Economic evaluation of nurse-led intensive care follow-up programmes compared with standard care: the PRaCTICaL trial.

OBJECTIVE: Following intensive care discharge, many patients suffer severe physical and psychological morbidity and a continuing high use of health services. Follow-up programmes have been proposed to improve the outcomes for these patients. We tested the hypothesis that nurse-led intensive care follow-up programmes are cost-effective. METHODS: A pragmatic, multicentre, randomised controlled trial of nurse-led intensive care unit follow-up programmes versus standard care. A cost-utility analysis was conducted after 12 months' follow-up to compare the two interventions. Costs were assessed from the perspective of the UK NHS and outcomes were measured in quality-adjusted life years (QALYs) based upon responses to the EQ-5D administered at baseline, 6 and 12 months. RESULTS: A total of 286 patients were recruited to the trial. Total mean cost was £ 5,789 for standard care and £ 7,577 for the discharge clinic. The adjusted difference in means was £ 2,435 [95 % confidence interval (CI) -297 to 5,566]. Mean QALYs were 0.58 for standard care and 0.60 for the discharge clinic. The adjusted mean difference was -0.003 (95 % CI -0.066 to 0.060). If society were willing to pay £ 20,000 per QALY then there would be a 93 % chance that standard care would be considered most efficient. CONCLUSIONS: A nurse-led intensive care unit (ICU) follow-up programme showed no evidence of being cost-effective at 12 months. Further work should focus on evidence-based development of discharge clinic services and current ICU follow-up programmes should review their practice in light of these results.

Systematic review and economic modelling of the relative clinical benefit and cost-effectiveness of laparoscopic surgery and robotic surgery for removal of the prostate in men with localised prostate cancer.

BACKGROUND: Complete surgical removal of the prostate, radical prostatectomy, is the most frequently used treatment option for men with localised prostate cancer. The use of laparoscopic (keyhole) and robot-assisted surgery has improved operative safety but the comparative effectiveness and cost-effectiveness of these options remains uncertain. OBJECTIVE: This study aimed to determine the relative clinical effectiveness and cost-effectiveness of robotic radical prostatectomy compared with laparoscopic radical prostatectomy in the treatment of localised prostate cancer within the UK NHS. DATA SOURCES: MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, BIOSIS, Science Citation Index and Cochrane Central Register of Controlled Trials were searched from January 1995 until October 2010 for primary studies. Conference abstracts from meetings of the European, American and British Urological Associations were also searched. Costs were obtained from NHS sources and the manufacturer of the robotic system. Economic model parameters and distributions not obtained in the systematic review were derived from other literature sources and an advisory expert panel. REVIEW METHODS: Evidence was considered from randomised controlled trials (RCTs) and non-randomised comparative studies of men with clinically localised prostate cancer (cT1 or cT2); outcome measures included adverse events, cancer related, functional, patient driven and descriptors of care. Two reviewers abstracted data and assessed the risk of bias of the included studies. For meta-analyses, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness was assessed using a discrete-event simulation model. RESULTS: The searches identified 2722 potentially relevant titles and abstracts, from which 914 reports were selected for full-text eligibility screening. Of these, data were included from 19,064 patients across one RCT and 57 non-randomised comparative studies, with very few studies considered at low risk of bias. The results of this study, although associated with some uncertainty, demonstrated that the outcomes were generally better for robotic than for laparoscopic surgery for major adverse events such as blood transfusion and organ injury rates and for rate of failure to remove the cancer (positive margin) (odds ratio 0.69; 95% credible interval 0.51 to 0.96; probability outcome favours robotic prostatectomy = 0.987). The predicted probability of a positive margin was 17.6% following robotic prostatectomy compared with 23.6% for laparoscopic prostatectomy. Restriction of the meta-analysis to studies at low risk of bias did not change the direction of effect but did decrease the precision of the effect size. There was no evidence of differences in cancer-related, patient-driven or dysfunction outcomes. The results of the economic evaluation suggested that when the difference in positive margins is equivalent to the estimates in the meta-analysis of all included studies, robotic radical prostatectomy was on average associated with an incremental cost per quality-adjusted life-year that is less than threshold values typically adopted by the NHS (£30,000) and becomes further reduced when the surgical capacity is high. LIMITATIONS: The main limitations were the quantity and quality of the data available on cancer-related outcomes and dysfunction. CONCLUSIONS: This study demonstrated that robotic prostatectomy had lower perioperative morbidity and a reduced risk of a positive surgical margin compared with laparoscopic prostatectomy although there was considerable uncertainty. Robotic prostatectomy will always be more costly to the NHS because of the fixed capital and maintenance charges for the robotic system. Our modelling showed that this excess cost can be reduced if capital costs of equipment are minimised and by maintaining a high case volume for each robotic system of at least 100-150 procedures per year. This finding was primarily driven by a difference in positive margin rate. There is a need for further research to establish how positive margin rates impact on long-term outcomes. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Clinical effectiveness and cost-effectiveness of imatinib dose escalation for the treatment of unresectable and/or metastatic gastrointestinal stromal tumours that have progressed on treatment at a dose of 400 mg/day: a systematic review and economic evaluation.

