Randomized phase III study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer.

Background: Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of ß2 glycoprotein 1 (ß2GP1) to exert an antitumor immune response. This phase III trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and methods: Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1 : 1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary end point was overall survival (OS). Results: A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI 0.88-1.29; P = 0.533). There was no difference in progression-free survival (HR 1.00; 95% CI 0.82-1.22; P = 0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum ß2GP1 levels ≥200 µg/ml, a nonsignificant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P = 0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P = 0.006). Conclusions: The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high ß2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation. Clinical trial number: NCT01999673.

Variability in circulating gas emboli after a same scuba diving exposure.

PURPOSE: A reduction in ambient pressure or decompression from scuba diving can result in ultrasound-detectable venous gas emboli (VGE). These environmental exposures carry a risk of decompression sickness (DCS) which is mitigated by adherence to decompression schedules; however, bubbles are routinely observed for dives well within these limits and significant inter-personal variability in DCS risk exists. Here, we assess the variability and evolution of VGE for 2 h post-dive using echocardiography, following a standardized pool dive in calm warm conditions. METHODS: 14 divers performed either one or two (with a 24 h interval) standardized scuba dives to 33 mfw (400 kPa) for 20 min of immersion time at NEMO 33 in Brussels, Belgium. Measurements were performed at 21, 56, 91 and 126 min post-dive: bubbles were counted for all 68 echocardiography recordings and the average over ten consecutive cardiac cycles taken as the bubble score. RESULTS: Significant inter-personal variability was demonstrated despite all divers following the same protocol in controlled pool conditions: in the detection or not of VGE, in the peak VGE score, as well as time to VGE peak. In addition, intra-personal differences in 2/3 of the consecutive day dives were seen (lower VGE counts or faster clearance). CONCLUSIONS: Since VGE evolution post-dive varies between people, more work is clearly needed to isolate contributing factors. In this respect, going toward a more continuous evaluation, or developing new means to detect decompression stress markers, may offer the ability to better assess dynamic correlations to other physiological parameters.

Do Environmental Conditions Contribute to Narcosis Onset and Symptom Severity?

Although many factors contributing to inert gas narcosis onset and severity have been put forward, the available evidence is not particularly strong. Using objective criteria, we have assessed brain impairment associated with narcosis under various environmental diving conditions. 40 volunteers performed a no-decompression dive (33 m for 20 min) either in a dry chamber, a pool or open sea. They were assessed by critical flicker fusion frequency before the dive, upon arriving at depth, 5 min before ascent, on surfacing and 30 min post-dive. Compared to the pre-dive value, the mean value of each measurement was significantly different. An increase of flicker fusion to 105.00±0.69% when arriving at depth is followed by a decrease to 94.05±0.65%. This impairment persists when surfacing and 30 min post-dive, decreasing further to 96.36±0.73% and 96.24±0.73%, respectively. Intragroup comparison failed to demonstrate any statistical difference. When objectively measured narcosis may not be influenced by external factors other than pressure and gas. This might be of importance for training to avoid any over- or underestimation of the severity of narcosis based only on subjective symptoms.

ENT indications for Hyperbaric Oxygen Therapy.

ENT indications for Hyperbaric Oxygen Therapy. Hyperbaric Oxygen (HBO) therapy is a treatment where patients breathe 100% oxygen while exposed to high environmental pressure in a hyperbaric chamber. This hyperoxygenation has several beneficial effects as an adjunctive treatment in a number of ENT-related conditions and diseases. These can be summarized as anti-ischaemic effects (delivery of oxygen to otherwise ischaemic tissues, reduction of ischaemia-reperfusion damage), anti-infectious effects (bacteriostasis, improved leucocyte phagocytosis bactericidal activity and optimization of antibiotic therapy) and wound-healing effects (stimulation of granulation tissue formation and stabilization). Since HBO therapy has a clear physiologic rationale, a demonstrated effect (although difficult to "prove" with placebo controlled randomized trials) in certain indications and certain side-effects, it is proposed that it should be considered an integral part of the (combined surgical and pharmacological) treatment of patients, and not simply as a supplementation of oxygen. Furthermore, the importance of a well-trained medical and technical staff to ensure proper selection and the correct follow-up of patients should not be underestimated.

Ear, nose and throat and non-acoustic barotrauma.

