24 results on '"Rivelli MA"'
Search Results
2. Vasodilatory and Secretagogue Roles of the Prostaglandin D2 (PGD2) Receptor in Nasal Mucosa and Airways of Different Species.
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Corboz, MR, primary, Rivelli, MA, additional, Skeans, S, additional, McCormick, K, additional, Chapman, R, additional, Phillips, JE, additional, and Anthes, JC, additional
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- 2009
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3. The learning curve of laparoscopic holecystectomy in general surgery resident training: old age of the patient may be a risk factor?
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Ferrarese Alessia, Gentile Valentina, Bindi Marco, Rivelli Matteo, Cumbo Jacopo, Solej Mario, Enrico Stefano, and Martino Valter
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cholecystectomy ,general surgery ,learning curve ,resident ,surgery ,Medicine - Abstract
A well-designed learning curve is essential for the acquisition of laparoscopic skills: but, are there risk factors that can derail the surgical method? From a review of the current literature on the learning curve in laparoscopic surgery, we identified learning curve components in video laparoscopic cholecystectomy; we suggest a learning curve model that can be applied to assess the progress of general surgical residents as they learn and master the stages of video laparoscopic cholecystectomy regardless of type of patient.
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- 2016
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4. Self-gripping mesh versus fibrin glue fixation in laparoscopic inguinal hernia repair: a randomized prospective clinical trial in young and elderly patients
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Ferrarese Alessia, Bindi Marco, Rivelli Matteo, Solej Mario, Enrico Stefano, and Martino Valter
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inguinal hernia ,laparoscopic repair ,transabdominal hernia repair ,Medicine - Abstract
Laparoscopic transabdominal preperitoneal inguinal hernia repair is a safe and effective technique. In this study we tested the hypothesis that self-gripping mesh used with the laparoscopic approach is comparable to polypropylene mesh in terms of perioperative complications, against a lower overall cost of the procedure.
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- 2016
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5. Abnormal right hepatic artery injury resulting in right hepatic atrophy: diagnosed by laparoscopic cholecystectomy
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Martino Valter, Ferrarese Alessia, Bindi Marco, Marola Silvia, Gentile Valentina, Rivelli Matteo, Ferrara Yuri, Enrico Stefano, Berti Stefano, and Solej Mario
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liver atrophy ,cholecystectomy ,right hepatic artery ,Medicine - Abstract
An intact hepatic artery is the gateway to successful hepato-biliary surgery. Introduction of laproscopic cholecystectomy (LC) has stimulated a renewed interest in the anatomy of hepatic artery. In this case report we have highlighted importance of variations of right hepatic artery in terms of origin and course We present a rare asymptomatic case of liver atrophy due to an intraoperative lesion of right hepatic artery. We also performed a literature review about surgical vascular lesions and tried to confirm the right concept behind “non trivial procedure” of the LC.
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- 2015
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6. Fertility knowledge and views on egg freezing and family planning among surgical specialty traineesAJOG Global Reports at a Glance
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Karine Matevossian, DO, Anne Rivelli, MA, MPH, and Meike L. Uhler, MD
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Family planning ,fertility preservation ,medical training ,oocyte cryopreservation ,infertility ,Gynecology and obstetrics ,RG1-991 - Abstract
BACKGROUND: There are limited studies focusing on resident and fellow attitudes on family planning and egg freezing. Surgical training programs are often longer and more time consuming than other fields. It is important to understand how this training affects family planning decisions. OBJECTIVE: This study aimed to describe fertility knowledge and viewpoints on family planning among US residents or fellows. STUDY DESIGN: The Advocate Aurora Health Institutional Review Board approved this study on October 8, 2019 (IRB# AHC-7213-S5500413). A 32-question survey was emailed to trainees across US programs in a variety of specialties (obstetrics/gynecology; ophthalmology; otolaryngology; urology; and neurology, plastic, general, thoracic and orthopedic surgery) to assess fertility knowledge. Pearson chi square tests were conducted to investigate differences in fertility knowledge by groups of interest (trainee specialty, gender, trainee program type). Demographics and viewpoints on family planning and egg freezing are described. All analyses were performed using SAS, version 9.4. RESULTS: A total of 447 surveys were collected from October 2019 to January 2020. Participants included 309 residents, 94 fellows, and 44 with unknown status across the 9 specialties. Participants were mostly female (73%), aged 26 to 30 years (48%), White (69%), married (59%), and heterosexual (95%), with no children (72%). When asked at what age a woman's fertility slightly decreases, obstetrics/gynecology trainees had 39% less likelihood of answering correctly compared with non–obstetrics/gynecology respondents (P=.0207). Female respondents had 18% less likelihood of answering correctly relative to male respondents, and trainees in academic programs were 20% to 60% more likely to answer correctly relative to those in community programs, but these findings were not statistically significant. Interestingly, female respondents had 2.89 times increased odds of having 0 children (P
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- 2022
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7. Role of α2-adrenoceptors in electrical field stimulation-induced contraction of pig nasal mucosa and pharmacologic characterization of a novel α2C-adrenoceptor agonist.
