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BACKGROUND: Tumor-infiltrating immune cells have been correlated with prognosis for patients treated with immune checkpoint inhibitor (ICI) treatment of various cancers. However, no robust biomarker has been described to predict treatment response yet. We hypothesized that the activation potency of circulating T cells may predict response to ICI treatment. METHODS: An exploratory analysis was conducted to investigate the association between the response to immune checkpoint inhibition (ICI) combined with stereotactic radiotherapy (SBRT) and the potency of circulating T cells to be activated. Blood-derived lymphocytes from 14 patients were stimulated ex vivo with, among others, Staphylococcal enterotoxin B (SEB) and compared to healthy controls (HCs). Patients were grouped into responders (>median progression free survival (PFS)) and non-responders (
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Background: Chronic constipation is common in people with intellectual disabilities, and seems to be highly prevalent in people with severe or profound intellectual and multiple disabilities (SPIMD). However, there is no current widely accepted definition for the constipation experienced by these individuals. Aim: This Delphi study aims to compile a list of operationalized criteria and symptoms of constipation in people with SPIMD based on practical experiences of and consensus between experts supporting them. Methods: A two-round Delphi study with an intermediate evaluation and analyses was conducted. Parents and relatives of persons with SPIMD and support professionals were included. The panel answered statements and open questions about symptoms and criteria of constipation. They were also requested to provide their opinion about classifying criteria and symptoms into domains. Answers to statements were analysed separately after both rounds with regard to consensus rate and displayed qualitatively; answers to open questions were analysed deductively. Results: In the first Delphi round (n = 47), consensus was achieved on criteria within the domains 'Defecation' and 'Physical features', that were assigned to broader categories. Symptoms retrieved within the domain 'Behavioural/Emotional' were brought back to the panel as statements. After the second Delphi round (n = 38), consensus was reached on questions about domains, and for eight criteria (domain 'Defecation' n = 5; domain 'Physical features n = 3). Within the domain 'Behavioural/Emotional', consensus was achieved for five symptoms. Criteria and symptoms with consensus >70% were considered 'generic' and <70% as 'personal'. Symptoms mentioned in the text boxes were used to operationalize categories. Discussion and conclusion: It was possible to compile a list of generic criteria related to the domains 'Defecation' (n = 5) and 'Physical features' (n = 3) supplemented with generic symptoms related to the domain 'Behavioural/Emotional' (n = 5). We propose using both generic as well as personal criteria and symptoms resulting in a personal profile for an individual with SPIMD. Based on the current results, we recommend follow-up research to develop a screening tool to be used by relatives and professional caregivers, and a definition of constipation. This may support reciprocal collaboration and lead to timely identification of constipation in people with SPIMD.
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Background: Alectinib is first-line therapy in patients with stage IV non-small cell lung carcinoma (NSCLC) and an anaplastic lymphoma kinase (ALK) fusion. A shorter median progression-free survival (mPFS) was observed when alectinib minimum plasma concentrations during steady state (Cmin,SS) were below 435 ng/mL. This may suggest that patients should have an alectinib Cmin,SS ≥ 435 ng/mL for a more favorable outcome. This potential target could be attained by using therapeutic drug monitoring (TDM), i.e. adjusting the dose based on measured plasma trough concentrations. Hypothetically, this will increase mPFS, but this has not yet been evaluated in a randomized controlled trial (RCT). Therefore, the ADAPT ALEC trial is designed, with the primary objective to prolong mPFS in NSCLC patients treated with alectinib by using TDM. Methods: ADAPT ALEC is a multicenter, phase IV RCT, in which patients aged ≥ 18 years with advanced ALK positive (+) NSCLC eligible for alectinib in daily care are enrolled. Participants will be randomized (1:1 ratio) into intervention arm A (TDM) or B (control), stratified by brain metastases and prior ALK treatments. Starting dose in both arms is the approved flat fixed dose of alectinib 600 mg taken twice daily with food. In case of alectinib Cmin,SS < 435 ng/mL, arm A will receive increased doses of alectinib till Cmin,SS ≥ 435 ng/mL when considered tolerable. The primary outcome is mPFS, where progressive disease is defined according to RECIST v1.1 or all-cause death and assessed by CT-scans and MRI brain. Secondary endpoints are feasibility and tolerability of TDM, patient and physician adherence, overall response rate, median overall survival, intracranial PFS, quality of life, toxicity, alectinib-M4 concentrations and cost-effectiveness of TDM. Exploratory endpoints are circulating tumor DNA and body composition. Discussion: The ADAPT ALEC will show whether treatment outcomes of patients with advanced ALK+ NSCLC improve when using TDM-guided dosing of alectinib instead of fixed dosing. The results will provide high quality evidence for deciding whether TDM should be implemented as standard of care and this will have important consequences for the prescribing of alectinib. Clinical trial registration: ClinicalTrials.gov, identifier NCT05525338.