BACKGROUND: Imatinib dose escalation is advocated for gastrointestinal stromal tumour (GIST) treatment, but its effectiveness compared with sunitinib and best supportive care (BSC) after failure at the 400 mg/day dose is unknown. OBJECTIVES: To assess the effectiveness and cost-effectiveness of imatinib at escalated doses of 600 or 800 mg/day for patients with unresectable and/or metastatic GISTs whose disease had progressed on 400 mg/day. DATA SOURCES: Electronic databases, including MEDLlNE, MEDLINE In-Process, EMBASE, BIOSIS, Science Citation Index, Health Management Information Consortium and the Cochrane Controlled Trials Register, were searched until September 2009. REVIEW METHODS: A systematic review of the literature was carried out according to standard methods. An economic model was constructed to assess the cost-effectiveness of seven alternative pathways for treating patients with unresectable and/or metastatic GISTs. RESULTS: Five primary studies involving 669 people were included for clinical effectiveness; four reported imatinib and one reported sunitinib. The data were essentially observational as none of the studies was designed to specifically assess treatment of patients whose disease had progressed on 400 mg/day imatinib. For 600 mg/day imatinib, between 26% and 42% of patients showed either a partial response (PR) or stable disease (SD). Median time to progression was 1.7 months (range 0.7-24.9 months). For 800 mg/day imatinib, between 29% and 33% of patients showed either a PR or SD. Median overall survival (OS) was 19 months [95% confidence interval (CI) 13 to 23 months]. Progression-free survival ranged from 81 days to 5 months (95% CI 2 to 10 months). Median duration of response was 153 days (range 37-574 days). Treatment progression led to 88% discontinuations but between 16% and 31% of patients required a dose reduction, and 23% required a dose delay. There was a statistically significant increase in the severity of fatigue (p < 0.001) and anaemia (p = 0.015) following dose escalation. For sunitinib, median OS was 90 weeks (95% CI 73 to 106 weeks). For the cost-effectiveness review, only one full-text study and one abstract were identified, comparing imatinib at an escalated dose, sunitinib and BSC, although neither was based on a UK context. The definition of BSC was not consistent across the studies, and the pattern of resources (including drugs for treatment) and measures of effectiveness also varied. Within the model, BSC (assumed to include continuing medication to prevent tumour flare) was the least costly and least effective. It would be the care pathway most likely to be cost-effective when the cost per quality-adjusted life-year threshold was < £25,000. Imatinib at 600 mg/day was most likely to be cost-effective at a threshold between £25,000 and £45,000. Imatinib at 600 mg/day followed by further escalation followed by sunitinib was most likely to be cost-effective at a threshold > £45,000. LIMITATIONS: The evidence base was sparse, data were non-randomised and potentially biased. The economic model results are surrounded by a considerable degree of uncertainty and open to biases of unknown magnitude and direction. CONCLUSIONS: Around one-third of patients with unresectable and/or metastatic GIST, who fail on 400 mg/day of imatinib, may show response or SD with escalated doses. Between a threshold of £25,000 and £45,000, provision of an escalated dose of imatinib would be most likely to be cost-effective. However, these results should be interpreted with caution owing to the limited evidence available on outcomes following imatinib dose escalation or sunitinib for this group of patients. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP).

