Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma.

BACKGROUND: Pazopanib, an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/c-Kit, is approved in locally advanced/metastatic renal cell carcinoma (RCC). METHODS: Data from trials in advanced solid tumours and advanced/metastatic RCC were used to explore the relationships between plasma pazopanib concentrations and biomarker changes, safety, and efficacy. Initially, the relationships between pharmacokinetic parameters and increased blood pressure were investigated, followed by analysis of steady-state trough concentration (Cτ) and sVEGFR2, safety, progression-free survival (PFS), response rate, and tumour shrinkage. Efficacy/safety end points were compared at Cτ decile boundaries. RESULTS: Strong correlation between increased blood pressure and Cτ was observed (r(2)=0.91), whereas weak correlation was observed between Cτ and decline from baseline in sVEGFR2 (r(2)=0.27). Cτ threshold of >20.5 µg ml(-1) was associated with improved efficacy (PFS, P<0.004; tumour shrinkage, P<0.001), but there was no appreciable benefit in absolute PFS or tumour shrinkage from Cτ >20.5 µg ml(-1). However, the association of Cτ with certain adverse events, particularly hand-foot syndrome, was continuous over the entire Cτ range. CONCLUSIONS: The threshold concentration for efficacy overlaps with concentrations at which toxicity occurs, although some toxicities increase over the entire Cτ range. Monitoring Cτ may optimise systemic exposure to improve clinical benefit and decrease the risk of certain adverse events.

A dose-escalating phase I of imatinib mesylate with fixed dose of metronomic cyclophosphamide in targeted solid tumours.

BACKGROUND: Preclinical findings suggest that imatinib mesylate (IM) and metronomic cyclophosphamide (MC) combination provides synergistic antiangiogenic activity on both pericytes and endothelial cells. METHODS: We have designed a 3+3 dose-escalating phase I trial with a fixed dose of MC (50 mg two times daily) plus IM (400 mg per day; 300 and 400 mg two times daily). Enrolled patients had IM- and sutininib-refractory advanced gastrointestinal stromal tumours (GIST) (n=17), chordoma (n=7) and mucosal melanoma (n=2). Dose-limiting toxicities were monitored for the first 6 weeks. Progression-free survival (PFS) and response assessment are based on RECIST 1.0 guidelines. Pharmacokinetics of IM were measured before and after exposure to MC. RESULTS: No dose-limiting toxicity was observed. Fourteen patients of the expanded cohort received 400 mg two times daily of IM with MC. Apart from a case of possibly related acute leukaemia occurring after 4 years of treatment, we did not see unexpected toxicity. No drug-drug pharmacokinetic interaction was observed. There was no objective response. We have observed long-lasting stable disease in chordoma patients (median PFS=10.2 months; range, 4.2-18+) and short-term stable disease in heavily GIST pretreated patients (median PFS=2.3 months; range, 2.1-6.6). CONCLUSION: This combination is feasible and may warrant further exploration in refractory GIST or chordoma patients.

Analysis of allergen immunotherapy studies shows increased clinical efficacy in highly symptomatic patients.

BACKGROUND: The assessment of allergen immunotherapy (AIT) efficacy in the treatment for seasonal allergic rhinoconjunctivitis (SAR) symptoms is challenging. Allergen immunotherapy differs from symptomatic therapy in that while symptomatic therapy treats patients after symptoms appear and aims to reduce symptoms, AIT is administered before symptoms are present and aims to prevent them. Thus, clinical studies of AIT can neither establish baseline symptom levels nor limit the enrolment of patients to those with the most severe symptoms. Allergen immunotherapy treatment effects are therefore diluted by patients with low symptoms for a particular pollen season. The objective of this analysis was to assess the effect possible to achieve with AIT in the groups of patients presenting the most severe allergic symptoms. METHODS: Study centres were grouped into tertiles categorized according to symptom severity scores observed in the placebo patients in each centre (low, middle and high tertiles). The difference observed in the average score in each tertile in active vs placebo-treated patients was assessed. This allowed an estimation of the efficacy that could be achieved in patients from sites where symptoms were high during the pollen season. RESULTS: An increased treatment effect was observed in the most severe patients and was independent of the study analysed and symptom score used. CONCLUSIONS: The use of a tertile approach to analyse efficacy in AIT in SAR clinical studies can give a more accurate assessment of potential clinical benefit.