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INTRODUCTION: This phase I study primarily addresses the safety and tolerability of Stereotactic radiotherapy on the primary tumor combined with double Immune Checkpoint Inhibition (SICI) in patients with non-small cell lung cancer (NSCLC). Increasing the release of neoantigens by radiotherapy might enhance response to immunotherapy. Especially, by targeting trunk mutations in the primary tumor. MATERIALS AND METHODS: In three sequential cohorts, immunotherapy regimes combined with stereotactic body radiotherapy (SBRT) on the primary tumor (1x20 Gy on 9 cc) were studied in stage IIIB/IV NSCLC patients progressing on chemotherapy. The first cohort (n = 3) received durvalumab. The second (n = 6) received a combination of tremelimumab and durvalumab followed by durvalumab monotherapy. The third cohort (n = 6) was similar except that the combination was reversed. Descriptive statistics were used to assess safety parameters and the exploratory outcomes of efficacy. Adverse events were reported using NCI CTCAE version 4.03. Exhaled breath was analyzed at baseline. RESULTS: Fifteen patients were included. Median irradiated volume was 9.13 cc, on a median primary tumor volume of 79 cc. There were seven patients with grade 1-2, and two patients with grade 3 treatment related adverse events. There was 1 dose limiting toxicity (colitis) with double immunotherapy. CONCLUSION: The combination of SBRT to the primary tumor and double immunotherapy in advanced NSCLC patients is safe and feasible.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Radiosurgery , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/etiology , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Patients with intermediate-high risk pulmonary embolism have a different mix of clinical symptoms. Optimal treatment of patients with intermediate high-risk pulmonary embolism is necessary to prevent short-term mortality. According to the current guidelines, the use of standard coagulation is the treatment of choice in hemodynamic stable patients with intermediate-high risk pulmonary embolism. Systemic thrombolytic therapy is recommended in patients with intermediate-high risk pulmonary embolism who circulatory deteriorate or who did not respond appropriately to standard anticoagulation. Catheter-guided thrombolysis is reserved for patients with intermediate-high risk pulmonary embolism who have a contraindication for systemic thrombolysis or did not respond to systemic thrombolysis. The timing and choice for the right treatment are significant treatment dilemmas. The development of pulmonary embolism response teams helps in the decision-making in patients with intermediate high-risk pulmonary embolism.
Subject(s)
Pulmonary Embolism , Fibrinolytic Agents/adverse effects , Humans , Pulmonary Embolism/diagnosis , Pulmonary Embolism/therapy , Thrombolytic TherapyABSTRACT
Correction to:Neth Heart J 2016 https://doi.org/10.1007/s12471-016-0849-z Unfortunately the original version of this article contained Electronic Supplementary Material which should not have been published with the article due to copyright reasons.The original version has been updated and the ESM .