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Corboz MR, Rivelli MA, Shah H, Boyce CW, McCormick KD, Chapman RW, and Hunter JC
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- Acridines pharmacology, Adrenergic Agonists pharmacology, Adrenergic Antagonists pharmacology, Animals, Clonidine pharmacology, Electric Stimulation, Excitation Contraction Coupling, Nasal Mucosa innervation, Organ Culture Techniques, Piperazines pharmacology, Saphenous Vein drug effects, Swine, Sympathetic Nervous System, Vasoconstriction drug effects, Yohimbine pharmacology, Nasal Mucosa drug effects, Receptors, Adrenergic, alpha-2 physiology
- Abstract
Background: Blood vessels of the nasal mucosa are richly innervated by sympathetic nerves and neural mechanism is of great interest in upper respiratory tract disorders. This study was designed to determine the role of α2-adrenoceptors and, more specifically, α2C-adrenoceptors, on neurogenic sympathetic vasoconstrictor responses in pig nasal mucosa, and to define the pharmacologic profile of a novel selective α2C-adrenoreceptor agonist., Methods: Electrical field stimulation (EFS) was applied to nasal mucosa strips placed in an organ bath and attached to force displacement transducers for continuous recording of isometric tension. The affinity and functional activity of compound B for α2C-adrenoceptors were determined by binding analysis and the ability of compound B to stimulate [(35)S]GTPγS binding to the receptors. Compound B was also tested in a postjunctional α2C-adrenoreceptor bioassay., Results: EFS-induced contractions were partly blocked by the α2-adrenoreceptor antagonist yohimbine (41.1%) and the α2C-adrenoreceptor antagonist JP-1302 had no effect. The α2-adrenoreceptor agonist clonidine, but not compound B, exerted a significant blockade (70.6%). Compound B had high affinity (K(i) = 18 nM), produced potent agonist (EC50 = 279 nM) and good efficacy (E(max) = 73%) responses at the α2C-adrenoceptors, and displayed good functional agonist potency in the human saphenous vein α2C-adrenoreceptor bioassay (pD2 = 6.2)., Conclusion: (1) Neurogenic vasomotor contractility is largely regulated through an α-adrenergic mechanism; (2) pig nasal mucosa possesses post- and prejunctional α2-adrenoceptors; (3) the α2C-adrenoreceptor subtype does not seem to be involved; and (4) compound B is a novel, highly selective, and potent α2C-adrenoreceptor agonist.
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- 2013
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8. Neuromodulation mediated by the tachykinin NK3-receptor agonist [MePhe7]-neurokinin B in the isolated perfused lung of nonsensitized nonchallenged and ovalbumin-sensitized and -challenged guinea pig.
- Author
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Corboz MR, Rivelli MA, Fernandez X, and Greenfeder S
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- Animals, Bronchoconstriction drug effects, Bronchoconstriction physiology, Electrodes, Guinea Pigs, Lung metabolism, Lung physiology, Male, Neurokinin A metabolism, Neurokinin B metabolism, Neurokinin B pharmacology, Piperidines pharmacology, Receptors, Neurokinin-2 metabolism, Receptors, Tachykinin metabolism, Vagus Nerve drug effects, Vagus Nerve metabolism, Vagus Nerve Stimulation methods, Lung drug effects, Neurokinin B analogs & derivatives, Neurotransmitter Agents pharmacology, Ovalbumin pharmacology, Receptors, Neurokinin-3 agonists, Receptors, Neurokinin-3 metabolism
- Abstract
The neuromodulatory action of the tachykinin NK(3)-receptor agonist [MePhe(7)]-neurokinin B ([MePhe(7)]-NKB) was evaluated on vagal stimulation-induced bronchoconstriction in nonsensitized nonchallenged and ovalbumin (OVA)-sensitized and -challenged guinea pig using the isolated perfused lung preparation. Lungs were placed inside a warmed (37°C) glass chamber and suspended from a force displacement transducer (Grass FT-03) with both vagi connected to a stimulating electrode. Isolated lungs were stimulated at a constant voltage (20 V) and pulse duration (5 ms) with electrical stimulation frequencies ranging from 1 to 128 Hz. The authors demonstrated that vagal stimulation produced frequency-dependent bronchoconstriction and [MePhe(7)]-NKB, at a dose (0.1 μM) that does not produce bronchoconstriction by itself, potentiated the vagally induced bronchoconstriction at all frequencies in nonsensitized nonchallenged animals and to a greater extent in OVA-sensitized and -challenged guinea pigs; the potentiations were totally inhibited by the tachykinin NK(3)-receptor antagonist SR 142801 (1 μM). In a second set of experiments, [MePhe(7)]-NKB produced bronchoconstriction in a dose-dependent (1 to 300 μg/mL) manner with similar potencies and maximum responses in nonsensitized nonchallenged (EC(50) = 8.6 ± 1.1 μM; E(Max) = 61.1 ± 3.5 mm Hg) and OVA-sensitized and -challenged (EC(50) = 8.5 ± 1.3 μM; E(Max) = 63.5 ± 3.7 mm Hg) animals. In conclusion, these results demonstrated that [MePhe(7)]-NKB potentiated vagal stimulation-induced bronchoconstriction via the tachykinin NK(3)-receptors and OVA sensitization caused development of airway hyperresponsiveness in these potentiations. However, OVA sensitization had no effect on airway responsiveness of vagal stimulation-and [MePhe(7)]-NKB-induced bronchoconstrictions.