[Introduction of an anticholinesterase drug in the context of myasthenia, in a severe asthmatic patient]. / Introduction d'un anticholinestérasique dans le contexte d'une myasthénie, chez une patiente asthmatique sévère.

Association of asthma with myasthenia gravis presents a twofold peculiarity. First, as dyspnea characterizes both conditions, diagnostic orientation is difficult. Second, from a therapeutic standpoint, the initiation of anticholinesterase treatment requires a multidisciplinary approach due to possible contraindication for asthma. We report on the case of a patient monitored for severe asthma and treated with biotherapy, and also monitored for myasthenia gravis, and treated with anticholinesterase.

Methoxpropamine (MXPr) in powder, urine and hair samples: Analytical characterization and metabolite identification of a new threat.

Methoxpropamine (MXPr) is an arylcyclohexylamine dissociative drug with structural similarities with 3-MeO-PCE, ketamine and deschloroketamine. MXPr was identified for the first time in Europe in October 2019 in Denmark and is considered a new psychoactive substance. We undertook the molecular identification and characterization of MXPr in urine, hair and powder samples. We used a combination of several analytical methods: liquid-state nuclear magnetic resonance (NMR), infra-red spectroscopy (IR) and liquid chromatography high-resolution mass spectrometry (LC-HRMS). The second objective was to explore the metabolism of MXPr in silico and in vitro. To detect characteristic metabolites that prove MXPr consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QToF-MS). A software algorithm (Unifi®) was used to predict in silico biotransformations of MXPr. Three metabolites were identified in the in vitro studies including N-despropyl(nor)MXPr, O-desmethyl MXPr and dihydroMXPr. Most of these phase II metabolites were confirmed to be present in urine and hair samples collected from an MXPr consumer. This is the first report of the identification of MXPr in France with analytical findings. This study highlights the challenge of identifying new psychoactive substances (NPS) when they are missing from compound libraries and if a standard is not available. The use of various complementary analytical methods combined with HRMS offers a promising approach for the molecular characterization of NPS.

Suitability of infrared spectroscopy for drug checking in harm reduction centres.

Drug checking is a service for people who use drugs that includes product analysis and an individual interview including results feedback and harm reduction counselling. It uses different analytical methods but few studies demonstrate their value in current practice. The main objective of this work is to compare the analytical performance of IR spectroscopy to laboratory reference method in the context of drug checking in a harm reduction centre. The secondary objectives are to carry out a description of the people who use drugs requesting a product analysis, and to compare the assumed compositions of products purchased with their real compositions. During 2018, all requests for drug testing analysis were included for on-site analysis by IR spectrometry in a harm reduction center and verified by the reference method (UPLC-HRMS) at Bordeaux University Hospital Center. Socioeconomic and product data were also collected. One hundred and thirty-six samples were collected. The results obtained with IR and UPLC-HRMS were compared. IR spectrometry results did not match with reference method in 8 % (n=11) of cases, corresponding to blotters, cannabis and some psychoactive substances present in mixture or in small quantities. Among the products collected, only 5.1 % (n=7) did not correspond to the declared product, either alone or with adulterants. The IR spectrometer allows a simple and rapid detection of at least one molecule, most often the one of interest. However, it is limited to powder and tablet type matrices and is not suitable for blotters, cannabis, mixed or low content substances for which high resolution mass spectrometry remains the reference method.

The determinants of dyspnoea evaluated by the mMRC scale: The French Palomb cohort.