ABSTRACT
Although Th2 driven inflammation is present in COPD, it is not clearly elucidated which COPD patients are affected. Since periostin is associated with Th2 driven inflammation and inhaled corticosteroid (ICS)-response in asthma, it could function as a biomarker in COPD. The aim of this study was to analyze if serum periostin is elevated in COPD compared to healthy controls, if it is affected by smoking status, if it is linked to inflammatory cell counts in blood, sputum and endobronchial biopsies, and if periostin can predict ICS-response in COPD patients.Serum periostin levels were measured using Elecsys Periostin immunoassay. Correlations between periostin and inflammatory cell count in blood, sputum and endobronchial biopsies were analyzed. Additionally, the correlation between serum periostin levels and treatment responsiveness after 6 and 30 months was assessed using i.e. ΔFEV1% predicted, ΔCCQ score and ΔRV/TLC ratio. Forty-five COPD smokers, 25 COPD past-smokers, 22 healthy smokers and 23 healthy never-smokers were included. Linear regression analysis of serum periostin showed positive correlations age (B = 0.02, 95%CI 0.01-0.03) and FEV1% predicted (B = 0.01, 95%CI 0.01-0.02) in healthy smokers, but not in COPD patients In conclusion, COPD -smokers and -past-smokers have significantly higher periostin levels compared to healthy smokers, yet periostin is not suitable as a biomarker for Th2-driven inflammation or ICS-responsiveness in COPD.
Subject(s)
Cell Adhesion Molecules/blood , Pulmonary Disease, Chronic Obstructive/blood , Smoking/blood , Th2 Cells/metabolism , Adult , Aged , Biomarkers/blood , Eosinophils/metabolism , Female , Humans , Inflammation/blood , Inflammation/diagnosis , Inflammation/epidemiology , Male , Middle Aged , Pulmonary Disease, Chronic Obstructive/diagnosis , Pulmonary Disease, Chronic Obstructive/epidemiology , Smoking/epidemiologyABSTRACT
BACKGROUND: The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is the first disease-specific instrument for pulmonary arterial hypertension (PAH) to assess patient-perceived symptoms, activity limitations and quality of life. To be able to use this questionnaire in the Netherlands, the aim of the study was to translate and validate this instrument for the Dutch-speaking population. METHODS: First the CAMPHOR was translated into Dutch (by means of a bilingual and a lay panel) and field-tested by means of cognitive debriefing interviews with ten PAH patients. For psychometric evaluation, 80 patients with PAH or chronic thromboembolic pulmonary hypertension (CTEPH) were asked to complete the CAMPHOR twice over a two-week period. To test for construct validity, participants also completed the Nottingham Health Profile (NHP). RESULTS: The Dutch version of the CAMPHOR showed high internal consistency for all scales (Cronbach's alpha 0.89-0.91) and excellent reproducibility over two weeks (reliability coefficients 0.87-0.91). Concurrent validity showed that the CAMPHOR scales correlated as expected with the NHP scales. The CAMPHOR was able to distinguish between patient groups based on self-reported general health status, disease severity and NYHA classification demonstrating evidence of known group validity. The CAMPHOR activity limitations scale correlated moderately with the distance walked during the 6minute walk test (r = -0.47, p < 0.01) and the symptoms scale with the Borg dyspnoea score (r = 0.51, p < 0.01). CONCLUSION: The Dutch version of the CAMPHOR is a reliable and valid measure of quality of life and health status in patients with PAH and CTEPH is recommended for use in routine care and in clinical research.
