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2.
ESMO Open ; 6(2): 100099, 2021 04.
Article in English | MEDLINE | ID: mdl-33819752

ABSTRACT

BACKGROUND: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting. PATIENTS AND METHODS: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant. RESULTS: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095). CONCLUSIONS: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials.


Subject(s)
Breast Neoplasms , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Female , Humans , Italy , Neoplasm Recurrence, Local/drug therapy , Prospective Studies , Receptor, ErbB-2/genetics , Receptor, ErbB-2/therapeutic use , Retrospective Studies , Taxoids/therapeutic use , Trastuzumab/therapeutic use
3.
BMJ Mil Health ; 167(4): 269-274, 2021 Aug.
Article in English | MEDLINE | ID: mdl-32759228

ABSTRACT

'We are at war', French President Emmanuel Macron said in an address to the nation on 16 March 2020. As part of this national effort, the French Military Medical Service (FMMS) is committed to the fight against COVID-19. This original report aimed to describe and detail actions that the FMMS has carried out in the nationwide fight against the COVID-19 pandemic in France, as well as overseas. Experts in the field reported major actions conducted by the FMMS during the COVID-19 pandemic in France. In just few weeks, the FMMS developed ad hoc medical capabilities to support national health authorities. It additionally developed adaptive, collective en route care via aeromedical and naval units and deployed a military intensive care field hospital. A COVID-19 crisis cell coordinated the French Armed Forces health management. The French Military Centre for Epidemiology and Public Health provided all information needed to guide the decision-making process. Medical centres of the French Armed Forces organised the primary care for military patients, with the widespread use of telemedicine. The Paris Fire Brigade and the Marseille Navy Fire Battalion emergency departments ensured prehospital management of patients with COVID-19. The eight French military training hospitals cooperated with civilian regional health agencies. The French military medical supply chain supported all military medical treatment facilities in France as well as overseas, coping with a growing shortage of medical equipment. The French Armed Forces Biomedical Research Institute performed diagnostics, engaged in multiple research projects, updated the review of the scientific literature on COVID-19 daily and provided expert recommendations on biosafety. Finally, even students of the French military medical academy volunteered to participate in the fight against the COVID-19 pandemic. In conclusion, in an unprecedented medical crisis, the FMMS engaged multiple innovative and adaptive actions, which are still ongoing, in the fight against COVID-19. The collaboration between military and civilian healthcare systems reinforced the shared objective to achieve the goal of 'saving the greatest number'.


Subject(s)
COVID-19 , Communicable Disease Control/organization & administration , Military Medicine/organization & administration , Pandemics , France , Humans , Military Personnel , Mobile Health Units , Public Health Administration
4.
Environ Sci Pollut Res Int ; 24(6): 5189-5206, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28013464

ABSTRACT

Sediment tends to accumulate inorganic and persistent hydrophobic organic contaminants representing one of the main sinks and sources of pollution. Generally, contaminated sediment poses medium- and long-term risks to humans and ecosystem health; dredging activities or natural resuspension phenomena (i.e., strongly adverse weather conditions) can remobilize pollution releasing it into the water column. Thus, ex situ traditional remediation activities (i.e., dredging) can be hazardous compared to in situ techniques that try to keep to a minimum sediment mobilization, unless dredging is compulsory to reach a desired bathymetric level. We reviewed in situ physico-chemical (i.e., active mixing and thin capping, solidification/stabilization, chemical oxidation, dechlorination, electrokinetic separation, and sediment flushing) and bio-assisted treatments, including hybrid solutions (i.e., nanocomposite reactive capping, bioreactive capping, microbial electrochemical technologies). We found that significant gaps still remain into the knowledge about the application of in situ contaminated sediment remediation techniques from the technical and the practical viewpoint. Only activated carbon-based technologies are well developed and currently applied with several available case studies. The environmental implication of in situ remediation technologies was only shortly investigated on a long-term basis after its application, so it is not clear how they can really perform.