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- 2012
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9. Pharmacological characterization of a novel α2C-adrenoceptor agonist N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N'-methylurea (compound A).
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Corboz MR, Rivelli MA, McCormick KD, Wan Y, Shah H, Umland S, Lieber G, Jia Y, McLeod RL, Morgan C, Varty GB, Wu J, Feng KI, Boyce CW, Aslanian RG, Palamanda J, Nomeir AA, Korfmacher W, Hunter JC, Anthes JC, and Hey JA
- Subjects
- Adrenergic Agonists metabolism, Animals, CHO Cells, Cricetinae, Cricetulus, Humans, Male, Methylurea Compounds metabolism, Mice, Mice, Inbred C57BL, Morpholines metabolism, Motor Activity physiology, Nasal Mucosa metabolism, Rats, Rats, Sprague-Dawley, Recombinant Proteins agonists, Recombinant Proteins metabolism, Saphenous Vein metabolism, Swine, Adrenergic Agonists chemistry, Adrenergic Agonists pharmacology, Methylurea Compounds chemistry, Methylurea Compounds pharmacology, Morpholines chemistry, Morpholines pharmacology, Motor Activity drug effects, Nasal Mucosa drug effects, Receptors, Adrenergic, alpha-2 metabolism, Saphenous Vein drug effects
- Abstract
We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.
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- 2011
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10. Bronchoconstrictor effect of the tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B and senktide in the isolated guinea pig lung.
- Author
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Corboz MR, Rivelli MA, and Eckel SP
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- Animals, CHO Cells, Cricetinae, Cricetulus, Disease Models, Animal, Guinea Pigs, In Vitro Techniques, Lung physiology, Male, Piperidines pharmacology, Substance P pharmacology, Bronchoconstriction drug effects, Bronchoconstrictor Agents pharmacology, Lung drug effects, Peptide Fragments pharmacology, Quinolines pharmacology, Receptors, Neurokinin-3 antagonists & inhibitors, Receptors, Neurokinin-3 biosynthesis, Substance P analogs & derivatives
- Abstract
To determine whether bronchoconstriction can be mediated via the tachykinin NK₃ receptors, isolated guinea pig lungs were challenged with the exogenous tachykinin NK₃-receptor agonists [MePhe⁷]-neurokinin B ([MePhe⁷]-NKB) and senktide. [MePhe⁷]-NKB induced bronchoconstriction (EC50 = 11.8 ± 1.7 µM) that was significantly inhibited by the tachykinin NK₃-receptor antagonist SB 223412 at 10 µM (EC50 = 24.4 ± 4.5 µM). Senktide also induced bronchoconstriction (EC50 = 96.2 ± 20.3 µM) and the bronchoconstriction was significantly reduced by SB 223412 at 1 and 10 µM (EC50 = 270.8 ± 78.9 µM and 388.3 ± 105.5 µM, respectively). Although the authors demonstrated that SB 223412, [MePhe⁷]-NKB, and senktide are potent and selective for the tachykinin NK3 receptors in binding and functional (Ca(2+) mobilization) assays, the tachykinin NK₁-receptor antagonist CP 99,994 at 1 µM (EC50 = 32.7 ± 8.5 µM) produced inhibition of [MePhe⁷]-NKB-induced bronchoconstriction, whereas the tachykinin NK₂-receptor antagonist SR 48968 at 0.1 µM (EC50 = 213.2 ± 42.9 µM) blocked senktide-induced bronchoconstriction. These data suggest that [MePhe⁷]-NKB and senktide caused bronchoconstriction in guinea pig through activation of the tachykinin NK₃-receptors but the tachykinin NK₁- and/or NK₂-receptors are also involved in the response.
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- 2010
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11. The synthesis and structure-activity relationship of 4-benzimidazolyl-piperidinylcarbonyl-piperidine analogs as histamine H3 antagonists.
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Ting PC, Lee JF, Albanese MM, Wu J, Aslanian R, Favreau L, Nardo C, Korfmacher WA, West RE, Williams SM, Anthes JC, Rivelli MA, Corboz MR, and Hey JA
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- Structure-Activity Relationship, Histamine H3 Antagonists chemical synthesis, Histamine H3 Antagonists pharmacology, Piperidines chemical synthesis, Piperidines pharmacology
- Abstract
A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i)
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- 2010
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12. Three-dimensional analysis of rodent paranasal sinus cavities from X-ray computed tomography (CT) scans.