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AIMS: To determine quality of life and adequacy of education and counselling in Australian patients with Graves' ophthalmopathy during the course of their illness. METHODS: A cross sectional study was conducted at the orbital and endocrinology clinics of Royal Brisbane Hospital on 162 consecutive patients with Graves' ophthalmopathy who were managed between the 1992 and 2000. The Graves' ophthalmopathy quality of life (GO-QOL) survey modified for Australian conditions was distributed to study participants. Of the 19 questions asked, nine questions related to visual functioning, eight questions were about the psychosocial consequences of changed appearance, and two questions referred to education and counselling. Additionally, clinical data on the severity of illness were collected retrospectively from the medical notes of these patients. RESULTS: Completed questionnaires were received from 128 patients. The majority of patients reported limitations in daily activities such as hobbies, driving, watching television and reading, as well as impaired self confidence. The mean GO-QOL scores in this study were (100 representing maximum QOL): visual functioning 59.0 (SD 28.0), psychosocial consequences of changed appearance 54.5 (28.4), and education and counselling 59.1 (38.8). Only about a quarter of patients indicated that education and counselling were adequate and helpful. CONCLUSION: Graves' ophthalmopathy profoundly affects QOL and adequate education and counselling are essential for helping patients to cope with their illness. The GO-QOL survey is a simple, practical tool that can be used easily in a clinic to determine the QOL issues in subjects with Graves' ophthalmopathy.
Subject(s)
Graves Disease/rehabilitation , Quality of Life , Activities of Daily Living , Adolescent , Adult , Aged , Aged, 80 and over , Counseling/standards , Cross-Sectional Studies , Female , Graves Disease/physiopathology , Graves Disease/psychology , Humans , Interpersonal Relations , Male , Middle Aged , Patient Education as Topic/standards , Patient Satisfaction , Self Concept , Severity of Illness Index , Surveys and Questionnaires , Vision, OcularABSTRACT
Medroxyprogesterone acetate (MPA) and acetazolamide (ACET) are two ventilatory stimulants which are used in hypoxic and hypercapnic patients with chronic obstructive pulmonary disease (COPD). In a double-blind randomised study, the effects of a 2-week treatment with MPA (30 mg b.i.d.) or ACET (250 mg b.i.d.), followed by a 2-week treatment with a combination of both drugs (MPA/ACET), on daytime and nocturnal ventilatory and blood gas parameters in 17 stable hypercapnic COPD patients were investigated. ACET, MPA and MPA/ACET treatment decreased mean daytime carbon dioxide tension in arterial blood by 0.4, 0.7 and 1.2 kPa, respectively. Minute ventilation was improved only with combined therapy, from 9.3 to 11.2 L x min(-1). With MPA/ACET therapy, the hypercapnic and hypoxic ventilatory responses significantly increased, from 3.7 to 5.8 L x min(-1) x kPa(-1) and from -0.13 to -0.40 L x min(-1) x %(-1), respectively. The mouth exclusion pressure response to hypoxia increased during combination therapy, from -0.01 to -0.03 kPa %(-1). Nocturnal end-tidal carbon dioxide tension decreased with MPA and MPA/ACET treatment, by 0.9 and 1.4 kPa, respectively. MPA/ACET significantly increased mean nocturnal arterial oxygen saturation values, from 85.5 to 90.2%. The authors conclude that short-term combined treatment with medroxyprogesterone acetate and acetazolamide has a more favourable effect on day and night-time blood gas values and chemical drive than single drug treatment.
Subject(s)
Acetazolamide/administration & dosage , Carbonic Anhydrase Inhibitors/administration & dosage , Medroxyprogesterone/administration & dosage , Pulmonary Disease, Chronic Obstructive/drug therapy , Aged , Carbon Dioxide/blood , Double-Blind Method , Drug Therapy, Combination , Humans , Hypercapnia/complications , Hypercapnia/drug therapy , Hypercapnia/physiopathology , Hypoxia/complications , Hypoxia/drug therapy , Hypoxia/physiopathology , Oxygen/blood , Pulmonary Disease, Chronic Obstructive/complications , Pulmonary Disease, Chronic Obstructive/physiopathology , Respiration/drug effectsSubject(s)
Hearing Loss, Sensorineural/genetics , Audiometry , Extracellular Matrix Proteins/genetics , Genotype , Hearing Loss, Sensorineural/classification , Hearing Loss, Sensorineural/diagnosis , Humans , Mutation , Phenotype , Retinitis Pigmentosa/genetics , Syndrome , Vestibular Diseases/geneticsABSTRACT
Identification of genes involved in hereditary vestibular disease is growing at a remarkable pace. Mutant mouse technology can be an important tool for understanding the biological mechanism of human vestibular diseases.