Subject(s)
Environmental Restoration and Remediation , Geologic Sediments , Charcoal/chemistry , Ecosystem , Environment , Environmental Pollution , Water , Water Pollutants, Chemical/analysis
5.
Rev. bras. cancerol ; 61(1): 15-21, jan./mar. 2015.
Article in Portuguese | LILACS | ID: biblio-833768

ABSTRACT

Introdução: O melanoma cutâneo representa 4% das neoplasias cutâneas, entretanto, é responsável por 80% das mortes desse grupo de neoplasias. A incidência e a prevalência dessa doença na região Oeste de Santa Catarina são maiores do que as médias nacionais. Objetivo: Identificar as diferenças clínico-epidemiológicas entre pacientes masculinos e femininos com diagnóstico de melanoma cutâneo no Oeste de Santa Catarina. Método: Foram avaliados pacientes procedentes da região Oeste de Santa Catarina, no período de janeiro/2010 a dezembro/2013. Para a coleta de dados, foi utilizado um protocolo adaptado do sistema on-line do Grupo Brasileiro de Melanoma. Resultados:Foram obtidos dados de 253 pacientes com melanoma cutâneo; dos quais, as mulheres representaram 62,45%. O tipo histológico prevalente em ambos os sexos foi o extensivo superficial. No sexo feminino, foi verificado maior número de neoplasias in situ (22,2%); e menor número de lesões cutâneas primárias com ulceração (22,8%), (p=0,02); além de menor profundidade de invasão (44,8%), (p=0,01). Conclusão: Na região Oeste do Estado de Santa Catarina, as mulheres com melanoma cutâneo apresentam características das lesões primárias que resultam em melhor prognóstico em relação ao sexo masculino.


Subject(s)
Humans , Male , Female , Epidemiology , Melanoma , Sex Factors , Skin Neoplasms/epidemiology
6.
Ecotoxicol Environ Saf ; 114: 93-101, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25618632

ABSTRACT

The effects of freshwater pollution in the highly contaminated river Sarno (Campania, Southern Italy) have been evaluated using bags containing the aquatic plant Lemna minor (Lemnacee, Arales), in order to determine morpho-physiological modifications as a response to pollutants. The exposition of Lemna bags for 7 days on three different sites along the river path showed alterations in chloroplasts and vacuoles shape and organization. Moreover, some specimens were exposed in vitro at the same heavy metal (HM) concentrations measured in the polluted sites of the river, and compared with data from the bag experiment; to verify the dose and time dependent effects, samples were exposed to HM in vitro at concentrations ranging from 10(-6) to 10(-4)M up to 7 days. Transmission electron microscopy (TEM) observations on in vitro plants confirmed that ultrastructural alterations affected most of plastids and the shape of different subcellular structures, namely vacuoles; in in vitro stressed specimens, Heat Shock Proteins 70 (Hsp70) levels changed, in dependence of changing levels of HM measured in different sites along the river path. Thus L. minor exhibited a possible correlation between the levels of HM pollution and Hsp70 occurrence; interestingly, the data presented showed that copper specifically increased Hsp70 levels at concentrations detected in polluted river waters, whereas cadmium and lead did not; on the other side, the latter represent highly toxic elements when specimens were exposed to higher levels in vitro. The effects of specific elements in vitro are compared to those observed in bags exposed along the river path; thus results are examined in order to propose L. minor as an organism able to be utilized to monitor heavy metals pollution; the possibility of using Hsp70s as specific markers of HM pollution is discussed.


Subject(s)
Araceae/drug effects , HSP70 Heat-Shock Proteins/biosynthesis , Metals, Heavy/toxicity , Plant Proteins/biosynthesis , Rivers , Water Pollutants, Chemical/toxicity , Araceae/metabolism , Araceae/ultrastructure , Biomarkers/metabolism , Italy
7.
Int J Phytoremediation ; 14(4): 374-87, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22567718

ABSTRACT

A comprehensive understanding of the uptake, tolerance, and transport of heavy metals by plants will be essential for the development of phytoremediation technologies. In the present paper, we investigated accumulation, tissue and intracellular localization, and toxic effects of cadmium (Cd), lead (Pb), zinc (Zn), and copper (Cu) in three aquatic macrophytes (the angiosperms Lemna minor and Elodea canadensis, and the moss Leptodictyum riparium). We also tested and compared their capacity to absorb heavy metal from water under laboratory conditions. Our data showed that all the three species examined could be considered good bioaccumulators for the heavy metals tested. L. riparium was the most resistant species and the most effective in accumulating Cu, Zn, and Pb, whereas L. minor was the most effective in accumulating Cd. Cd was the most toxic metal, followed by Pb, Cu, and Zn. At the ultrastructural level, sublethal concentrations of the heavy metals tested caused induced cell plasmolysis and alterations of the chloroplast arrangement. Heavy metal removal experiments revealed that the three macrophytes showed excellent performance in removing the selected metals from the solutions in which they are maintained, thus suggesting that they could be considered good candidates for wastewaters remediation purpose.