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Phillips JE, Ji L, Rivelli MA, Chapman RW, and Corboz MR
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- Animals, Female, Guinea Pigs, Male, Mice, Models, Animal, Paranasal Sinuses diagnostic imaging, Rats, Sinusitis pathology, Paranasal Sinuses anatomy & histology, Rodentia anatomy & histology, Tomography, X-Ray Computed veterinary
- Abstract
Continuous isometric microfocal X-ray computed tomography (CT) scans were acquired from an AKR/J mouse, Brown-Norway rat, and Hartley guinea pig. The anatomy and volume of the paranasal sinus cavities were defined from 2-dimensional (2-D) and 3-dimensional (3-D) CT images. Realistic 3-D images were reconstructed and used to determine the anterior maxillary, posterior maxillary, and ethmoid sinus cavity airspace volumes (mouse: 0.6, 0.7, and 0.7 mm(3), rat: 8.6, 7.7, and 7.0 mm(3), guinea pig: 63.5, 46.6 mm(3), and no ethmoid cavity, respectively). The mouse paranasal sinus cavities are similar to the corresponding rat cavities, with a reduction in size, while the corresponding maxillary sinus cavities in the guinea pig are different in size, location, and architecture. Also, the ethmoid sinus cavity is connected by a common drainage pathway to the posterior maxillary sinus in mouse and rat while a similar ethmoid sinus was not present in the guinea pig. We conclude that paranasal sinus cavity airspace opacity (2-D) or volume (3-D) determined by micro-CT scanning may be used to conduct longitudinal studies on the patency of the maxillary sinus cavities of rodents. This represents a potentially useful endpoint for developing and testing drugs in a small animal model of sinusitis.
- Published
- 2009
13. Mechanism of decongestant activity of alpha 2-adrenoceptor agonists.
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Corboz MR, Rivelli MA, Mingo GG, McLeod RL, Varty L, Jia Y, and Hey JA
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- Administration, Topical, Animals, Azepines pharmacology, Blood Pressure drug effects, Cats, Dose-Response Relationship, Drug, Epinephrine pharmacology, Female, Male, Muscle Contraction physiology, Nasal Mucosa innervation, Nasal Mucosa physiology, Oxymetazoline pharmacology, Receptors, Adrenergic, alpha-2, Swine, p-Methoxy-N-methylphenethylamine pharmacology, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists pharmacology, Nasal Decongestants
- Abstract
The vascular bed in nasal mucosa of different species, including human, is highly vascularized and an extensive sinusoidal network of large capacitance vessels is present deep within the submucosa. When this network of venous sinusoids is engorged with blood, the swollen mucosa reduces the size of the airway lumen and congestion ensues. Nasal vasculature tone is strongly influenced by the sympathetic nervous system and the only drugs approved specifically to relieve vascular nasal obstruction are alpha-adrenoceptor sympathomimetic agents. Due to their vasoconstrictor action, the sympathomimetic decongestants oppose vasodilation, reducing nasal airway resistance and thus facilitating nose breathing. However, standard decongestants that are non-selective alpha-adrenoceptor agonists are associated with the potential for side-effect liabilities including hypertension, stroke, insomnia and nervousness. We propose than a selective alpha 2-adrenoceptor agonist, by acting preferentially on nasal venous capacitance vessels, will elicit decongestion with a reduced side-effect liability. In the present study, we evaluated the effects of the selective alpha 2-adrenoceptor agonist BHT-920 in a real-time tissue contractility assay using isolated pig nasal explants and in an in vivo cat model of congestion. The vasoconstrictor and decongestant effects of BHT-920 were compared to the non-selective alpha-adrenoceptor agonist epinephrine and the standard decongestant oxymetazoline. Our results showed that the alpha 2-adrenoceptor agonist BHT-920 preferentially contracts venous sinusoids confirming previous observations [Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, et al. Effects of an alpha 2-adrenoceptor agonist in nasal mucosa. Arch Physiol Biochem 2003;11: 335-6, Corboz MR, Rivelli MA, Varty LM, Mutter J, Cartwright M, Rizzo CA, et al. Pharmacological characterization of postjunctional alpha-adrenoceptor in human nasal mucosa. Am J Rhinol 2005;19: 495-502] and displays decongestion without affecting blood pressure. Therefore, an alpha 2-adrenoceptor agonist, by causing constriction in the capacitance vessels of nasal mucosa, can produce nasal decongestion without the effects on blood pressure observed with the standard selective alpha 1-adrenoceptor and non-selective alpha-adrenoceptor sympathomimetic decongestants.
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- 2008
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14. alpha2-adrenoceptor agonists as nasal decongestants.