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of eltrombopag for the treatment of adults with chronic idiopathic (immune) thrombocytopenic purpura (ITP), based on a review of the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. ITP is an autoimmune disorder by which antibodies are formed against platelets with annual incidence rates in the UK/USA ranging from 1.13 to 6.62 cases per 100,000 adults. Eltrombopag increases the production of platelets at a rate that outpaces their destruction by the immune system, and has a UK marketing authorisation both for the treatment of adult ITP in splenectomised patients who are refractory to other treatments and as a second-line treatment for adult non-splenectomised patients for whom surgery is contraindicated. Both splenectomised and non-splenectomised patient groups were considered in the analysis. Two economic models were presented, one for a watch-and-rescue treatment scenario and the second for the long-term treatment of patients with more severe ITP. The submission's evidence was sourced from the relatively high-quality RAISE [RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag] randomised controlled trial. The study indicated a statistically significant difference in favour of eltrombopag compared with placebo in the odds of achieving the primary outcome of a platelet count of between 50 and 400 × 109/l during the 6-month treatment period (odds ratio 8.2, 99% confidence interval 3.6 to 18.7). In the eltrombopag group, 50/83 (60%) non-splenectomised patients and 18/49 (37%) splenectomised patients achieved this outcome. Median duration of response for all patients was 10.9 weeks (splenectomised patients 6 weeks and non-splenectomised patients 13.4 weeks). Patients treated with eltrombopag required less rescue medication and had lower odds of bleeding events than placebo-treated subjects in both patient groups. In the watch-and-rescue economic model, the ERG found that substantial reductions in the cost of eltrombopag are needed for the incremental cost-effectiveness ratio (ICER) to fall below £ 30,000. Further analyses found that the ICER varied from £33,561 to £ 103,500 per quality-adjusted life-year (QALY) (splenectomised) and from £ 39,657 to £ 150,245 per QALY (non-splenectomised). Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG found that using non-randomised non-comparative data may result in biased estimates of unknown magnitude and direction. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £ 30,000. The base-case results, using a 2-year time horizon and prescribing eltrombopag as second-line treatment post rituximab, were found to be favourable towards eltrombopag. In conclusion, based on the MS and additional ERG work, eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, there is no robust evidence on long-term efficacy or cost-effectiveness of eltrombopag, and there is a lack of robust direct evidence on the effectiveness and cost-effectiveness of eltrombopag compared with other relevant comparators. NICE did not recommend eltrombopag for the treatment of chronic ITP within its marketing authorisation for splenectomised or non-splenectomised patients.

Systematic review and economic modelling of the effectiveness and cost-effectiveness of non-surgical treatments for women with stress urinary incontinence.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of non-surgical treatments for women with stress urinary incontinence (SUI) through systematic review and economic modelling. DATA SOURCES: The Cochrane Incontinence Group Specialised Register, electronic databases and the websites of relevant professional organisations and manufacturers, and the following databases: CINAHL, EMBASE, BIOSIS, Science Citation Index and Social Science Citation Index, Current Controlled Trials, ClinicalTrials.gov and the UKCRN Portfolio Database. STUDY SELECTION: The study comprised three distinct elements. (1) A survey of 188 women with SUI to identify outcomes of importance to them (activities of daily living; sex, hygiene and lifestyle issues; emotional health; and the availability of services). (2) A systematic review and meta-analysis of non-surgical treatments for SUI to find out which are most effective by comparing results of trials (direct pairwise comparisons) and by modelling results (mixed-treatment comparisons - MTCs). A total of 88 randomised controlled trials (RCTs) and quasi-RCTs reporting data from 9721 women were identified, considering five generic interventions [pelvic floor muscle training (PFMT), electrical stimulation (ES), vaginal cones (VCs), bladder training (BT) and serotonin-noradrenaline reuptake inhibitor (SNRI) medications], in many variations and combinations. Data were available for 37 interventions and 68 treatment comparisons by direct pairwise assessment. Mixed-treatment comparison models compared 14 interventions, using data from 55 trials (6608 women). (3) Economic modelling, using a Markov model, to find out which combinations of treatments (treatment pathways) are most cost-effective for SUI. DATA EXTRACTION: Titles and abstracts identified were assessed by one reviewer and full-text copies of all potentially relevant reports independently assessed by two reviewers. Any disagreements were resolved by consensus or arbitration by a third person. RESULTS: Direct pairwise comparison and MTC analysis showed that the treatments were more effective than no treatment. Delivering PFMT in a more intense fashion, either through extra sessions or with biofeedback (BF), appeared to be the most effective treatment [PFMT extra sessions vs no treatment (NT) odds ratio (OR) 10.7, 95% credible interval (CrI) 5.03 to 26.2; PFMT + BF vs NT OR 12.3, 95% CrI 5.35 to 32.7]. Only when success was measured in terms of improvement was there evidence that basic PFMT was better than no treatment (PFMT basic vs NT OR 4.47, 95% CrI 2.03 to 11.9). Analysis of cost-effectiveness showed that for cure rates, the strategy using lifestyle changes and PFMT with extra sessions followed by tension-free vaginal tape (TVT) (lifestyle advice-PFMT extra sessions-TVT) had a probability of greater than 70% of being considered cost-effective for all threshold values for willingness to pay for a QALY up to 50,000 pounds. For improvement rates, lifestyle advice-PFMT extra sessions-TVT had a probability of greater than 50% of being considered cost-effective when society's willingness to pay for an additional QALY was more than 10,000 pounds. The results were most sensitive to changes in the long-term performance of PFMT and also in the relative effectiveness of basic PFMT and PFMT with extra sessions. LIMITATIONS: Although a large number of studies were identified, few data were available for most comparisons and long-term data were sparse. Challenges for evidence synthesis were the lack of consensus on the most appropriate method for assessing incontinence and intervention protocols that were complex and varied considerably across studies. CONCLUSIONS: More intensive forms of PFMT appear worthwhile, but further research is required to define an optimal form of more intensive therapy that is feasible and efficient for the NHS to provide, along with further definitive evidence from large, well-designed studies.