Subject(s)
Araceae/metabolism , Bryopsida/metabolism , Hydrocharitaceae/metabolism , Metals, Heavy/metabolism , Water Pollutants, Chemical/metabolism , Araceae/drug effects , Araceae/growth & development , Araceae/ultrastructure , Biodegradation, Environmental , Bryopsida/drug effects , Cadmium/analysis , Cadmium/metabolism , Cadmium/toxicity , Copper/analysis , Copper/metabolism , Copper/toxicity , Hydrocharitaceae/drug effects , Lead/analysis , Lead/metabolism , Lead/toxicity , Metals, Heavy/analysis , Metals, Heavy/toxicity , Organ Specificity , Plant Leaves/drug effects , Plant Leaves/growth & development , Plant Leaves/metabolism , Plant Leaves/ultrastructure , Plant Stems/drug effects , Plant Stems/growth & development , Plant Stems/metabolism , Plant Stems/ultrastructure , Time Factors , Water Pollutants, Chemical/toxicity , Water Purification , Zinc/analysis , Zinc/metabolism , Zinc/toxicity
8.
Int J Phytoremediation ; 14(4): 443-55, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22567723

ABSTRACT

The effects of heavy metals, both toxic (Pb, Cd) and essential (Cu, Zn) on the ultrastructure and the induction of Heat Shock Protein 70 (HSP70) have been studied in the aquatic moss Leptodictyum riparium Hedw. In vitro cultured L. riparium was treated with different heavy metals, both toxic, as cadmium or lead; and essential microelements such as Copper or Zinc concentrations ranging from 10(-3) to 10(-6) M to investigate both ultrastructural damage and HSP induction. TEM observations showed that sub-lethal concentrations of heavy metals caused only slight changes, largely localized in the chloroplasts. Among all the heavy metals tested, cadmium caused the most severe modifications. Heavy metals caused the decrease of the soluble protein content and the enhancement of proteins reacting versus HSP70 antibodies, suggesting that molecular chaperons might be involved in the resistance to toxic effects of lead, cadmium, copper and zinc. Therefore, the induction of HSP70 in L. riparium would confer a higher resistance to pollutants under stressful conditions lethal for other mosses and higher plant species. These results suggest that the moss L. riparium can tolerate heavy metals stress without incurring severe cellular/subcellular damage. Therefore it can be used as a useful indicator of heavy metals accumulation.


Subject(s)
Bryopsida/drug effects , Bryopsida/ultrastructure , Environmental Pollutants/toxicity , HSP70 Heat-Shock Proteins/metabolism , Metals, Heavy/toxicity , Bryopsida/metabolism , Cadmium/metabolism , Cadmium/toxicity , Copper/metabolism , Copper/toxicity , Electron Probe Microanalysis , Environmental Pollutants/metabolism , Lead/metabolism , Lead/toxicity , Metals, Heavy/metabolism , Microscopy, Electron, Transmission , Zinc/metabolism , Zinc/toxicity
9.
Environ Pollut ; 157(8-9): 2255-60, 2009.
Article in English | MEDLINE | ID: mdl-19446383

ABSTRACT

In this study, a biomonitoring project using the moss Scorpiurum circinatum was carried out to evaluate the deposition and biological effects of heavy metals in the area of Acerra (Naples, S Italy), one of the vertices of the sadly called "Italian triangle of death" owing to the dramatic increase in tumours. The results clearly indicated that the study area is heavily polluted by heavy metals, a large proportion of which is likely present in the atmosphere in particulate form. The ultrastructural organization of exposed samples was essentially preserved, but cell membrane pits, cytoplasm vesicles and concentric multilamellar/multivesicular bodies, probably induced by pollution, were found, which may be involved in the tolerance mechanisms to metal pollution in this moss species. Although severe biological effects were not found at the ultrastructural level in the exposed moss, effects on humans, especially after long-term exposure, are to be expected.


Subject(s)
Air Pollutants/analysis , Bryophyta/chemistry , Environmental Monitoring/methods , Metals, Heavy/analysis , Air Pollutants/toxicity , Atmosphere/chemistry , Bryophyta/drug effects , Bryophyta/ultrastructure , Italy , Metals, Heavy/toxicity
10.
Environ Pollut ; 151(2): 401-7, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18179850

ABSTRACT

This study compared the heavy metal bioaccumulation capacity in the epiphytic moss Scorpiurum circinatum and the epiphytic lichen Pseudevernia furfuracea, exposed in bags for 3 months in the urban area of Acerra (S Italy). The content of Al, As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Ti, V, and Zn was measured by ICP-MS. The results showed that both species accumulated all the heavy metals assayed. The moss had the highest bioaccumulation capacity for all metals and showed a more constant and linear accumulation trend than the lichen. Intra-tissue heavy metal bioaccumulation was assessed by X-ray microanalysis applied to ESEM operated in high and low vacuum and ESEM modes.