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Corboz MR, Mutter JC, Rivelli MA, Mingo GG, McLeod RL, Varty L, Jia Y, Cartwright M, and Hey JA
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- Adrenergic alpha-2 Receptor Antagonists, Adrenergic alpha-Agonists administration & dosage, Adrenergic alpha-Antagonists pharmacology, Animals, Azepines pharmacology, Cats, Dogs, Dose-Response Relationship, Drug, Epinephrine pharmacology, Female, In Vitro Techniques, Macaca fascicularis, Macaca mulatta, Male, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular physiology, Nasal Decongestants administration & dosage, Nasal Mucosa blood supply, Nasal Mucosa physiology, Prazosin pharmacology, Swine, Swine, Miniature, Vasoconstriction drug effects, Yohimbine pharmacology, p-Methoxy-N-methylphenethylamine pharmacology, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists pharmacology, Nasal Decongestants pharmacology, Nasal Mucosa drug effects
- Abstract
Nasal congestion, one of the major disease features of rhinitis, is induced by the filling of venous sinusoids causing mucosal engorgement with resultant obstruction of nasal airflow. The only available drugs that directly target the underlying vascular features driving nasal obstruction are the sympathomimetic alpha-adrenoceptor agonists due to their vasoconstrictor action. However, standard decongestants are nonselective alpha-adrenoceptor agonists, which have the potential for side-effects liabilities such as hypertension, stroke, insomnia and nervousness. In the present study, the effects of nonsubtype selective alpha(2)-adrenoceptor agonists BHT-920 and PGE-6201204 were evaluated in several isolated nasal mucosa contractile bioassays including dog, pig and monkey, and in a real-time tissue contractility assay using isolated pig nasal explants for BHT-920. The decongestant activity of PGE-6201204 was evaluated in vivo in a cat model of experimental congestion. Our results showed that alpha(2)-adrenoceptor agonists (1) contract nasal mucosa of different species, (2) exert a preferential vasoconstrictor effect on the capacitance vessels (veins and sinusoids), and (3) elicit decongestion. In conclusion, a selective alpha(2)-adrenoceptor agonist causing constriction preferentially in the large venous sinusoids and veins of nasal mucosa and producing nasal decongestion is expected to show efficacy in the treatment of nasal congestion without the characteristic arterio-constrictor action of the standard nonselective sympathomimetic decongestants.
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- 2007
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15. Reduction of CYP450 inhibition in the 4-[(1H-imidazol-4-yl)methyl]piperidine series of histamine H3 receptor antagonists.
- Author
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Berlin M, Ting PC, Vaccaro WD, Aslanian R, McCormick KD, Lee JF, Albanese MM, Mutahi MW, Piwinski JJ, Shih NY, Duguma L, Solomon DM, Zhou W, Sher R, Favreau L, Bryant M, Korfmacher WA, Nardo C, West RE Jr, Anthes JC, Williams SM, Wu RL, Susan She H, Rivelli MA, Corboz MR, and Hey JA
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- Animals, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Guinea Pigs, Haplorhini, Histamine Antagonists chemical synthesis, Histamine Antagonists chemistry, Humans, Imidazoles chemical synthesis, Imidazoles chemistry, Molecular Structure, Piperidines chemical synthesis, Piperidines chemistry, Rats, Structure-Activity Relationship, Tissue Distribution, Cytochrome P-450 Enzyme Inhibitors, Enzyme Inhibitors pharmacology, Histamine Antagonists pharmacology, Imidazoles pharmacology, Piperidines pharmacology, Receptors, Histamine H3 drug effects
- Abstract
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
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- 2006
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16. Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold.
- Author
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Vaccaro WD, Sher R, Berlin M, Shih NY, Aslanian R, Schwerdt JH, McCormick KD, Piwinski JJ, West RE Jr, Anthes JC, Williams SM, Wu RL, She HS, Rivelli MA, Mutter JC, Corboz MR, Hey JA, and Favreau L
- Subjects
- Cytochrome P-450 CYP2D6 Inhibitors, Drug Evaluation, Preclinical, Histamine Antagonists chemical synthesis, Histamine Antagonists chemistry, Humans, Imidazoles chemical synthesis, Imidazoles chemistry, In Vitro Techniques, Molecular Structure, Piperidines chemical synthesis, Piperidines chemistry, Structure-Activity Relationship, Histamine Antagonists pharmacology, Imidazoles pharmacology, Piperidines pharmacology, Receptors, Histamine H3 drug effects
- Abstract
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
- Published
- 2006
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17. Pharmacological characterization of postjunctional alpha-adrenoceptors in human nasal mucosa.
- Author
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Corboz MR, Rivelli MA, Varty L, Mutter J, Cartwright M, Rizzo CA, Eckel SP, Anthes JC, and Hey JA
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- Adrenergic alpha-Agonists pharmacology, Adrenergic alpha-Antagonists pharmacology, Adult, Aged, Arteries physiology, Epinephrine pharmacology, Female, Humans, In Vitro Techniques, Male, Norepinephrine pharmacology, Oxymetazoline pharmacology, Prazosin pharmacology, Turbinates, Vasoconstriction drug effects, Veins physiology, Yohimbine pharmacology, Nasal Mucosa blood supply, Receptors, Adrenergic, alpha physiology
- Abstract
Background: Functional alpha1- and alpha2-adrenoreceptor subtype pharmacology was characterized in an in vitro human nasal mucosa contractile bioassay., Methods: Nasal mucosa was obtained from 49 donor patients and mucosal strips were placed in chambers filled with Krebs-Ringer solution and attached to isometric force transducers., Results: Nonselective a-adrenoreceptor agonists epinephrine, norepinephrine, and oxymetazoline produced concentration-dependent contractions of isolated human nasal mucosa (pD2 = 5.2, 4.9, and 6.5, respectively). The alpha2-adrenoreceptor agonist BHT-920 (10 microM)-induced contractions were blocked by yohimbine (0.01-1 microM) and prazosin (0.01-1 microM) inhibited the contractile response to the alpha1-adrenoreceptor agonist phenylephrine (10 microM). Histological analysis showed that phenylephrine and BHT-920 differentially contracted the arteries and veins of human nasal mucosa, respectively., Conclusion: Our results indicate that functional alpha1- and alpha2-adrenoceptors are present and functional in human nasal mucosa. The alpha2-adrenoceptors display a predominant role in contracting the veins and the alpha1-adrenoceptors appear to preferentially constrict the human nasal arteries.