INTRODUCTION AND OBJECTIVE: Dyspnoea is a major symptom in COPD patients, but the determinants that could be associated with a higher dyspnoea mMRC score in COPD patients remain unclear. Our research aimed to study the determinants of dyspnoea at the threshold of 1, 2, 3 and 4 mMRC. PATIENTS AND METHODS: Diagnosis of COPD was made using spirometry with post-bronchodilator FEV1FVC<70%. An online questionnaire has been employed by pulmonologists to recruit COPD patients. The following variables were collected: age, gender, BMI, FEV1, RV, IC, TLC, FRC, mMRC, frequency of exacerbations and comorbidities. The LASSO was used to select the variables associated with the mMRC dyspnoea scale in a subgroup (who had no missing IC, RV and FRC values) of 421 COPD patients defined by the previously mentioned variables. RESULTS: One thousand nine hundred and sevety-three patients (65.3% males, average age=66±10, 38% current smokers) were included. Dyspnoea was correlated with a low FEV1 and with the number of exacerbations in the past 12 months. Multivariate analysis showed that the determinants of dyspnoea(mMRC≥2) are: FEV1: OR=3.71[2.86-4.82]; anxiety: OR=2.52[1.82-3.47]; cough: OR=1.94[1.57-2.40]; bronchiectasis: OR=1.84[1.03-3.29]; age: OR=1.80[1.45-2.24]; hyperinflation (RV/TLC): OR=1.68[1.34-2.11]; ischemic cardiopathy: OR=1.63[1.22-2.18]; hypertension: OR=1.52[1.21-1.91]; exacerbations (≥2): OR=1.41[1.10-1.81]; women: OR=1.39[1.10-1.74] and overweight: OR=1.33[1.06-1.67]. The subgroup analysis showed that: FEV1: OR=3.47[1.96-6.12]; exacerbations (≥2) OR=2.31[1.33-4.17] and hyperinflation (IC/TLC) OR=0.57[0.35-0.85] were associated with higher dyspnoea (mMRC≥2). CONCLUSION: Our results showed that dyspnoea is related to the severity of airflow limitation, gender, exacerbations, comorbidities and hyperinflation.

Chloroquine and hydroxychloroquine in the management of COVID-19: Much kerfuffle but little evidence.

Chloroquine and hydroxychloroquine are drugs that have shown in vitro activity on the replication of certain coronaviruses. In the context of the SARS-Cov-2 epidemic, the virus responsible for the novel coronavirus disease (COVID-19), these two drugs have been proposed as possible treatments. The results of the first clinical studies evaluating the effect of hydroxychloroquine do not support any efficacy of this drug in patients with COVID-19, due to major methodological weaknesses. Yet, these preliminary studies have aroused considerable media interest, raising fears of massive and uncontrolled use. In the absence of evidence of clinical benefits, the main risk is of exposing patients unnecessarily to the well-known adverse effects of hydroxychloroquine, with a possibly increased risk in the specific setting of COVID-19. In addition, widespread use outside of any recommendation risks compromising the completion of good quality clinical trials. The chloroquine hype, fueled by low-quality studies and media announcements, has yielded to the implementation of more than 150 studies worldwide. This represents a waste of resources and a loss of opportunity for other drugs to be properly evaluated. In the context of emergency, rigorous trials are more than ever needed in order to have, as soon as possible, reliable data on drugs that are possibly effective against the disease. Meanwhile, serious adverse drug reactions have been reported in patients with COVID-19 receiving hydroxychloroquine, justifying to limit its prescription, and to perform suitable cardiac and therapeutic drug monitoring.

Death related to nicotine replacement therapy: A case report.

Transdermal nicotine patches and nicotine tablets are widely used for substitution therapies after cessation of smoking. Toxic concentrations of nicotine and cotinine, its main metabolite, are rarely reported, either in cases of misuse or in a fatal context. We report here a rare fatal case due to massive exposure to nicotine replacement therapy. A 41-year-old man was found dead by his cellmate with 7 nicotine patches on the body. There were 14 nicotine patches (21 mg) and 5 empty blisters of nicotine tablets (Nicopass® 1.5 mg) in the bin. External, internal, and histological examinations revealed asphyxia syndrome. Toxicological analyses indicated lethal concentrations of nicotine and cotinine in femoral (2239 and 1230 ng/mL) and cardiac blood (1344 and 1090 ng/mL). Screening for ethanol, drugs, and illicit drugs revealed therapeutic concentrations of cyamemazine, lormetazepam, nordiazepam, oxazepam, and buprenorphine and its metabolite. THC and its metabolites were also detected, reflecting use of cannabis. The findings highlight the risk of nicotine poisoning in persons using nicotine patches. This case emphasises the importance of carrying out complete toxicological analyses to prevent other instances of nicotine poisoning from being overlooked.

[Assessment of the handling of inhaler devices: an observational study of children in primary care]. / Comparaison de l'utilisation des dispositifs d'inhalation par les enfants asthmatiques en pratique de ville.