Subject(s)
Bryophyta/metabolism , Environmental Monitoring/methods , Environmental Pollutants/metabolism , Lichens/metabolism , Metals, Heavy/metabolism , Bryophyta/chemistry , Cities , Electron Probe Microanalysis , Environmental Pollutants/analysis , Italy , Lichens/chemistry , Metals, Heavy/analysis , Microscopy, Electron, Scanning , Spectrum Analysis
11.
Neuropeptides ; 35(3-4): 137-47, 2001.
Article in English | MEDLINE | ID: mdl-11884203

ABSTRACT

We have investigated the pharmacological properties of MEN 11467, a novel partially retro-inverse peptidomimetic antagonist of tachykinin NK(1) receptors. MEN 11467 potently inhibits the binding of [(3)H] substance P (SP) to tachykinin NK(1) receptors in the IM9 limphoblastoid cell line (pK(i) = 9.4 +/- 0.1). MEN 11467 is highly specific for the human tachykinin NK(1) receptors, since it has negligible effects (pK(i) <6) on the binding of specific ligands to tachykinin NK(2) or NK(3) receptors and to a panel of 30 receptors ion channels unrelated to tachykinin receptors. The antagonism exerted by MEN 11467 at tachykinin NK(1) receptors is insurmountable in saturation binding experiments, both K(D) and B(max) of SP were significantly reduced by MEN 11467 (0.3-10 nM). In the guinea-pig isolated ileum, MEN 11467 (0.03-1 nM) produced a nonparallel rightward shift of the concentration-response curve to SP methylester with a concomitant reduction of the Emax to the agonist (pK(B) = 10.7 +/- 0.1). Moreover the antagonist activity of MEN 11467 was hardly reversible despite prolonged washout. In vivo, MEN 11467 produced a long lasting (> 2-3h) dose-dependent antagonism of bronchoconstriction induced by the selective tachykinin NK(1) receptor agonist, [Sar(9), Met(O(2))(11)]SP in anaesthetized guinea-pigs (ID(50)s' = 29+/-5, 31+/-12 and 670+/-270 microg/kg, after intravenous, intranasal and intraduodenal administration, respectively), without affecting bronchoconstriction induced by methacholine. After oral administration MEN 11467 produced a dose-dependent inhibition of plasma protein extravasation induced in guinea-pig bronchi by [Sar(9), Met(O(2))(11)] (ID(50) = 6.7 +/- 2 mg/kg) or by antigen challenge in sensitized animals (ID(50) = 1.3 mg/kg). After i.v. administration MEN 11467 weakly inhibited the GR 73632-induced foot tapping behaviour in gerbil (ED(50) = 2.96 +/- 2 mg/kg), indicating a poor ability to block central tachykinin NK(1) receptors. These results demonstrate that MEN 11467 is a potent, highly selective and orally effective insurmountable pseudopeptide antagonist of peripheral tachykinin NK(1) receptors with a long duration of action.


Subject(s)
Cyclohexylamines/pharmacology , Indoles/pharmacology , Neurokinin-1 Receptor Antagonists , Substance P/analogs & derivatives , Administration, Oral , Animals , Bronchoconstriction/drug effects , Cyclohexylamines/administration & dosage , Cyclohexylamines/chemistry , Gerbillinae , Guinea Pigs , Indoles/administration & dosage , Indoles/chemistry , Lymphoma/metabolism , Male , Peptide Fragments/pharmacology , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-3/antagonists & inhibitors , Substance P/metabolism , Substance P/pharmacology , Tumor Cells, Cultured
12.
Neuropeptides ; 34(6): 355-9, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11162292

ABSTRACT

We have evaluated the potential protective activity of nepadutant, a selective tachykinin NK2 receptor antagonist, in a model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. The injury was quantified visually by using a macroscopic injury score, and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of nepadutant (0.3-10 mg/kg s.c., 1 h before acetic acid) markedly reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early phase of the injury. Single administration of nepadutant (3 mg/kg s.c.) reduced the macroscopic score and myeloperoxidase activity at the top (24 h) of inflammation. Repeated administration (3 mg/kg s.c. three times during 24 h) or co-administration of the tachykinin NK1 receptor antagonist MEN 11467 (3 mg/kg s.c.) did not enhance the antiulcer effect obtained with the single treatment with nepadutant. These data suggest the involvement of tachykinin NK2 receptors in the first phases of inflammation induced by acetic acid.