- Published
- 2005
18. Effects of an alpha2-adrenoceptor agonist in nasal mucosa.
- Author
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Corboz MR, Varty LM, Rivelli MA, Mutter JC, Mingo G, McLeod R, and Hey JA
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- Animals, Arteries drug effects, Azepines pharmacology, Dogs, Humans, Nasal Mucosa blood supply, Phenylephrine pharmacology, Swine, Veins drug effects, Adrenergic alpha-2 Receptor Agonists, Nasal Mucosa drug effects
- Published
- 2003
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19. Pharmacological characterization of alpha 2-adrenoceptor-mediated responses in pig nasal mucosa.
- Author
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Corboz MR, Varty LM, Rizzo CA, Mutter JC, Rivelli MA, Wan Y, Umland S, Qiu H, Jakway J, McCormick KD, Berlin M, and Hey JA
- Subjects
- Adrenergic alpha-Antagonists pharmacology, Animals, CHO Cells, Cricetinae, Dose-Response Relationship, Drug, Female, Humans, In Vitro Techniques, Male, Nasal Mucosa drug effects, Protein Binding drug effects, Protein Binding physiology, Swine, Adrenergic alpha-2 Receptor Antagonists, Adrenergic alpha-Antagonists metabolism, Nasal Mucosa metabolism, Receptors, Adrenergic, alpha-2 metabolism
- Abstract
1. Pig nasal mucosal strips were incubated with alpha-adrenoceptor antagonists followed by alpha2-adrenoceptor agonist concentration-response curves. 2. Contractions elicited by the alpha2-adrenoceptor agonists BHT-920 (pD2 = 6.16 +/- 0.07), UK 14,304 (pD2 = 6.89 +/- 0.13) and PGE-6201204 (pD2 = 7.12 +/- 0.21) were blocked by the alpha2-adrenoceptor antagonist yohimbine (0.1 microm). In contrast, the alpha1-adrenoceptor antagonist prazosin (0.03 microm) had no effect on the BHT-920-, UK 14,304- and PGE-6201204-induced contractions, but blocked the contractile response to the alpha(1)-adrenoceptor agonist phenylephrine (pD2 = 5.38 +/- 0.04) and the mixed alpha1- and alpha2-adrenoceptor agonist oxymetazoline (pD(2) = 6.30 +/- 0.22). 3. The alpha2-adrenoceptor antagonist yohimbine (0.01-0.1 microm, pA2 = 8.04), alpha2B/C-adrenoceptor antagonist ARC 239 (10 microm, pK(b) = 6.33 +/- 0.21), alpha2A/C-adrenoceptor antagonist WB 4101 (0.3 microm, pK(b) = 8.01 +/- 0.24), alpha2A-adrenoceptor antagonists BRL44408 (0.1 microm, pK(b) = 6.82 +/- 0.34) and RX 821002 (0.1 microm, pKb = 8.31 +/- 0.35), alpha2C-adrenoceptor antagonists spiroxatrine (1 microm, pKb = 7.32 +/- 0.32), rauwolscine (0.1 microm, pKb = 8.16 +/- 0.14) and HV 723 (0.3 microm, pKb = 7.68 +/- 0.14) inhibited BHT-920-induced contractions in pig nasal mucosa. 4. The present antagonist potencies showed correlations with binding affinity estimates (pKi) obtained for these antagonists at the human recombinant alpha2A- and alpha2C-adrenoceptors (r = 0.78 and 0.83, respectively) and with binding affinity estimates (pKd) obtained in pig native alpha2A- and alpha2C-monoreceptor assays (r = 0.85 and 0.78, respectively). No correlation was observed for the alpha2B-subtype. 5. In conclusion, contractile responses to phenylephrine, BHT-920, UK 14,304, PGE-6201204 and oxymetazoline indicate that alpha1- and alpha2-adrenoceptors are present and mediate vasoconstriction in pig nasal mucosa. Furthermore, correlation analysis comparing antagonist potency in pig nasal mucosa with affinities for human recombinant alpha2-adrenoceptors and native pig alpha2-adrenoceptors suggest that alpha2A- and alpha2C-adrenoceptor subtypes constrict pig nasal mucosa vasculature.
