Phase I Studies of Acebilustat: Biomarker Response and Safety in Patients with Cystic Fibrosis.

There is a significant unmet need for safe and effective anti-inflammatory treatment for cystic fibrosis. The aim of this study was to evaluate the safety of acebilustat, a leukotriene A4 hydrolase inhibitor, and its effect on inflammation biomarkers in patients with cystic fibrosis. Seventeen patients with mild to moderate cystic fibrosis were enrolled and randomized into groups receiving placebo or doses of 50 mg or 100 mg acebilustat administered orally, once daily for 15 days. Sputum neutrophil counts were reduced by 65% over baseline values in patients treated with 100 mg acebilustat. A modestly significant 58% reduction vs. placebo in sputum elastase was observed with acebilustat treatment. Favorable trends were observed for reduction of serum C-reactive protein and sputum neutrophil DNA in acebilustat-treated patients. No changes in pulmonary function were observed. Acebilustat was safe and well tolerated. The results of this study support further clinical development of acebilustat for treatment of cystic fibrosis.

Ventilation heterogeneity in children with well controlled asthma with normal spirometry indicates residual airways disease.

BACKGROUND: In adults with asthma, ventilation heterogeneity, independent of inflammation, has been hypothesised to be associated with airway remodelling. Bronchial biopsy in preschool children with wheeze demonstrates early structural changes. Ventilation heterogeneity is sensitive to airway disease in other paediatric respiratory conditions such as cystic fibrosis, so may be sensitive to early airway disease in asthma. An observational study was performed in which it was hypothesised that ventilation heterogeneity (lung clearance index (LCI) and phase III slope indices (S(cond) and S(acin))) were more sensitive than conventional measurements (forced expiratory volume in 1 s (FEV(1)) and exhaled nitric oxide (Feno)) for detecting residual airways disease in children with well controlled asthma. METHODS: In 31 children with asthma of mean age 10.6 years (range 5-15), FEV(1), LCI, S(cond) and S(acin) were measured at two separate visits, before and after blinded salbutamol or placebo, with Feno measured once. 29 healthy volunteers of mean age 11.2 years (range 5-16) completed measurements at one visit only. RESULTS: Baseline mean (SD) LCI was significantly higher in children with asthma than in controls (6.69 (0.91) vs 6.24 (0.47), p = 0.02). There were no significant differences in FEV(1) or median Feno. Following salbutamol there was a small significant change in mean (SD) FEV(1) (from -1.26 (1.25) to -0.93 (0.23), p = 0.03) but not in LCI, S(cond) or S(acin). Importantly, LCI remained significantly higher after bronchodilator in children with asthma than in controls (6.64 (0.69), p = 0.01). CONCLUSION: This study identifies the presence of residual ventilation heterogeneity in children with well controlled asthma and normal FEV(1). The role of LCI in measuring early airway disease in children with asthma requires further exploration, possibly as a surrogate of structural remodelling.

Lung clearance index is a sensitive, repeatable and practical measure of airways disease in adults with cystic fibrosis.

BACKGROUND: Lung clearance index (LCI) is a sensitive marker of early lung disease in children but has not been assessed in adults. Measurement is hindered by the complexity of the equipment required. The aims of this study were to assess performance of a novel gas analyser (Innocor) and to use it as a clinical tool for the measurement of LCI in cystic fibrosis (CF). METHODS: LCI was measured in 48 healthy adults, 12 healthy school-age children and 33 adults with CF by performing an inert gas washout from 0.2% sulfur hexafluoride (SF6). SF6 signal:noise ratio and 10-90% rise time of Innocor were compared with a mass spectrometer used in similar studies in children. RESULTS: Compared with the mass spectrometer, Innocor had a superior signal:noise ratio but a slower rise time (150 ms vs 60 ms) which may limit its use in very young children. Mean (SD) LCI in healthy adults was significantly different from that in patients with CF: 6.7 (0.4) vs 13.1 (3.8), p<0.001. Ten of the patients with CF had forced expiratory volume in 1 s > or = 80% predicted but only one had a normal LCI. LCI repeats were reproducible in all three groups of subjects (mean intra-visit coefficient of variation ranged from 3.6% to 5.4%). CONCLUSIONS: Innocor can be adapted to measure LCI and affords a simpler alternative to a mass spectrometer. LCI is raised in adults with CF with normal spirometry, and may prove to be a more sensitive marker of the effects of treatment in this group.

Handheld computers in medicine: the way forward.

Handheld computers are now a common sight in medicine, but there are scarce data on who actually uses them and what functions are found to be most useful. This is the first study of handheld computer use in a British hospital, and shows that there is already considerable use and acceptance of the technology, with 22 of 55 (40%) physicians possessing and using such a device. Doctors in training grades are more likely to make use of medical software, particularly textbooks, calculators, and formularies. The main barriers to greater use of this technology were cost of software and poor applicability to UK practice.

Massage for promoting growth and development of preterm and/or low birth-weight infants.