Subject(s)
Vestibular Diseases/genetics , Animals , Dyneins , Eye Movements , Humans , Immunohistochemistry , Mice , Mice, Mutant Strains , Myosin VIIa , Myosins/metabolism , Potassium Channels/genetics , Potassium Channels/physiology , Reflex, Vestibulo-Ocular , Shaker Superfamily of Potassium Channels , Vestibular Diseases/metabolism , Vestibular Diseases/physiopathologySubject(s)
Antibiotics, Antineoplastic/isolation & purification , Antifungal Agents/isolation & purification , Mitosporic Fungi/chemistry , Trichothecenes/isolation & purification , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Crystallography, X-Ray , Humans , Magnetic Resonance Spectroscopy , Soil Microbiology , Trichothecenes/chemistry , Trichothecenes/pharmacology , Tumor Cells, CulturedABSTRACT
Bioassay-guided fractionation of the organic extract from a culture of Phomopsis longicolla, an endophytic fungus of the endangered mint Dicerandra frutescens, led to the isolation of dicerandrols A, B, and C. Extensive NMR and HRFABMS experiments were used to identify these new yellow antibiotic and cytotoxic compounds as 2,2'-dimeric tetrahydroxanthones.
Subject(s)
Antibiotics, Antineoplastic/isolation & purification , Ascomycota/chemistry , Xanthenes/isolation & purification , Xanthones , Antibiotics, Antineoplastic/chemistry , Antibiotics, Antineoplastic/pharmacology , Bacillus subtilis/drug effects , Colonic Neoplasms , Florida , Geotrichum/drug effects , Humans , Lamiaceae , Lung Neoplasms , Magnetic Resonance Spectroscopy , Molecular Structure , Saccharomyces cerevisiae/drug effects , Spectrophotometry, Infrared , Spectrophotometry, Ultraviolet , Staphylococcus aureus/drug effects , Stereoisomerism , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Xanthenes/chemistry , Xanthenes/pharmacologyABSTRACT
It is still debated to what extent the vestibular deficits in Usher patients are due to either central vestibulocerebellar or peripheral vestibular problems. Here, we determined the origin of the vestibular symptoms in Usher 1B patients by subjecting them to compensatory eye movement tests and by investigating the shaker-1 mouse model, which is known to have the same mutation in the myosin-VIIa gene as Usher 1B patients. We show that myosin-VIIa is not expressed in the human or mouse cerebellum and that the vestibulocerebellum of both Usher 1B patients and shaker-1 mice is functionally intact in that the gain and phase values of their optokinetic reflex are normal. In addition, Usher 1B patients and shaker-1 mice do not show an angular vestibuloocular reflex even though eye movement responses evoked by electrical stimulation of the vestibular nerve appear intact. Finally, we show histological abnormalities in the vestibular hair cells of shaker-1 mice at the ultrastructural level, while the distribution of the primary vestibular afferents and the vestibular brainstem circuitries are unaffected. We conclude that the vestibular dysfunction of Usher 1B patients and shaker-1 mice is peripheral in origin.
Subject(s)
Blindness/physiopathology , Deafness/physiopathology , Vestibular Diseases/etiology , Animals , Blotting, Western , Cerebellum/metabolism , Dyneins , Electric Stimulation , Eye Movements/physiology , Hair Cells, Auditory/pathology , Hair Cells, Auditory/ultrastructure , Humans , Immunohistochemistry , Mice , Mice, Neurologic Mutants , Microscopy, Electron , Myosin VIIa , Myosins/genetics , Neurons, Afferent/physiology , Neurons, Efferent/physiology , Syndrome , Vestibular Diseases/pathology , Vestibular Diseases/physiopathologyABSTRACT
[structure] Organic extracts from cultures of endophytic fungi collected in the Guanacaste Conservation Area of Costa Rica were screened for antibiotic activity. Two endophytes CR200 (Cytospora sp.) and CR146 (Diaporthe sp.) were found to have potent antibiotic activity. Bioassay-guided fractionation of the extracts from these fungi led to the identification of cytosporones D and E, antibacterial active trihydroxybenzene lactones, and three related but inactive metabolites. The five new octaketides were characterized using X-ray crystallography and NMR.