- Published
- 2003
- Full Text
- View/download PDF
20. Nociceptin/orphanin FQ inhibits capsaicin-induced guinea-pig airway contraction through an inward-rectifier potassium channel.
- Author
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Jia Y, Wang X, Aponte SI, Rivelli MA, Yang R, Rizzo CA, Corboz MR, Priestley T, and Hey JA
- Subjects
- Animals, Bronchi physiology, Bronchoconstriction physiology, Capsaicin antagonists & inhibitors, Guinea Pigs, In Vitro Techniques, Lung physiology, Male, Nodose Ganglion cytology, Nodose Ganglion drug effects, Nodose Ganglion physiology, Opioid Peptides pharmacology, Potassium Channels, Inwardly Rectifying agonists, Potassium Channels, Inwardly Rectifying antagonists & inhibitors, Tachykinins metabolism, Nociceptin, Bronchi drug effects, Bronchoconstriction drug effects, Capsaicin pharmacology, Lung drug effects, Opioid Peptides physiology, Potassium Channels, Inwardly Rectifying physiology, Vasoconstrictor Agents pharmacology, Vasodilator Agents pharmacology
- Abstract
Nociceptin/orphanin FQ (N/OFQ), an endogenous opioid-like orphan receptor (NOP receptor, previously termed ORL1 receptor) agonist, has been found to inhibit capsaicin-induced bronchoconstriction in isolated guinea-pig lungs and in vivo. The underlying mechanisms are not clear. In the present studies, we tested the effect of N/OFQ on VR1 channel function in isolated guinea-pig nodose ganglia cells. Capsaicin increased intracellular Ca(2+) concentration in these cells through activation of vanilloid receptors. Capsaicin-induced Ca(2+) responses were attenuated by pretreatment of nodose neurons with N/OFQ (1 microM). N/OFQ inhibitory effect on the Ca(2+) response in nodose ganglia cells was antagonized by tertiapin (0.5 microM), an inhibitor of inward-rectifier K(+) channels, but not by verapamil, a voltage gated Ca(2+) channel blocker, indicating that an inward-rectifier K(+) channel is involved in N/OFQ inhibitory effect. In isolated guinea-pig bronchus, N/OFQ (1 microM) inhibited capsaicin-induced airway contraction. Tertiapin (0.5 microM) abolished the N/OFQ inhibition of capsaicin-induced bronchial contraction. Capsaicin (10 microg) increased pulmonary inflation pressure in the isolated perfused guinea-pig lungs. This response was significantly attenuated by pretreatment with N/OFQ (1 microM). Tertiapin also abolished the N/OFQ inhibitory effect on capsaicin-induced bronchoconstriction in perfused lungs. Capsaicin increased the release of substance P and neurokinin A from isolated lungs. N/OFQ (1 microM) blocked the capsaicin-induced tachykinin release. These results indicate that N/OFQ-induced hyperpolarization of tachykinin containing airway sensory nerves, through an inward-rectifier K(+) channel activation, accounts for the inhibition of capsaicin-evoked broncoconstriction.
- Published
- 2002
- Full Text
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21. Nociceptin inhibits capsaicin-induced bronchoconstriction in isolated guinea pig lung.
- Author
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Corboz MR, Rivelli MA, Egan RW, Tulshian D, Matasi J, Fawzi AB, Benbow L, Smith-Torhan A, Zhang H, and Hey JA
- Subjects
- Animals, Benzimidazoles pharmacology, CHO Cells, Capsaicin pharmacology, Cricetinae, Guanosine 5'-O-(3-Thiotriphosphate) metabolism, Guinea Pigs, In Vitro Techniques, Naloxone pharmacology, Piperidines pharmacology, Sulfur Radioisotopes, Nociceptin Receptor, Nociceptin, Bronchoconstriction drug effects, Capsaicin antagonists & inhibitors, Lung drug effects, Narcotic Antagonists pharmacology, Opioid Peptides pharmacology, Receptors, Opioid agonists
- Abstract
The isolated perfused guinea pig lung was used to investigate the effect of nociceptin against bronchoconstriction elicited by endogenous and exogenous tachykinins. The opioid receptor-like 1 (ORL1) receptor agonist, nociceptin/orphanin FQ (0.001-1 microM) produced a dose-related inhibition of the capsaicin-induced bronchoconstriction (10(-5)-10(3) microg) in isolated guinea pig lung (P<0.05), a response mediated by the release of endogenous tachykinins from lung sensory nerves. The new ORL1 receptor antagonist 1-[(3R, 4R)-1-Cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1, 3-dihydro-2H-benzimidazol-2-one (J-113397) (0.3 microM) significantly blocked the inhibitory effect of nociceptin/orphanin FQ (0.01 microM) on capsaicin-induced bronchoconstriction, whereas the non-selective opioid receptor antagonist naloxone (1 microM) had no effect. Nociceptin/orphanin FQ (1 microM) did not affect the bronchoconstriction induced exogenously by the tachykinin NK2 receptor agonist neurokinin A. In conclusion, the present data provide evidence that nociceptin inhibits capsaicin-evoked tachykinin release from sensory nerve terminals in guinea pig lung by a prejunctional mechanism. This inhibitory action occurs independently from activation of opioid receptors. The present study also indicates that J-113397 is a potent ORL1 receptor antagonist.