UNLABELLED: The correct use of inhaler devices is important for the efficacy of the treatment of childhood asthma. Few studies have compared the use of inhaler devices in real life, in particular in children. AIM: To determine whether such devices were correctly used in asthmatic children within a primary care setting. POPULATION AND METHODS: Three hundred and sixty-four children aged 5 to 18 years (mean+/-SD: 14.1+/-3.3) treated for at least 1 month by an inhaler device were included. During a routine visit to the doctor, the primary care physician assessed the childrens' handling of their current device, using a checklist established for each device from the package leaflet. RESULTS: At least half of the patients made at least 1 error, regardless of the inhaler used. The best result was obtained with the Diskus (46% error-rate) and the worst with the pressurized metered-dose inhaler (pMDI) (78% error-rate). The rank order of increasing critical-error rate (at least 1 error) was as follows: Diskus (6%)

Acute Methiopropamine Intoxication After "Synthacaine" Consumption.

Use of methiopropamine (MPA), a synthetic metamfetamine analog, has been detected since 2011 in Europe, but there is limited information on its acute toxicity. A 30-year-old man was admitted to the emergency department in a confused state, with paranoid delusion, auditory and visual hallucinatory experiences, and incoherent speech following the use of "synthacaine" (a slang term derived from "synthetic" and "cocaine"). Toxicological screening for pharmaceuticals and drugs of abuse by liquid chromatography-diode-array detector, gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry (LC-MS-MS) detected MPA, which was subsequently quantified by a specific LC-MS-MS method. Of note, 13 h after presentation to the emergency department, the plasma concentration of MPA was 14 ng/mL. This case report confirms the toxicity of MPA and the need for toxicological analysis to confirm the substance actually ingested by users of new psychoactive substances.

Paradoxal effect of salbutamol in an in vitro model of bronchoprotection.

Salbutamol-induced hyperresponsiveness to acetylcholine was investigated in human and guinea-pig isolated airways and cultured human airway smooth muscle cells. Salbutamol (10(-7)-10(-5) m) inhibited contractions induced by low concentrations of acetylcholine (10(-8)-10(-7) m) but potentiated contractions induced by higher concentrations of acetylcholine (10(-5)-10(-3) m). Pretreatment with the calcium channel antagonist nicardipine suppressed salbutamol-induced hyperresponse. Stimulation of cultured human airway smooth muscle cells with salbutamol (10(-6) m) amplified intracellular calcium concentration rise induced by acetylcholine (10(-5) m). Propranolol (10(-7) m), a beta1- and beta2-adrenoceptor antagonist, and ICI 118551 (10(-7)-10(-6) m), a beta2-adrenoceptor antagonist, suppressed the inhibitory effect of salbutamol but did not inhibit the hyperresponse on high concentrations of acetylcholine. In contrast, higher concentration of propranolol (10(-6) m) inhibited salbutamol-induced hyperreactivity. Effects of salbutamol were not affected by atenolol, a beta1-adrenoceptor blocker. Salbutamol-induced hyperresponsiveness is mediated through a mechanism involving calcium channel activation.

Indirect muscarinic receptor activation by pentamidine on airway smooth muscle.

1. Pentamidine is routinely used to reduce the incidence of Pneumocystis carinii pneumonia in patients infected with human immunodeficiency virus, but it has been described as inducing pulmonary adverse effects, such as cough and bronchospasm. 2. In this paper we have investigated the effects of pentamidine on guinea-pig isolated main bronchi and human isolated bronchi. Pentamidine induced a concentration-dependent contraction in both preparations with pD2 values of 9.64 +/- 0.07 (n = 8) and 9.73 +/- 0.06 (n = 8) and a maximal effect (Emax) of 40 +/- 4% and 34 +/- 5% of the response to acetylcholine (1 mM) in guinea-pig and human bronchi respectively. Atropine (0.01 to 0.1 microM) and the muscarinic M3 receptor antagonist, hexahydro-siladiphenidol (0.1 and 1 microM) inhibited pentamidine-induced concentration-responses in both preparations in a non-competitive manner, whereas only high concentrations of the M1 receptor antagonist pirenzipine (1 microM) inhibited pentamidine concentration-response curves. 3. The cholinesterase inhibitor, tacrine (1 microM), potentiated the effect of pentamidine; in contrast, morphine inhibited pentamidine-induced responses. 4. The bronchoconstrictor effect of pentamidine on guinea-pig and human isolated bronchi was not modified by the H1 histamine receptor antagonist, mepyramine, by indomethacin or by the neurokinin NK1 and NK2 receptor antagonists, CP-96,345 and SR 48969 respectively, suggesting that neither histamine receptor stimulation, arachidonic acid derivative formation, nor tachykinin release are involved in pentamidine-induced contraction of human and guinea-pig airways. 5. Our overall results suggest that pentamidine induces contraction of guinea-pig and human isolated bronchi through prejunctional cholinergic nerve stimulation.