Subject(s)
Anti-Bacterial Agents/isolation & purification , Benzopyrans/isolation & purification , Lactones/isolation & purification , Mitosporic Fungi/metabolism , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/isolation & purification , Antifungal Agents/pharmacology , Bacteria/drug effects , Benzopyrans/chemistry , Benzopyrans/pharmacology , Crystallography, X-Ray , Fermentation , Lactones/chemistry , Lactones/pharmacology , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Mitosporic Fungi/chemistry , Models, MolecularABSTRACT
Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.
Subject(s)
Abnormalities, Multiple/genetics , Chromosomes, Human, Pair 10/genetics , Deafness/genetics , Genetic Heterogeneity , Retinitis Pigmentosa/genetics , Chromosome Mapping , Consanguinity , DNA Mutational Analysis , Genes, Recessive/genetics , Humans , Lod Score , Mutation/genetics , SyndromeABSTRACT
Temporal bones of 2 patients with Usher syndrome type I were examined using light microscopy. In both patients, findings from histopathologic examination of the cochlea were characterized by degeneration of the organ of Corti, which was most marked in the basal turn, atrophy of the stria vascularis, and a decrease in the number of spiral ganglion cells. The cochlear nerve appeared to be diminished. The sensory epithelium of the saccular and utricular maculae of patient 1 was normal for age. The left temporal bone of patient 2, classified as Usher syndrome genetic subtype USH1D or USH1F, demonstrated the typical signs of severe cochleosaccular degeneration. Present cases and cases from the literature were reviewed in search of an explanation for the above-described differences in histologic findings.
Subject(s)
Hearing Loss, Sensorineural/complications , Retinitis Pigmentosa/complications , Temporal Bone/pathology , Aged , Aged, 80 and over , Atrophy/pathology , Cochlear Nerve/pathology , Female , Humans , Male , Middle Aged , Organ of Corti/pathology , Spiral Ganglion/pathology , Stria Vascularis/pathology , SyndromeABSTRACT
Both medroxyprogesterone acetate (MPA) and acetazolamide (ACET) increase ventilation. Combined administration of these agents could result in an additional improvement of blood gases, for example in patients with chronic obstructive pulmonary diseases. The aim of this study in anaesthetized female (ovariohysterectomized, pre-treated with 17-beta-estradiol) cats was to compare the effects on the CO2 response curve of MPA alone (4 microg kg(-1), i.v.) with those after MPA followed by ACET (4 mg kg(-1) i.v.). We performed dynamic end-tidal CO2 forcing and analysed the data with a two-compartment model comprising a fast peripheral and slow central compartment, characterized by CO2 sensitivities (Sp and Sc, respectively) and a single offset (the apnoeic threshold B). MPA reduced Sp from 0.22 +/- 0.09 (mean +/- S.D.) to 0.13 +/- 0.06 L min(-1) kPa(-1) (P < 0.01) and Sc from 1.01 +/- 0.38 to 0.88 +/- 0.32 L min(-1) kPa(-1) (P < 0.01). B decreased from 4.02 +/- 0.27 to 3.64 +/- 0.42 kPa (P < 0.01). Subsequent administration of ACET reduced Sp and Sc further to 0.09 +/- 0.06 and to 0.70 +/- 0.49 L min(-1) kPa(-1) (P < 0.01), respectively. The apnoeic threshold decreased further to 2.46 +/- 1.50 kPa (P < 0.01). Because both treatments reduced ventilatory CO2 sensitivity, we conclude that a simulating effect on ventilation is due to a decrease in the apnoeic threshold. Combined administration of MPA and ACET may lead to larger increases in ventilation than treatment with either drugs alone.