BACKGROUND: It has been argued that infants in Neonatal Intensive Care Units are subject both to a highly stressful environment - continuous, high-intensity noise and bright light - and to a lack of the tactile stimulation that they would otherwise experience in the womb or in general mothering care. As massage seems to both decrease stress and provide tactile stimulation, it has been recommended as an intervention to promote growth and development of preterm and low-birth weight infants. OBJECTIVES: To determine whether preterm and/or low birth-weight infants exposed to massage experience improved weight gain and earlier discharge compared to infants receiving standard care; to determine whether massage has any other beneficial or harmful effects on this population. SEARCH STRATEGY: The following databases were searched: the specialized register of the Cochrane Neonatal Review Group and that of the Cochrane Complementary Medicine Field. Searches were also undertaken of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2003), MEDLINE, EMBASE, Psychlit, CINAHL and Dissertation Abstracts International (up to July 1, 2003). Further references were obtained by citation tracking, checking personal files and by correspondence with appropriate experts. Data provided in published reports was supplemented by information obtained by correspondence with authors. There were no language restrictions. SELECTION CRITERIA: Randomised trials in which infants with gestational age at birth <37 weeks or weight at birth <2500g received systematic tactile stimulation by human hands. At least one outcome assessing weight gain, length of stay, behaviour or development must be reported. DATA COLLECTION AND ANALYSIS: Data extracted from each trial were baseline characteristics of sample, weight gain, length of stay and behavioural and developmental outcomes. Physiological and biochemical outcomes were not recorded. Data were extracted by three reviewers independently. Statistical analysis was conducted using the standard Cochrane Collaboration methods. MAIN RESULTS: Massage interventions improved daily weight gain by 5.1g (95% CI 3.5, 6.7g). There is no evidence that gentle, still touch is of benefit (increase in daily weight gain 0.2g; 95% CI -1.2, 1.6g). Massage interventions also appeared to reduce length of stay by 4.5 days (95% CI 2.4, 6.5) though there are methodological concerns about the blinding of this outcome. There was also some evidence that massage interventions have a slight, positive effect on postnatal complications and weight at 4 - 6 months. However, serious concerns about the methodological quality of the included studies, particularly with respect to selective reporting of outcomes, weaken credibility in these findings. REVIEWERS' CONCLUSIONS: Evidence that massage for preterm infants is of benefit for developmental outcomes is weak and does not warrant wider use of preterm infant massage. Where massage is currently provided by nurses, consideration should be given as to whether this is a cost-effective use of time. Future research should assess the effects of massage interventions on clinical outcome measures, such as medical complications or length of stay, and on process-of-care outcomes, such as care-giver or parental satisfaction.

Massage for promoting growth and development of preterm and/or low birth-weight infants.

BACKGROUND: It has been argued that infants in Neonatal Intensive Care Units are subject both to a highly stressful environment - continuous, high-intensity noise and bright light - and to a lack of the tactile stimulation that they would otherwise experience in the womb or in general mothering care. As massage seems to both decrease stress and provide tactile stimulation, it has been recommended as an intervention to promote growth and development of preterm and low-birth weight infants. OBJECTIVES: To determine whether preterm and / or low birth-weight infants exposed to massage experience improved weight gain and earlier discharge compared to infants receiving standard care; to determine whether massage has any other beneficial or harmful effects on this population. SEARCH STRATEGY: Databases were searched using the term 'massage', 'touch' or 'tactile stimulation' with 'infant - newborn', 'infant - premature' and 'infant - low birth weight'. The main databases searched were those of the Cochrane Collaboration Field in Complementary Medicine and the Neonatal Collaborative Review Group. SELECTION CRITERIA: Randomised trials in which infants with gestational age at birth < 37 weeks or weight at birth < 2500g received systematic tactile stimulation by human hands. At least one outcome assessing weight gain, length of stay, behaviour or development must be reported. DATA COLLECTION AND ANALYSIS: Data extracted from each trial were baseline characteristics of sample, weight gain, length of stay and behavioural and developmental outcomes. Physiological and biochemical outcomes were not recorded. Data were extracted by three reviewers independently. Statistical analysis was conducted using the standard Cochrane Collaboration methods. MAIN RESULTS: Massage interventions improved daily weight gain by 5g (95% CI 3.5, 6.7g). There is no evidence that gentle, still touch is of benefit (increase in daily weight gain -0.2g; 95% CI -2.4, 1.9g). Massage interventions also appeared to reduce length of stay by 4.6 days (95% CI 2.6, 6.6) though there are methodological concerns about the blinding of this outcome. There was also some evidence that massage interventions have a slight, positive effect on postnatal complications and weight at 4 - 6 months. However, serious concerns about the methodological quality of the included studies, particularly with respect to selective reporting of outcomes, weaken credibility in these findings. REVIEWER'S CONCLUSIONS: Evidence that massage for preterm infants is of benefit for developmental outcomes is weak and does not warrant wider use of preterm infant massage. Where massage is currently provided by nurses, consideration should be given as to whether this is a cost-effective use of time. Future research should assess the effects of massage interventions on clinical outcome measures, such as medical complications or length of stay, and on process-of-care outcomes, such as care-giver or parental satisfaction.

Antihypertensive thiadiazoles. 2. Vasodilator activity of some 2-aryl-5-guanidino-1,3,4-thiadiazoles.

Some 2-aryl-5-guanidino-(or N-substituted guanidino)-1,3,4-thiadiazoles and closely related analogues were found to lower blood pressure in metacorticoid (DOCA) hypertensive rats. In the unsubstituted guanidines that exhibited low toxicity, optimum activity resulted when the aryl group was a 2-methylphenyl ring (11). Modifications to the guanidine group did not increase antihypertensive activity, but, in the 2-methylphenyl series, the N-n-butyl- and N-(2-methoxyethyl)guanidines (63 and 78) and the related iminoimidazolidine 93 were of comparable activity to that of the unsubstituted guanidine 11. The iminoimidazolidine 93 showed a somewhat longer duration of action than the guanidine derivatives. Preliminary studies in a pithed rat preparation indicated that these thiadiazole derivatives (11, 63, and 93) lowered blood pressure by a direct relaxant effect on vascular smooth muscle.