Formoterol and salbutamol inhibit bradykinin- and histamine-induced airway microvascular leakage in guinea-pig.

1. The effects of the beta 2-adrenoceptor agonists, salbutamol and formoterol, on the increase of microvascular permeability induced by histamine or bradykinin in guinea-pig airways have been studied in vivo. Extravasation of intravenously injected Evans blue dye was used as an index of permeability. The effects of salbutamol and formoterol on the increase in pulmonary airway resistance induced by histamine or bradykinin have also been studied. 2. The increase in pulmonary airway resistance induced by histamine or bradykinin was totally inhibited by salbutamol and formoterol. The ED50 of the two mediators were 0.59 +/- 0.21 (n = 5) and 0.20 +/- 0.14 (n = 5) micrograms kg-1 respectively for salbutamol, and 0.13 +/- 0.12 (n = 6) and 0.02 +/- 0.01 (n = 6) micrograms kg-1 respectively for formoterol. 3. Salbutamol (10 and 30 micrograms kg-1) and formoterol (1 and 10 micrograms kg-1) inhibited the increase of microvascular permeability induced by histamine (30 micrograms kg-1) in the guinea-pig airways. The inhibitory effect was predominant in the trachea and the main bronchi, with a maximum inhibition of 20 to 50%. The two drugs had little or no inhibitory effect on the other structures studied, viz. nasal mucosa, larynx, proximal and distal intrapulmonary airways. 4. Salbutamol and formoterol (1 and 10 micrograms kg-1) abolished the increase in microvascular permeability induced by bradykinin (0.3 micrograms kg-1). This inhibitory effect of two beta-adrenoceptor stimulants was predominant in the trachea and the nasal mucosa where it was observed with 1 microgram kg-1 of the beta-adrenoceptor agonists.In the main bronchi, and in the proximal and distal intrapulmonary airways, the effects of bradykinin were abolished by 10 pg kg- of formoterol and salbutamol.5. The effects of bradykinin, but not those of histamine, were significantly reduced (nasal mucosa, main bronchi and distal intrapulmonary airways) or abolished (trachea, proximal intrapulmonary airways) by morphine 10mgkg-1, i.v. These results suggest that an indirect effect, through non-adrenergic noncholinergic (NANC) nerves is involved in the action of bradykinin on the microvascular permeability.6. In conclusion, intravenously injected beta-adrenoceptor stimulants can inhibit, partially or totally, the increase of airways microvascular permeability induced by intravenous histamine or bradykinin. However, these effects require doses that are higher than those that inhibit the increase in pulmonary airway resistance induced by these mediators. As suggested by the results obtained with morphine, the higher efficacy of beta2-adrenoceptor agonists versus bradykinin may occur through activation of presynaptic receptors of the non-adrenergic non-cholinergic (NANC) nerves preventing release of inflammatory neuropeptides such as substance P and neurokinin A.

Furosemide inhibits bradykinin-induced contraction of human bronchi: role of thromboxane A2 receptor antagonism.

Bradykinin contracts human isolated small bronchi through prostanoid release and subsequent TP receptor stimulation. Furosemide 10(-4) to 10(-3) M concentration dependently inhibited bradykinin- and the stable TP receptor agonist U-46619-induced contraction of human isolated small airways. The inhibitory effect of furosemide on U-46619-induced contraction involves competitive antagonism at TP receptors. Such an inhibition of TP receptors could a least partly explain the inhibitory effect of furosemide on bradykinin-induced contraction, and could be one of the mechanisms of the protective effect of furosemide in asthma.

Role of thromboxane A2 in bradykinin-induced human isolated small bronchi contraction.

We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.

SR 140333 prevents potentiation by citric acid of plasma exudation induced by histamine in airways.