- Published
- 2000
- Full Text
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22. Pharmacological characterization of histamine H3 receptors in human saphenous vein and guinea pig ileum.
- Author
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Valentine AF, Rizzo CA, Rivelli MA, and Hey JA
- Subjects
- Adrenergic alpha-Antagonists pharmacology, Aged, Animals, Dose-Response Relationship, Drug, Electric Stimulation, Female, Guinea Pigs, Histamine Agonists pharmacology, Histamine Antagonists pharmacology, Humans, Ileum physiology, Imidazoles pharmacology, In Vitro Techniques, Male, Methylhistamines pharmacology, Middle Aged, Muscle Contraction drug effects, Piperidines pharmacology, Prazosin pharmacology, Receptors, Histamine H3 metabolism, Saphenous Vein physiology, Tetrodotoxin pharmacology, Thiourea analogs & derivatives, Thiourea pharmacology, Yohimbine pharmacology, Ileum drug effects, Receptors, Histamine H3 drug effects, Saphenous Vein drug effects
- Abstract
Studies were performed to assess the functional activity of histamine H3 receptors on neurogenic sympathetic end organ responses in cryopreserved human saphenous vein. (R)-alpha-methylhistamine inhibited electrical field stimulation-evoked contractile responses in a dose dependent manner (pD2 = 8.20). Prazosin (1 microM) and tetrodotoxin (1 microM) blocked the electrical field stimulation-evoked contractile responses in human saphenous vein indicating a sympathetic neural origin of these contractions. The histamine H3 antagonists thioperamide (pA2 = 8.41) and clobenpropit (pA2 = 10.10) produced parallel rightward shifts in the concentration response curve to (R)-alpha-methylhistamine in human saphenous vein and guinea pig ileum (pA2 = 8.59 and 9.83, respectively). Pretreatment with (R)-alpha-methylhistamine (1 microM) did not alter contractions to exogenous norepinephrine in human saphenous vein. In addition, clonidine (pD2 = 10.28) inhibited electrical field stimulation-evoked contractile responses in human saphenous vein which were blocked by yohimbine (30 nM, pA2 = 9.92) but did not alter the (R)-alpha-methylhistamine dose response curve. These results demonstrate the presence of functional presynaptic histamine H3 heteroreceptors on cryopreserved human saphenous vein sympathetic nerves that, upon activation, attenuate electrical field stimulation-evoked contractile responses in this vessel.
- Published
- 1999
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23. Novel H3 receptor antagonists. Sulfonamide homologs of histamine.
- Author
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Wolin R, Connolly M, Afonso A, Hey JA, She H, Rivelli MA, Willams SM, and West RE Jr
- Subjects
- Animals, Brain metabolism, Cell Membrane metabolism, Drug Design, Guinea Pigs, Histamine chemical synthesis, Histamine chemistry, Histamine pharmacology, Histamine Antagonists chemistry, Histamine Antagonists pharmacology, Kinetics, Molecular Structure, Piperidines chemistry, Piperidines pharmacology, Receptors, Histamine H3 drug effects, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacology, Histamine analogs & derivatives, Histamine Antagonists chemical synthesis, Piperidines chemical synthesis, Receptors, Histamine H3 physiology, Sulfonamides chemical synthesis
- Abstract
Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.
- Published
- 1998
- Full Text
- View/download PDF
24. Tachykinin NK1 receptor-mediated vasorelaxation in human pulmonary arteries.
- Author
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Corboz MR, Rivelli MA, Ramos SI, Rizzo CA, and Hey JA
- Subjects
- Dose-Response Relationship, Drug, Humans, Phenylephrine pharmacology, Piperidines pharmacology, Pulmonary Artery drug effects, Pulmonary Artery metabolism, Receptors, Neurokinin-1 drug effects, Substance P pharmacology, Vasoconstrictor Agents pharmacology, Pulmonary Artery physiology, Receptors, Neurokinin-1 physiology, Vasodilation drug effects
- Abstract
Tachykinin NK1 receptors are present on human pulmonary arteries. Addition of the specific tachykinin NK1 receptor agonist, [Met-OMe11]substance P produced a concentration-dependent relaxation (0.1 nM to 100 nM) in pulmonary arteries preconstricted with phenylephrine (30 microM). The EC50 (agonist concentration needed to produce 50% of the maximal relaxation) value for [Met-OMe11]substance P was 3.7+/-0.7 nM. The relaxation induced by [Met-OMe11]substance P was selectively inhibited by the tachykinin NK1 receptor antagonist CP 99994 (1 nM), with a pKb of 9.9+/-0.3. Treatment with the tachykinin NK2 receptor antagonist SR 48968 (100 nM) did not significantly affect the vasorelaxation due to [Met-OMe11]substance P (P > 0.05, one-way analysis of variance; ANOVA).
- Published
- 1998
- Full Text
- View/download PDF
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