The organs of the ear, nose and throat (ENT) contain air- or gas-filled cavities, which make them sensitive to pressure changes. There is a specific pathophysiology involved when these structures are exposed to non-acoustic press ure changes, which are usually not traumatic in normals. The concepts of pathophysiology, diagnosis and treatment of these traumas in an emergency setting are reviewed.

Cilengitide combined with cetuximab and platinum-based chemotherapy as first-line treatment in advanced non-small-cell lung cancer (NSCLC) patients: results of an open-label, randomized, controlled phase II study (CERTO).

BACKGROUND: This multicentre, open-label, randomized, controlled phase II study evaluated cilengitide in combination with cetuximab and platinum-based chemotherapy, compared with cetuximab and chemotherapy alone, as first-line treatment of patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients were randomized 1:1:1 to receive cetuximab plus platinum-based chemotherapy alone (control), or combined with cilengitide 2000 mg 1×/week i.v. (CIL-once) or 2×/week i.v. (CIL-twice). A protocol amendment limited enrolment to patients with epidermal growth factor receptor (EGFR) histoscore ≥200 and closed the CIL-twice arm for practical feasibility issues. Primary end point was progression-free survival (PFS; independent read); secondary end points included overall survival (OS), safety, and biomarker analyses. A comparison between the CIL-once and control arms is reported, both for the total cohorts, as well as for patients with EGFR histoscore ≥200. RESULTS: There were 85 patients in the CIL-once group and 84 in the control group. The PFS (independent read) was 6.2 versus 5.0 months for CIL-once versus control [hazard ratio (HR) 0.72; P = 0.085]; for patients with EGFR histoscore ≥200, PFS was 6.8 versus 5.6 months, respectively (HR 0.57; P = 0.0446). Median OS was 13.6 for CIL-once versus 9.7 months for control (HR 0.81; P = 0.265). In patients with EGFR ≥200, OS was 13.2 versus 11.8 months, respectively (HR 0.95; P = 0.855). No major differences in adverse events between CIL-once and control were reported; nausea (59% versus 56%, respectively) and neutropenia (54% versus 46%, respectively) were the most frequent. There was no increased incidence of thromboembolic events or haemorrhage in cilengitide-treated patients. αvß3 and αvß5 expression was neither a predictive nor a prognostic indicator. CONCLUSIONS: The addition of cilengitide to cetuximab/chemotherapy indicated potential clinical activity, with a trend for PFS difference in the independent-read analysis. However, the observed inconsistencies across end points suggest additional investigations are required to substantiate a potential role of other integrin inhibitors in NSCLC treatment. CLINICAL TRIAL REGISTRATION ID NUMBER: NCT00842712.

Two biomarker-directed randomized trials in European and Chinese patients with nonsmall-cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies.

BACKGROUND: In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and receptor-associated protein 80 (RAP80) expression was significantly associated with outcome in Caucasian patients with nonsmall-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients. PATIENTS AND METHODS: Eligibility criteria included stage IIIB-IV NSCLC and sufficient tumor specimen for molecular analysis. Randomization to the control or experimental arm was 1 : 1 in the SLCG trial and 1 : 3 in the Chinese trial. In both trials, patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel/cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone. The primary end point was progression-free survival (PFS). RESULTS: Two hundred and seventy-nine patients in the SLCG trial and 124 in the Chinese trial were assessable for PFS. PFS in the control and experimental arms in the SLCG trial was 5.49 and 4.38 months, respectively [log rank P = 0.07; hazard ratio (HR) 1.28; P = 0.03]. In the Chinese trial, PFS was 4.74 and 3.78 months, respectively (log rank P = 0.82; HR 0.95; P = 0.82). CONCLUSION: Accrual was prematurely closed on the SLCG trial due to the absence of clinical benefit in the experimental over the control arm. However, the BREC studies provide proof of concept that an international, nonindustry, biomarker-directed trial is feasible. Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to elucidate DNA repair mechanisms will help define novel therapeutic approaches. TRIAL REGISTRATION: NCT00617656/GECP-BREC and ChiCTR-TRC-12001860/BREC-CHINA.

Long term effects of recreational SCUBA diving on higher cognitive function.