We here report a model of potentiation by citric acid of airway microvascular leakage induced by histamine and its modification by the tachykinin NK1 and NK2 receptor antagonists, SR 140333 ((S)1-{2-[3-(3,4-dichlorophenyl)-1-(3-iso-propoxyphenylacetyl)p iperidin- 3-yl]ethyl}-phenyl-1-azoniabicyclo[2.2.2]octane, chloride) and SR 48968 (S)-N-methyl-N-[4-(4-acetyl-amino-4-phenylpiperidino)-2-(3,4- dichlorophenyl-butyl]benzamide. Guinea-pigs exposed to an acrosol of citric acid 0.4 M for 1 h developed 24 h later a hyperresponsiveness to histamine-induced microvascular leakage measured by Evans blue dye extravasation. SR 140333, but not SR 48968 (1 mg kg-1 given each once 30 min before citric acid exposure), prevented this potentiation. These results provide further evidence of the role of tachykinin and tachykinin NK1 receptor stimulation on airway hyperresponsiveness and its neurogenic inflammatory component.

Interleukin-1beta-induced hyperresponsiveness to [Sar9,Met(O2)11]substance P in isolated human bronchi.

Interleukin-1beta has been reported to induce airway hyperresponsiveness in several animal models. In this study, we have investigated whether interleukin-1beta was able to potentiate the contractions of human isolated small bronchi (internal diameter < or = 1 mm) provoked by a specific tachykinin NK1 receptor agonist, [Sar9,Met(O2)11]substance P. Pre-incubation of human isolated small bronchi with interleukin-1beta (10 ng/ml, in Krebs-Henseleit solution, at 21 degrees C for 15 h) potentiated the contractile response to [Sar9,Met(O2)11]substance P. It also increased the [Sar9,Met(O2)11]substance P-induced release of thromboxane B2, the stable metabolite of thromboxane A2. Indomethacin (10(-6) M), a non-specific cyclooxygenase inhibitor, or GR 32191 ((1R-(1alpha(Z)),2beta,3beta,5alpha))-(+)-7-(5-(((1,1' -biphenyl)-4-yl)-methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-hept enoic acid, hydrochloride) (10(-6) M), a prostanoid TP-receptor antagonist, blocked the contractions induced by [Sar9,Met(O2)11]substance P both in control experiments and after interleukin-1beta pre-treatment, indicating that prostanoids and thromboxane receptors are directly implicated in the [Sar9,Met(O2)11]substance P-induced contractile response. The thromboxane mimetic U-46619 (10(-8)-10(-6) M) (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F2alpha)-induced contractions of human isolated small bronchi were not enhanced by interleukin-1beta pre-treatment, suggesting that no up-regulation of thromboxane receptors occurred. Furthermore, the cyclooxygenase-2 inhibitor CGP 28238 (6-(2,4-difluorophenoxy)-5-methyl-sulfonylamino-1-indanon e) (10(-6) M) had no direct effect on [Sar9,Met(O2)11]substance P-provoked contractions, but inhibited the interleukin-1beta-induced potentiation of [Sar9,Met(O2)11]substance P response. In conclusion, our results show that interleukin-1beta pre-treatment is able to potentiate the contractions of isolated human small bronchi provoked by [Sar9,Met(O2)11]substance P both by increasing prostanoid synthesis and by inducing a cyclooxygenase-2 pathway.

In vitro effects of HOE 140 in human bronchial and vascular tissue.

Bradykinin is a potent inflammatory mediator which may be involved in various airway diseases. A selective and potent antagonist of the bradykinin B2 receptor has recently been discovered (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin). The purpose of this study was to evaluate the potency of this compound in isolated human tissue (bronchus, pulmonary artery endothelium, umbilical artery and vein smooth muscle). Bradykinin induced contractions of the isolated human bronchus and umbilical artery and vein (the umbilical vessels were pretreated with indomethacin and L-nitro-arginine to inhibit prostaglandin and nitric oxide synthesis). It provoked an endothelium-dependent relaxation in the human pulmonary artery. HOE 140 was a non-competitive antagonist in human bronchial tissue (pKB: 8.19 +/- 0.30) and a competitive one in vascular tissue (pA2: 7.97 +/- 0.12, 8.16 +/- 0.16 and 8.00 +/- 0.11 in human pulmonary artery, umbilical artery and vein respectively). The effect of HOE 140 was selective as it did not influence the umbilical vein contractile response to serotonin and histamine. HOE 140 up to 3 x 10(-6) M was devoid of residual agonistic activity in the various human preparations studied. Furthermore, although the effects of HOE 140 were fully reversible, in isolated bronchial airways and umbilical veins, HOE 140 (10(-6) M) still possessed activity 1 h after being washed out in both tissues. Our results indicate that HOE 140 is a potent and potentially long-acting antagonist of the human bradykinin B2 receptor.