Subject(s)
Peptides, Cyclic/therapeutic use , Proctocolitis/prevention & control , Receptors, Neurokinin-2/antagonists & inhibitors , Tachykinins/physiology , Acetic Acid/toxicity , Animals , Cyclohexylamines/pharmacology , Guinea Pigs , Indoles/pharmacology , Male , Neurokinin-1 Receptor Antagonists , Peptides, Cyclic/pharmacology , Peroxidase/analysis , Proctocolitis/chemically induced , Proctocolitis/pathology
13.
Eur J Pharmacol ; 374(2): 277-83, 1999 Jun 18.
Article in English | MEDLINE | ID: mdl-10422769

ABSTRACT

The aim of this study was to evaluate the effect of MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent tachykinin NK1 receptor antagonist, in an experimental model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. This effect was compared to that of mesalazine (5-amino-2-hydroxybenzoic acid). The injury was quantified visually by using a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of MEN 11467 (0.3-10 mg/kg s.c., I h before acetic acid) reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early acute phase of the injury (death at 2.5 h). Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the plasma protein extravasation. Repeated administration of MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the macroscopic score and myeloperoxidase activity but not the plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. These results suggest a greater involvement of tachykinin NK1 receptors in the early phase than in the late phase of colonic inflammation in response to chemical injury.


Subject(s)
Blood Proteins/analysis , Cyclohexylamines/therapeutic use , Extravasation of Diagnostic and Therapeutic Materials/etiology , Indoles/therapeutic use , Peroxidase/metabolism , Proctocolitis/drug therapy , Receptors, Tachykinin/antagonists & inhibitors , Acetic Acid/adverse effects , Acute Disease , Administration, Rectal , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Disease Models, Animal , Drug Interactions , Guinea Pigs , Male , Mesalamine/pharmacology , Proctocolitis/chemically induced , Time Factors
14.
J Auton Pharmacol ; 18(5): 313-7, 1998 Oct.
Article in English | MEDLINE | ID: mdl-9831232

ABSTRACT

1. The aim of this study was to characterize the tachykinin receptors involved in producing plasma protein extravasation and contractile responses of the guinea-pig oesophageal sphincter. 2. In anaesthetized guinea-pigs, the selective tachykinin NK-1 receptor agonist [Sar9,Met(O2)11]substance P produced plasma protein extravasation (PPE) which was not affected by the treatment with the tachykinin NK-2 receptor antagonist MEN 10627 (1 micromol kg(-1) i.v.) or the histamine H1-receptor antagonist, diphenhydramine (34.5 micromol kg(-1) i.v.). However, the [Sar9,Met(O2)11]substance P-induced PPE was blocked by the previous administration of the peptide tachykinin NK-1 receptor antagonist FK 888 or by the non-peptide antagonist SR 140333, yielding ED50 values of 1.1 +/- 0.2 and 0.01 +/- 0.004 micromol kg(-1) i.v., respectively. 3. The tachykinin NK-2 or NK-3 receptor agonists [beta-Ala8]neurokinin A (4-10) or [MePhe7]neurokinin B, respectively, produced a weak PPE at high doses. The effect of [MePhe7]neurokinin B-induced PPE was inhibited by SR 140333. 4. In the guinea-pig isolated oesophageal sphincter, [Sar9,Met(O2)11]substance P did not exert any contractile effect up to 10 microM. The selective tachykinin NK-2 receptor agonist ([beta-Ala8]neurokinin A (4-10), produced concentration-dependent contractions (pD2 = 7.6 +/- 0.03) which were inhibited by the selective tachykinin NK-2 receptor antagonist, MEN 10627 (pA2 = 8.6 +/- 0.1). Also, the tachykinin NK-3 receptor selective agonist [MePhe7]neurokinin B induced concentration-dependent contractile responses, but these responses were inhibited by MEN 10627. 5. Altogether, these data indicate that the stimulation of tachykinin NK-1 receptor produces a vascular inflammatory response, while activation of tachykinin NK-2 receptors mediate the contraction of the guinea-pig oesophageal sphincter.


Subject(s)
Extravasation of Diagnostic and Therapeutic Materials , Inflammation/physiopathology , Muscle, Smooth/drug effects , Peptides, Cyclic/pharmacology , Receptors, Neurokinin-3/antagonists & inhibitors , Receptors, Tachykinin , Substance P/analogs & derivatives , Substance P/pharmacology , Animals , Dipeptides/pharmacology , Diphenhydramine/pharmacology , Dose-Response Relationship, Drug , Esophagogastric Junction/drug effects , Evans Blue/pharmacokinetics , Guinea Pigs , Indoles/pharmacology , Male , Muscle Contraction/drug effects , Neurokinin-1 Receptor Antagonists , Receptors, Neurokinin-1/agonists , Receptors, Neurokinin-2/agonists , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-3/agonists , Receptors, Tachykinin/classification , Receptors, Tachykinin/physiology
15.
Angiology ; 49(5): 361-71, 1998 May.
Article in English | MEDLINE | ID: mdl-9591528

