Osamu Suga

Antiinflammatory and analgesic activity of a non-peptide substance P receptor antagonist

CP-96,345, a potent non-peptide antagonist of the substance P (SP) receptor, inhibited SP-, neurokinin A (NKA)- and neurokinin B-induced plasma extravasation in guinea pig dorsal skin. The inhibition was specific for the three tachykinins; CP-96,345 was not active against plasma leakage caused by histamine, bradykinin, platelet-activating factor or leukotriene D4. CP-96,345 inhibited capsaicin-induced plasma extravasation in the ureter, an inflammatory response caused by neuropeptides released from afferent C-fibers. Thus, the NK1 receptor appears to play a major role in vascular permeability increases induced by exogenous and endogenous tachykinins. In contrast, CP-96,345 was inactive against SP- and NKA-induced contraction of guinea pig ureter, suggesting that the smooth muscle contraction is not NK1-mediated. CP-96,345 exhibited analgesic activity in acetic acid-induced abdominal stretching in mice, indicating for the first time that SP plays a critical role in this model. The results of these studies support a pathophysiological role of SP and NK1 receptor under acute neurogenic inflammatory conditions and in pain.

Discovery and stereoselective synthesis of the novel isochroman neurokinin-1 receptor antagonist ‘CJ-17,493’

A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine CJ-17,493 (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.

Anti-Emetic Activity of the Novel Nonpeptide Tachykinin NK1 Receptor Antagonist Ezlopitant (CJ-11,974) against Acute and Delayed Cisplatin-Induced Emesis in the Ferret

The anti-emetic effects of a novel tachykinin NK1 receptor antagonist, ezlopitant ((2S,3S-cis)-2-diphenylmethyl)- N--1-azabicyclo- [2.2.2]octan-3-amine), were investigated in ferrets. Ezlopitant inhibited [3H]substance P ([3H]SP) binding to the human, guinea pig, ferret and gerbil NK1 receptors (Ki = 0.2, 0.9. 0.6 and 0.5 nmol/l, respectively), but had no affinity to NK2 and NK3 receptors up to 1 µmol/l. Ezlopitant also inhibited SP-induced contraction of guinea pig trachea with a pA2 value of 7.8, but had no effects on the baseline tension and maximum contractile response. In ferrets, ezlopitant, either orally (0.03–3 mg/kg) or subcutaneously (0.3–3 mg/kg), prevented acute retching and vomiting responses induced by intraperitoneal injection of cisplatin (10 mg/kg). In addition, repeated subcutaneous injection of ezlopitant significantly inhibited delayed retching and vomiting responses that occurred in ferrets treated with the lower dose of cisplatin (5 mg/kg, i.p.). Ezlopitant (0.1–1 mg/kg, s.c.) also produced a dose-dependent inhibition of hindpaw tapping induced by intracerebroventricular injection of [Sar9,Met(O2)11]SP in gerbils, which is known to be mediated by NK1 receptors in the brain. These findings indicate that ezlopitant is a potent and selective NK1 receptor antagonist, and that it inhibits both acute and delayed emetic reactions induced by cisplatin in ferrets via acting on NK1 receptors in the central nervous system.

Ca2+-independent contraction of uterine smooth muscle induced by vanadate and its inhibition by Ca2+

Vanadate, 30 microM, contracts uterine smooth muscle of estrogen-dominated non-pregnant rats in Ca(2+)-free medium after preincubation with 3 mM EGTA. In spite of the phosphorylation of the myosin light chain during this contraction, studies with fura-2 suggested that this contraction was not accompanied by an increase in the cytosolic Ca2+ level. Inhibitors of the myosin light chain kinase and protein kinase C partly inhibited this contraction. Vanadate seems to enter the cell through anion channels to inhibit phosphatases, resulting in phosphorylation via basal activities of the myosin light chain kinase and protein kinase C. An increase in the cytosolic free Ca2+ level resulted in relaxation of the contracting muscle in the same manner as in the oxytocin-induced Ca(2+)-free contraction.

Discovery of CP-96,345 and its characterization in disease models involving substance P.

Studies with CP-96,345, a potent, selective, orally active, nonpeptide NK1 receptor antagonist, have provided considerable insight into SP pharmacology. Rather than being a primary neurotransmitter, SP prolongs the nociception produced by other neurotransmitters. By controlling endothelial permeability, SP plays a major role in inflammation and inflammatory aspects of asthma, possibly by regulating the access of neutrophils to an inflammatory site. These results indicate potential therapeutic applications for SP antagonists in the treatment of chronic pain, inflammation, and inflammatory aspects of asthma, and signal a new era in the clinical management of these important diseases.

Contact Dermatitis after Prescription of an Ophthalmic Ointment Containing Fradiomycin Sulfate: A Retrospective Database Study Using Japanese Health Insurance Claims Data

BackgroundTopical ointments containing fradiomycin sulfate, such as fradiomycin sulfate/methylprednisolone (F/M) and fradiomycin sulfate/betamethasone sodium phosphate (F/B), are known to cause allergic contact dermatitis (CD) in some patients, especially when used for the periocular region. F/M is commonly prescribed to patients for various conditions; however, there are no reports with respect to the incidence of CD caused by F/M in actual practice.ObjectiveThe aim was to investigate the incidence of CD using a data-based retrospective cohort study.MethodsUsing a Japanese health insurance claims database [MinaCare Co. Ltd. healthcare database (MinaCare HDB)], a comparative assessment was conducted of F/M and another combination drug (F/B) and two single-drug treatments (ophthalmic ointments with either an antibiotic or a steroid). The total data set consisted of 1,176,082 individuals in the MinaCare HDB, with 54,016 having received prescriptions for one of the four investigational drug regimens.ResultsOverall, the incidences of CD were similar in three of the four groups in this study (F/M 0.091; F/B 0.092; steroids 0.102), while being lower in the fourth group (antibiotics 0.060). Even after confirmation of a diagnosis of CD, prescriptions for the investigational drugs were repeatedly filled for some patients.ConclusionThis study demonstrated that there was no clear difference in the incidence of CD after filling prescriptions for F/M, F/B, and ophthalmic ointment containing a steroid, while the incidence with antibiotics was lower by 0.03–0.04 compared with the other groups. Considering the observation that the investigational drugs were repeatedly prescribed even after the diagnosis of CD, it is critical that the risk of CD with these prescribed topical ointments is better understood by primary care physicians in order to take appropriate countermeasures.

Gtp-binding protein amplifies contractile responses of α-toxin-permeabilized uterine smooth muscle to Ca2+

1. alpha-toxin of Staphylococcus aureus readily permeabilized rat uterine smooth muscle after incubation for a short time. 2. The permeabilized muscle responded to Ca2+ dose-dependently and repeatedly in the same manner. 3. The threshold concentration of Ca2+ for contraction was 0.1-0.3 microM and the maximal contraction was achieved with 1 or 3 microM Ca2+. 4. GTP gamma S or GTP augmented the contractile response to Ca2+. 5. GDP beta S or GDP suppressed the contraction. 6. The role of GTP-binding protein in sensitization of Ca(2+)-induced contractile response of smooth muscle is discussed.