We investigated long-term effects of SCUBA diving on cognitive function using a battery of neuropsychometric tests: the Simple Reaction Time (REA), Symbol Digit Substitution (SDS), Digit Span Backwards (DSB), and Hand-Eye Coordination tests (EYE). A group (n = 44) of experienced SCUBA divers with no history of decompression sickness was compared to non-diving control subjects (n = 37), as well as to professional boxers (n = 24), who are considered at higher risk of long term neurological damage. The REA was significantly shorter in SCUBA divers compared to the control subjects, and also more stable over the time course of the test. In contrast, the number of digits correctly memorized and reordered (DSB) was significantly lower for SCUBA divers compared to the control group. The results also showed that boxers performed significantly worse than the control group in three out of four tests (REA, DSB, EYE). While it may be concluded that accident-free SCUBA diving may have some long-term adverse effects on short-term memory, there is however, no evidence of general higher cognitive function deficiency.

Nitric oxide-related endothelial changes in breath-hold and scuba divers.

OBJECTIVE: Scuba and breath-hold divers are compared to investigate whether endothelial response changes are similar despite different exposure(s) to hyperoxia. DESIGN: 14 divers (nine scuba and five breath-holding) performed either one scuba dive (25m/25 minutes) or successive breath-hold dives at a depth of 20 meters, adding up to 25 minutes of immersion time in a diving pool. Flow-mediated dilation (FMD) was measured using echography. Peripheral post-occlusion reactive hyperemia (PORH) was assessed by digital plethysmography and plasmatic nitric oxide (NO) concentration using a nitrate/nitrite colorimetric assay kit. RESULTS: The FMD decreased in both groups. PORH was reduced in scuba divers but increased in breath-hold divers. No difference in circulating NO was observed for the scuba group. Opposingly, an increase in circulating NO was observed for the breath-hold group. CONCLUSION: Some cardiovascular effects can be explained by interaction between NO and superoxide anion during both types of diving ending to less NO availability and reducing FMD. The increased circulating NO in the breath-hold group can be caused by physical exercise. The opposite effects found between FMD and PORH in the breath-hold group can be assimilated to a greater responsiveness to circulating NO in small arteries than in large arteries.

Changing preferences for information and participation in the last phase of life: a longitudinal study among newly diagnosed advanced lung cancer patients.

PURPOSE: The objective is to explore changes over time in the information and participation preferences of newly diagnosed stage IIIb/IV non-small-cell lung cancer patients. METHODS: Patients were recruited by physicians in 13 hospitals and interviewed every 2 months until the fourth and every 4 months until the sixth interview. RESULTS: Sixty-seven patients were interviewed three times. Over a period of 4 months from diagnosis, half of patients changed their information preferences for palliative care and end-of-life decisions with a possible or certain life-shortening effect (ELDs, e.g., non-treatment decisions) in both directions, from not wanting to wanting the information, but also--and as much--from wanting to no longer wanting it. The latter were more likely to be in a better physical condition. Preferences for participation in medical decision making also changed: 50% to 78%, depending on the type of decision (general, treatment, transfer or ELD), changed their preference towards wanting more or less participation. Pain seemed to be a trigger for patients wanting more involvement, which contrasts with studies suggesting that patients who are more ill tend to give up more control. CONCLUSIONS: Doctors should regularly ask their advanced lung cancer patients how much information and participation they want because preferences do change in unexpected ways.

Persistence of critical flicker fusion frequency impairment after a 33 mfw SCUBA dive: evidence of prolonged nitrogen narcosis?

One of the possible risks incurred while diving is inert gas narcosis (IGN), yet its mechanism of action remains a matter of controversy. Although providing insights in the basic mechanisms of IGN, research has been primarily limited to animal studies. A human study, in real diving conditions, was needed. Twenty volunteers within strict biometrical criteria (male, age 30-40 years, BMI 20-23, non smoker) were selected. They performed a no-decompression dive to a depth of 33 mfw for 20 min and were assessed by the means of critical flicker fusion frequency (CFFF) measurement before the dive, during the dive upon arriving at the bottom, 5 min before the ascent, and 30 min after surfacing. After this late measurement, divers breathed oxygen for 15 min and were assessed a final time. Compared to the pre-dive value the mean value of each measurement was significantly different (p < 0.001). An increase of CFFF to 104 ± 5.1 % upon arriving to the bottom is followed by a decrease to 93.5 ± 4.3 %. This impairment of CFFF persisted 30 min after surfacing, still decreased to 96.3 ± 8.2 % compared to pre-dive CFFF. Post-dive measures made after 15 min of oxygen were not different from control (without nitrogen supersaturation), 124.4 ± 10.8 versus 124.2 ± 3.9 %. This simple study suggests that IGN (at least partially) depends on gas-protein interactions and that the cerebral impairment persists for at least 30 min after surfacing. This could be an important consideration in situations where precise and accurate judgment or actions are essential.

