/2) following IV administration was 4.5 hours. In contrast, following DPI administration, plasma MF concentrations were below the limit of quantification (LOQ, 50 pg/mL) for many subjects (10 of 24), and the systemic bioavailability by this route was estimated to be less than 1%. Only two plasma samples following MDI‐AP administration had plasma concentrations of MF above the LOQ, indicating no detectable systemic bioavailability in 92% of the subjects. A separate study with 6 healthy male subjects administered a single dose of3H‐MF (200 μCi) by DPI revealed that much of the dose (∼ 41%) was excreted unchanged in the feces (0–72 hours), while that which was absorbed was extensively metabolized. These results indicate that inhaled MF has negligible systemic bioavailability and is extensively metabolized and should therefore be well tolerated in the chronic treatment of asthma.

The Toxicity of SCH 351591, a Novel Phosphodiesterase-4 Inhibitor, in Cynomolgus Monkeys

SCH351591, a novel phosphodiesterase-4 inhibitor under investigation as a potential therapeutic for asthma and chronic obstructive pulmonary disease (COPD), was evaluated in a 3-month rising-dose study in Cynomolgus monkeys. Four groups, containing four monkeys/sex, received vehicle control or rising doses up to 12, 24, or 48 mg/kg of SCH351591 daily. Although initial exposure produced clinical signs of emesis, reduced food intake, and reduced body weight, tachyphylaxis to the emesis allowed dose escalation up to 48 mg/kg/day. Two monkeys died and 3 were sacrificed in moribund condition over the course of the study. Early mortality, involving monkeys dosed with 12 or 24 mg/kg, was attributed to sepsis (2 monkeys) or colon inflammation (3 monkeys). Leukocyte function assays on low- and mid-dose group survivors revealed an inhibition of T lymphocyte proliferation for 12 mg/kg group males and 24 mg/kg group monkeys of both sexes. Necropsy findings, unassociated with early mortality, included reduced size and weight of the thymus, depletion of body fat, red discoloration of the gastric mucosa, and perivascular hemorrhage of the stomach and heart. Stomach and heart gross findings were present in the high-dose group only. Histopathologic lesions, in addition to those attributed to concurrent bacterial infection, included thymic atrophy, serous atrophy of fat, myocardial degeneration and acute to chronic inflammation of small to medium-sized arteries in various organs and tissues including the heart, kidneys, stomach, salivary glands, pancreas, esophagus, gallbladder, and mesentery. The findings of this study demonstrate the potential of a PDE4 inhibitor to alter immunologic response as well as to produce arteriopathy in nonhuman primates.

Dose Ranging Study of Mometasone Furoate (Nasonex) in Seasonal Allergic Rhinitis

BACKGROUND Topical nasal corticosteroids are rapidly gaining acceptance as first-line therapy for seasonal allergic rhinitis, but there is a desire for effective corticosteroids with an improved safety profile over existing products. OBJECTIVE A multicenter, double-blind dose ranging study was conducted to compare the activity and tolerance of four doses of mometasone furoate nasal spray (tradename Nasonex) and placebo in adult patients with seasonal allergic rhinitis. METHODS Four hundred eighty patients with seasonal allergic rhinitis were enrolled and randomized to receive mometasone furoate nasal spray 50 micrograms (n = 96), 100 micrograms (n = 95), 200 micrograms (n = 98) or 800 micrograms (n = 95), or placebo vehicle (n = 95) once daily for 28 days. RESULTS All of the doses of mometasone furoate nasal spray showed activity in reducing the severity of rhinitis. The 200-microgram dose reduced total nasal symptom scores and total symptom scores throughout the study (P < .05 versus placebo vehicle). The 50-microgram dose and the 100-microgram dose showed less consistent activity at early timepoints (days 3 and 7), while the 800 microgram dose did not provide significant additional benefits over the 200-microgram dose. All dose levels were well tolerated CONCLUSION The results of this trial indicate that 200 micrograms once daily is the optimum dose of mometasone furoate nasal spray for the treatment of seasonal allergic rhinitis.

Synthesis and profile of SCH351591, a novel PDE4 inhibitor

The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).

Antihistamine activity, central nervous system and cardiovascular profiles of histamine H1 antagonists: comparative studies with loratadine, terfenadine and sedating antihistamines in guinea‐pigs

Background Sedation limits the clinical utility of classical H, antihistamines. while newer antihistamincs such as loratadine and terfenadine arc non‐sedating. However, clinical use of terfenadine has been associated with rare but severe cardiac arrhythmias, in particular lorsades de pointes.