ABSTRACT

The etiology of carotid abnormalities is both congenital than acquired. The aim of this study was to clarify the role of aging and atherosclerosis in the acquired cases, and the role of these abnormalities in hemodynamic alterations and neurologic symptoms. Over a 1-year period the authors studied all the subjects undergoing carotid examination by continuous-wave and color-coded Doppler sonography at an Angiology Unit. They evaluated neurologic symptoms; risk factors for atherosclerosis; number, sites, and kinds of carotid abnormalities; atherosclerotic lesions; stenosis; hemodynamic alterations of the carotid; and other localizations of atherosclerotic diseases. There were 469 subjects: 272 (58%) with abnormalities (group 1) and 197 (42%) without abnormalities (group 2). The total number of abnormalities was 479 (104 tortuosities, 262 kinkings, and 113 coilings). The abnormalities were more prevalent in the elderly (P<0.001) and in women (P<0.001). In group 1 they found significant prevalences of hyperlipemia (P<0.001), hypertension (P<0.01), chronic cigarette smoking (P<0.01), and ischemic heart disease (P<0.05). Carotid atherosclerotic lesions were more prevalent in group 1 than in group 2 (P<0.001); among the patients with atherosclerotic carotid lesions, those in group 1 were older than those in group 2 (P<0.001). Tortuosity seemed to be associated with fewer hemodynamic alterations. The authors conclude that atherosclerosis, hypertension, and aging may play an important role in producing carotid abnormalities. The aging seemed more important than atherosclerosis. Only a prospective study of patients with carotid abnormalities and no atherosclerotic lesion will clarify the role of hemodynamics and neurologic symptomatology.


Subject(s)
Aging/pathology , Arteriosclerosis/complications , Carotid Arteries/pathology , Carotid Artery Diseases/etiology , Adult , Age Factors , Aged , Aged, 80 and over , Aging/physiology , Arteriosclerosis/diagnostic imaging , Arteriosclerosis/pathology , Arteriosclerosis/physiopathology , Blood Flow Velocity/physiology , Carotid Arteries/diagnostic imaging , Carotid Arteries/physiopathology , Carotid Artery Diseases/diagnostic imaging , Carotid Artery Diseases/pathology , Carotid Artery Diseases/physiopathology , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/etiology , Carotid Stenosis/pathology , Carotid Stenosis/physiopathology , Female , Hemodynamics/physiology , Humans , Hyperlipidemias/complications , Hypertension/complications , Male , Middle Aged , Myocardial Ischemia/complications , Neurologic Examination , Prevalence , Prospective Studies , Pulsatile Flow/physiology , Risk Factors , Sex Factors , Smoking/adverse effects , Ultrasonography, Doppler , Ultrasonography, Doppler, Color , Vascular Patency/physiology , Vascular Resistance/physiology
16.
Eur J Pharmacol ; 341(2-3): 201-9, 1998 Jan 12.
Article in English | MEDLINE | ID: mdl-9543241

ABSTRACT

In this study we investigated the pharmacological properties of MEN 11149, 2-(2-naphthyl)-1-N-[(1R,2S)-2-N-[1(H)indol-3-ylcarbonyl]aminocy clohexanecarbonyl]-1-[N'-methyl-N'-(4-methylphenylacetyl)]di aminoethane, a novel partially retro-inverse pseudo peptide antagonist of tachykinin NK1 receptors. MEN 11149 potently inhibits the binding of [3H]substance P to tachykinin NK1 sites in IM9 cells (pKi = 8.5 +/- 0.1). The compound is highly specific for the human tachykinin NK1 receptors, since it has negligible effects (pKi < 6) on the binding of specific ligands to tachykinin NK2, NK3 receptors and a battery of central and peripheral receptors or ion channels. The tachykinin NK1 receptor antagonism of MEN 11149 appears to be insurmountable since, in saturation binding experiments, both K(D) and Bmax are significantly affected by incubation with the compound (1-30 nM). In isolated guinea-pig ileum, MEN 11149 (0.1-100 nM) shifts to the right in a non-parallel way the substance P methyl ester-induced cumulative concentration-response curve with progressive inhibition of the maximal response (pK(B) = 9.6 +/- 0.1). When tested for reversibility at 5 nM in the same preparation, the compound displays a slow dissociation rate compared to the fast dissociation rate with FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)alaninamide) at 5 nM. In the same preparation, MEN 11149 (10 microM) did not affect the cumulative concentration-response curve to acetylcholine. In vivo, MEN 11149 dose dependently antagonizes [Sar9,Met(O2)11]substance P-induced bronchoconstriction in anaesthetized guinea-pigs (ID50 = 83 +/- 31 nmol/kg i.v.). The duration of the effect exceeds 3 h. MEN 11149 does not affect the bronchoconstriction induced by neurokinin A. The compound dose dependently inhibits [Sar9,Met(O2)11]substance P-induced plasma protein extravasation in guinea-pig bronchi whether administered intravenously (ID50 = 0.22 +/- 0.02 micromol/kg) or orally (ID50 = 0.97 +/- 0.21 micromol/kg). These results demonstrate that MEN 11149 is a potent, highly selective and orally effective insurmountable antagonist of tachykinin NK1 receptors with a long duration of action.