Prognostic factors of spinal cord decompression sickness in recreational diving: retrospective and multicentric analysis of 279 cases.

BACKGROUND: This study aims to determine the potential risk factors associated with the development of severe diving-related spinal cord decompression sickness (DCS). METHODS: Two hundred and seventy nine injured recreational divers (42 ± 12 years; 53 women) presenting symptoms of spinal cord DCS were retrospectively included from seven hyperbaric centers in France and Belgium. Diving information, symptom latency after surfacing, time interval between symptom onset and hyperbaric treatment were studied. The initial severity of spinal cord DCS was rated with the Boussuges severity score, and the presence of sequelae was evaluated at 1 month. Initial recompression treatment at 2.8 ATA with 100% oxygen breathing or deeper recompression up to 4 or 6 ATA with nitrogen or helium-oxygen breathing mixture were also recorded. RESULTS: Twenty six percent of DCS had incomplete resolution after 1 month. Multivariate analysis revealed several independent factors associated with a bad recovery: age ≥ 42 [OR 1.04 (1-1.07)], depth ≥ 39 m [OR 1.04 (1-1.07)], bladder dysfunction [OR 3.8 (1.3-11.15)], persistence or worsening of clinical symptoms before recompression [OR 2.07 (1.23-3.48)], and a Boussuges severity score >7 [OR 1.16 (1.03-1.31)]. However, the time to recompression and the choice of initial hyperbaric procedure did not significantly influence recovery after statistical adjustment. CONCLUSIONS: Clinical symptoms of spinal cord DCS and their initial course before admission to the hyperbaric center should be considered as major prognostic factors in recovery. A new severity score is proposed to optimize the initial clinical evaluation for spinal cord DCS.

Computational fluid dynamics can detect changes in airway resistance in asthmatics after acute bronchodilation.

The effect of a bronchodilator in asthmatics is only partially described by changes in spirometric values since no information on regional differences can be obtained. Imaging techniques like high-resolution computed tomography (HRCT) provide further information but lack detailed information on specific airway responses. The aim of the present study was to improve the actual imaging techniques by subsequent analysis of the imaging data using computational fluid dynamics (CFD). We studied 14 mild to moderately severe asthmatics. Ten patients underwent HRCT before and 4h after inhalation of a novel long acting beta(2) agonist (LABA) that acts shortly after inhalation. Four patients were studied for chronic effects and underwent CT scans twice after adequate wash-out of bronchodilators. In the active group, a significant bronchodilator response was seen with a forced expiratory volume in 1s (FEV1) increase of 8.78 +/- -6.27% pred vs -3.38 +/- 6.87% pred in the control group. The changes in FEV1 correlated significantly with the changes in distal airway volume (r = 0.69, p = 0.007), total airway resistance (r = -0.73, p = 0.003) and distal airway resistance (r = -0.76, p = 0.002) as calculated with the CFD method. The changes in distal R(aw) were not fully homogeneous. In some patients with normal FEV1 at baseline, CFD-based changes in R(aw) were still detectable. We conclude that CFD calculations, based on airway geometries of asthmatic patients, provide additional information about changes in regional R(aw). All changes in the CFD-based calculated R(aw) significantly correlate with the observed changes in spirometric values therefore validating the CFD method for the studied application.

Flow analyses in the lower airways: patient-specific model and boundary conditions.

Computational fluid dynamics (CFD) is increasingly applied in the respiratory domain. The ability to simulate the flow through a bifurcating tubular system has increased the insight into the internal flow dynamics and the particular characteristics of respiratory flows such as secondary motions and inertial effects. The next step in the evolution is to apply the technique to patient-specific cases, in order to provide more information about pathological airways. This study presents a patient-specific approach where both the geometry and the boundary conditions (BC) are based on individual imaging methods using computed tomography (CT). The internal flow distribution of a 73-year-old female suffering from chronic obstructive pulmonary disease (COPD) is assessed. The validation is performed through the comparison of lung ventilation with gamma scintigraphy. The results show that in order to obtain agreement within the accuracy limits of the gamma scintigraphy scan, both the patient-specific geometry and the BC (driving pressure) play a crucial role. A minimal invasive test (CT scan) supplied enough information to perform an accurate CFD analysis. In the end it was possible to capture the pathological features of the respiratory system using the imaging and computational fluid dynamics techniques. This brings the introduction of this new technique in the clinical practice one step closer.