Subject(s)
Ileum/drug effects , Indoles/pharmacology , Muscle Contraction/drug effects , Naphthalenes/pharmacology , Receptors, Tachykinin/antagonists & inhibitors , Tachykinins/metabolism , Administration, Oral , Animals , Blood Proteins/drug effects , Bronchoconstriction/drug effects , Guinea Pigs , Humans , Ileum/physiology , Ion Channels/drug effects , Male , Receptors, Tachykinin/drug effects , Substance P/metabolism , Substance P/pharmacology , Tumor Cells, Cultured/drug effects
17.
Eur J Pharmacol ; 318(2-3): 419-24, 1996 Dec 30.
Article in English | MEDLINE | ID: mdl-9016933

ABSTRACT

The nature of the tachykinin receptors involved in the contraction of the circular muscle of dog colon has been investigated. The following rank order of potency for agonists was obtained: [Sar9,Met(O2)11]substance P > or = neurokinin A > [beta-Ala8]neurokinin A-(4-10) >> [MePhe7]neurokinin B. The efficacy of the tachykinin NK2 receptor agonists was significantly greater than that of the tachykinin NK1 receptor agonists and of carbachol. A concentration-dependent rightward shift of the motor response to neurokinin A (obtained in the presence of (+/-)-CP 96,345) was induced by peptide and non-peptide tachykinin NK2 receptor antagonists with this rank order: MEN 10,627 = SR 48,968 >> L 659,877 > MEN 10,376 > MDL 28,564. MEN 10,627 and SR 48,968 affinities were similar to those measured in human tissues. In conclusion, the tachykinin NK2 receptor plays a predominant role in tachykinin-induced contraction of the canine colonic circular muscle and this tissue could be useful to predict the pharmacological actions of MEN 10,627 and SR 48,968 in human colon.


Subject(s)
Benzamides/pharmacology , Colon/drug effects , Peptides, Cyclic/pharmacology , Piperidines/pharmacology , Receptors, Neurokinin-2/antagonists & inhibitors , Animals , Biphenyl Compounds/pharmacology , Colon/physiology , Dogs , Dose-Response Relationship, Drug , Gastrointestinal Motility/drug effects , In Vitro Techniques , Muscle Contraction/drug effects , Receptors, Neurokinin-2/physiology
18.
Neurosci Lett ; 219(3): 155-8, 1996 Nov 29.
Article in English | MEDLINE | ID: mdl-8971803

ABSTRACT

A double retrograde axonal tracing technique has been used to ascertain the localization of neuronal cell bodies which give rise to branching axons innervating both the urinary bladder and the urethra in male rat. Application of fluorescent tracers Fast blue (FB) and Diamidino yellow (DY) to postganglionic fibers to the urinary bladder and to the urethra (penile nerve), respectively, produced the double-labeling of neurons located in the dorsal root ganglia and in the 'intermediolateral nucleus'.


Subject(s)
Axons/physiology , Spinal Cord/physiology , Synaptic Transmission , Urethra/innervation , Urinary Bladder/innervation , Afferent Pathways/physiology , Amidines , Animals , Efferent Pathways/physiology , Ganglia, Spinal/cytology , Ganglia, Spinal/physiology , Lumbosacral Region , Male , Neurons/physiology , Rats , Rats, Inbred Strains
19.
J Pharmacol Exp Ther ; 276(1): 212-8, 1996 Jan.
Article in English | MEDLINE | ID: mdl-8558433