Glucocorticosteroids as antioxidants in treatment of asthma and COPD. New application for an old medication?

Inhaled corticosteroids (ICS) are the standard of care in asthma and are widely used in the treatment of patients with COPD. The influence of steroids on inflammatory processes has long been established since glucocorticoids and their receptor belong to the regulatory network involved in inhibition of several inflammatory pathways. Inflammatory processes are usually accompanied by an increased oxidative burden followed by a depletion of antioxidants. Therefore, the effects of steroids on antioxidant status have been investigated revealing possible positive effects on the reduced antioxidant enzyme activity. Nevertheless, the mechanisms of this modulation have not been fully elucidated yet. It is possible that antioxidant enzyme activity is regulated at the level of transcription. Additionally, because of the fact that antioxidant enzymes are trace element dependent, steroids may affect their activity through influence on trace element accumulation. This review summarizes the effects of steroids on the antioxidant enzymes activity in vitro and in vivo in relation to asthma and COPD.

Correlation between severity of sleep apnea and upper airway morphology based on advanced anatomical and functional imaging.

Determination of the apnea hypopnea index (AHI) as a measure of the severity of obstructive sleep apnea/hypopnea syndrome (OSAHS) is a widely accepted methodology. However, the outcome of such a determination depends on the method used, is time consuming and insufficient for prediction of the effect of all treatment modalities. For these reasons more methods for evaluating the severity of OSAHS, based on different imaging modalities, have been looked into and recent studies have shown that anatomical properties determined from three-dimensional (3D) computed tomography (CT) images are good markers for the severity of the OSAHS. Therefore, we correlated anatomical measurements of a 3D reconstruction of the upper airway together with flow simulation results with the severity of OSAHS in order to find a combination of variables to indicate the severity of OSAHS in patients. The AHI of 20 non-selected, consecutive patients has been determined during a polysomnography. All patients also underwent a CT scan from which a 3D model of the upper airway geometry was reconstructed. This 3D model was used to evaluate the anatomical properties of the upper airway in OSAHS patients as well as to perform computational fluid dynamics (CFD) computations to evaluate the airflow and resistance of this upper airway. It has been shown that a combination of the smallest cross-sectional area and the resistance together with the body mass index (BMI) form a set of markers that predict very well the severity of OSAHS in patients within this study. We believe that these markers can be used to evaluate the outcome of an OSAHS treatment.

Effect of varying deep stop times and shallow stop times on precordial bubbles after dives to 25 msw (82 fsw).

In our previous research, a deep 5-min stop at 15 msw (50 fsw), in addition to the typical 3-5 min shallow stop, significantly reduced precordial Doppler detectable bubbles (PDDB) and "fast" tissue compartment gas tensions during decompression from a 25 msw (82 fsw) dive; the optimal ascent rate was 10 msw (30 fsw/min). Since publication of these results, several recreational diving agencies have recommended empirical stop times shorter than the 5 min stops that we used, stops of as little as 1 min (deep) and 2 min (shallow). In our present study, we clarified the optimal time for stops by measuring PDDB with several combinations of deep and shallow stop times following single and repetitive open-water dives to 25 msw (82 fsw) for 25 mins and 20 minutes respectively; ascent rate was 10 msw/min (33 fsw). Among 15 profiles, stop time ranged from 1 to 10 min for both the deep stops (15 msw/50 fsw) and the shallow stops (6 msw/20 fsw). Dives with 2 1/2 min deep stops yielded the lowest PDDB scores--shorter or longer deep stops were less effective in reducing PDDB. The results confirm that a deep stop of 1 min is too short--it produced the highest PDDB scores of all the dives. We also evaluated shallow stop times of 5, 4, 3, 2 and 1 min while keeping a fixed time of 2.5 min for the deep stop; increased times up to 10 min at the shallow stop did not further reduce PDDB. While our findings cannot be extrapolated beyond these dive profiles without further study, we recommend a deep stop of at least 2 1/2 mins at 15 msw (50 fsw) in addition to the customary 6 msw (20 fsw) for 3-5 mins for 25 meter dives of 20 to 25 minutes to reduce PDDB.

Hyperbaric oxygen therapy after failure of conventional therapy for sudden deafness.

PROBLEMS/OBJECTIVES: We investigated the effect of secondary hyperbaric oxygen therapy (HBO) for patients with idiopathic sudden sensorineural hearing loss after unsuccessful conventional treatment. METHODOLOGY: We retrospectively evaluated 3 groups: 100 patients without further treatment (group 1), 160 patients with secondary HBO at 1.5 ATA (group 2), and 56 patients with secondary HBO at 2.5 ATA (group 3). RESULTS: In group 1, a mean hearing gain (MHG) of 2.6 +/- 15 dB was found at the end of the follow-up period. After HBO, a MHG of 3.1 +/- 9 dB in group 2 and 19.7 +/- 23 dB in group 3 was achieved. The results in group 3 were statistically significant in comparison to group 1 (p < 0.007) and to group 2 (p < 0.009). With HBO after initial therapy failure, there is a significant correlation of MHG with time delay before HBO (p < 0.03). CONCLUSIONS: HBO at 2.5 ATA in patients with idiopathic sudden sensorineural hearing loss after unsuccessful conventional treatment yields significant improvement of hearing. MHG is higher when time delay before HBO is shorter.

Modulation by 5-HT1A receptors of the 5-HT2 receptor-mediated tachykinin-induced contraction of the rat trachea in vitro.

1. In the Fisher 344 rat, tachykinins have been shown to cause the release of 5-hydroxytryptamine (5-HT) from airway mast cells, which then causes direct smooth muscle activation as well as the release of acetylcholine from cholinergic nerves. The aim of the present study was to examine the modulatory effects of 5-HT receptors on the neurokinin A (NKA)-induced release of endogenous 5-HT and airway smooth muscle contraction in the isolated Fisher 344 rat trachea. 2. The selective 5-HT2 receptor antagonist ketanserin (0.1 microM) produced an almost complete inhibition of the contractions caused by NKA (n=4, P<0.0001, two-way ANOVA), and a significant rightward shift of the concentration-response curve to 5-HT (n=8, P<0.001, two-way ANOVA). 3. The partial agonist for 5-HT1A receptors, 8-OH-DPAT (1 microM), and the full agonist for 5-HT1 receptors, 5-CT (0.3 microM), potentiated the submaximal contractions induced by the 5-HT2 receptor agonist alpha-methyl-5-HT (0.1 microM) (n=4; P<0.005 and P<0.05, respectively). 8-OH-DPAT (1 microM), as well as the 5-HT1A receptor antagonists pMPPI, SDZ 216525 and NAN-190 (0.1 microM each), caused significant inhibition of the tracheal contractions induced both by NKA (10 nM-3 microM) and 5-HT (10 nM-10 microM) (n=4-10). This suggests that activation of 5-HT1A receptors potentiates the 5-HT2 receptor-mediated contractions. 4. SDZ 216525 (0.1 microM) significantly reduced the maximal contraction produced by 1 microM NKA (n=10, P< 0.001), without affecting the release of endogenous 5-HT. These data rule out the involvement of a 5-HT1A receptor-mediated positive feedback mechanism of the 5-HT release from mast cells. 5. Even in the presence of atropine (1 microM), 8-OH-DPAT (1 microM) further reduced the maximal NKA-induced contraction (n=4, P<0.0001), while the contractions of the rat isolated trachea induced by electrical field stimulation and the concentration-response curve to carbachol were unaffected by pMPPI (0.1 microM), SDZ 216525 (0.1 microM), NAN-190 (0.1 microM) and 8-OH-DPAT (1 microM) (n=4-6). These data demonstrate that the 5-HT1A receptor-mediated potentiation of contractile responses is not due to nonspecific inhibition of airway smooth muscle contraction or to modulation of postganglionic nerve activation. 6. The selective 5-HT1B/1D receptor antagonist GR 127935, the selective 5-HT3 receptor antagonist tropisetron and the selective 5-HT4 receptor antagonists SB 204070 and GR 113808 (0.1 microM each) had no effect on the concentration-response curve for NKA (n=6-10), ruling out the involvement of 5-HT1B/1D, 5-HT3 and 5-HT4 receptors. 7. The alpha-adrenoreceptor antagonist phentolamine (1 microM) had no effect on the 5-HT-induced contractions (n=4), ruling out the involvement of alpha-adrenoreceptors. 8. In conclusion, the tachykinin-induced contraction of the F334 rat isolated trachea is mediated by the stimulation of 5-HT2 receptors. Activation of 5-HT1A receptors located on airway smooth muscle potentiates the direct contractile effects of 5-HT2 receptor activation. The 5-HT1B/1D, 5-HT3 and 5-HT4 receptors are not involved in the NKA-induced contraction of rat airways.