ABSTRACT

We investigated the electrocortical (E.Co.G) correlates of visceral (topical capsaicin application or overdistension of the urinary bladder) and somatic (perineal pinching) painful stimulation in urethane-anesthetized rats and their modulation by intrathecal application of selective tachykinins receptors (NK 1 and NK 2) antagonists. Vesical overdistension or topical capsaicin on the bladder serosal surface produced an immediate and lasting E.Co.G. desynchronization resembling a cortical arousal. A second application of capsaicin was ineffective. Bladder contraction induced by topical acetylcholine did not alter E.Co.G. A desynchronized E.Co.G. was also induced by pinching of the perineal area of the rat. Intrathecal administration of lidocaine at lumbosacral level abolished the E.Co.G. desynchronization induced by both visceral and somatic noxious stimulation. On the other hand capsaicin-induced or over-distension (but not pinching-induced) E.Co.G. desynchronization disappeared in animals systemically pretreated with capsaicin or after intrathecal administration of NK 1 tachykinin receptor antagonists such as the peptide GR 82334 or the nonpeptide RP 67580, whereas the inactive enantiomer RP 68651 or the nonpeptide NK 2 antagonists SR 48968 were ineffective. In conclusion, the experimental model described herein, allowing a quantitative analysis of the E.Co.G. correlates of visceral and somatic noxious stimulation in urethane-anesthetized rats, provides evidence for a specific neural pathway carrying bladder-arising visceral (both mechanical and chemical) nociception that uses pelvic capsaicin-sensitive afferents projecting to NK 1 (but not NK 2) bearing spinal neurons and that ultimately leads to activation of cortical areas.


Subject(s)
Benzamides/pharmacology , Cortical Synchronization/drug effects , Indoles/pharmacology , Physalaemin/analogs & derivatives , Piperidines/pharmacology , Receptors, Tachykinin/antagonists & inhibitors , Acetylcholine/toxicity , Administration, Topical , Anesthesia , Animals , Capsaicin/toxicity , Electric Stimulation , Injections, Spinal , Isoindoles , Lidocaine , Male , Perineum/innervation , Perineum/physiology , Physalaemin/pharmacology , Rats , Rats, Wistar , Sensitivity and Specificity , Urethane , Urinary Bladder/innervation
20.
Eur J Pharmacol ; 278(2): 117-24, 1995 May 15.
Article in English | MEDLINE | ID: mdl-7671996

ABSTRACT

Electrical field stimulation of isolated mouse vas deferens elicited sympathetic twitch whose amplitude was transiently enhanced by the selective tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P (0.3-30 nM), but not by selective NK2 and NK3 receptor agonists. Potentiation by [Sar9,Met(O2)11]substance P was antagonized by (+/-)-CP 96,345 [(2S,3S)-cis-2-(diphenylmethyl)-N- [(2-methoxyphenyl)-methyl]-1-azabicyclo[2.2.2]octan-3-amine] (IC50 = 0.1 microM). On the other hand, electrical field stimulation-induced contractions were inhibited by calcitonin gene-related peptide, CGRP (0.1-30 nM), and this action was reduced by its antagonist, human CGRP-(8-37) (3 microM). [Sar9,Met(O2)11]substance P (3 nM) did not affect either high-K+ or noradrenaline-induced contraction, while CGRP (3 nM) significantly reduced the noradrenaline-induced motor response. Capsaicin (1 microM) inhibited sympathetic twitches, and this effect was partially antagonized by human CGRP-(8-37). In the presence of this antagonist, capsaicin induced a short-living and (+/-)-CP 96,345-sensitive twitch enhancement. These data suggest that the sympathetic control of mouse vas deferens motility can be modulated in an opposite manner by tachykinin NK1 (prejunctionally located) and by CGRP (pre- and/or postjunctionally located) receptors.


Subject(s)
Muscle, Smooth/drug effects , Muscle, Smooth/innervation , Receptors, Calcitonin Gene-Related Peptide/drug effects , Receptors, Neurokinin-1/drug effects , Sympathetic Nervous System/physiology , Vas Deferens/drug effects , Vas Deferens/innervation , Animals , Calcitonin Gene-Related Peptide/pharmacology , Electric Stimulation , Humans , In Vitro Techniques , Male , Mice , Miotics/pharmacology , Muscle Contraction/drug effects , Neurokinin-1 Receptor Antagonists , Norepinephrine/pharmacology , Oxidopamine , Peptide Fragments/pharmacology , Potassium Chloride/pharmacology , Receptors, Neurokinin-1/agonists , Receptors, Neurokinin-2/agonists , Receptors, Neurokinin-2/antagonists & inhibitors , Receptors, Neurokinin-3/agonists , Receptors, Neurokinin-3/antagonists & inhibitors , Sympathectomy, Chemical , Sympathetic Nervous System/drug effects
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