The PRaCTICaL study of nurse led, intensive care follow-up programmes for improving long term outcomes from critical illness: a pragmatic randomised controlled trial.

OBJECTIVES: To test the hypothesis that nurse led follow-up programmes are effective and cost effective in improving quality of life after discharge from intensive care. DESIGN: A pragmatic, non-blinded, multicentre, randomised controlled trial. SETTING: Three UK hospitals (two teaching hospitals and one district general hospital). PARTICIPANTS: 286 patients aged >or=18 years were recruited after discharge from intensive care between September 2006 and October 2007. INTERVENTION: Nurse led intensive care follow-up programmes versus standard care. Main outcome measure(s) Health related quality of life (measured with the SF-36 questionnaire) at 12 months after randomisation. A cost effectiveness analysis was also performed. RESULTS: 286 patients were recruited and 192 completed one year follow-up. At 12 months, there was no evidence of a difference in the SF-36 physical component score (mean 42.0 (SD 10.6) v 40.8 (SD 11.9), effect size 1.1 (95% CI -1.9 to 4.2), P=0.46) or the SF-36 mental component score (effect size 0.4 (-3.0 to 3.7), P=0.83). There were no statistically significant differences in secondary outcomes or subgroup analyses. Follow-up programmes were significantly more costly than standard care and are unlikely to be considered cost effective. CONCLUSIONS: A nurse led intensive care follow-up programme showed no evidence of being effective or cost effective in improving patients' quality of life in the year after discharge from intensive care. Further work should focus on the roles of early physical rehabilitation, delirium, cognitive dysfunction, and relatives in recovery from critical illness. Intensive care units should review their follow-up programmes in light of these results. TRIAL REGISTRATION: ISRCTN 24294750.

A ruby (rubor!) anniversary: the Scottish Skin Biology Club 1969-2009.

The 40th birthday of the Scottish Skin Biology Club (SSBC) was celebrated in Spring 2009. The SSBC, formerly The Skin Biology Club, has played a vital role in providing a forum and a means of networking for skin researchers in Scotland. This paper summarizes the history of the club.

Thrombolytic therapy for acute stroke in the United Kingdom: experience from the safe implementation of thrombolysis in stroke (SITS) register.

AIM: To describe the United Kingdom (UK) experience with thrombolytic therapy with intravenous alteplase (rt-PA) for stroke, as captured by the Implementation of Thrombolysis in Stroke (SITS) project. METHODS: The multinational Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) was an observational study to assess the safety and efficacy of thrombolytic therapy, when administered within the first 3 h after onset of ischaemic stroke. SITS-MOST was embedded within the Safe Implementation of Thrombolysis in Stroke-International Stroke Thrombolysis Register (SITS-ISTR), an internet-based, international monitoring registry for auditing the safety and efficacy of routine therapeutic use of thrombolysis in acute ischaemic stroke. We performed an analysis of data contributed to SITS-MOST and SITS-ISTR from UK centres. RESULTS: A total of 614 patients received thrombolysis for stroke between December 2002 and April 2006, 327 were registered to SITS-MOST and 287 to SITS-ISTR. Thirty-one centres treated patients in the UK, of which 23 registered patients in both SITS-MOST and SITS-ISTR and eight solely to SITS-ISTR. The median age from the UK SITS-MOST was identical to the non-UK SITS-MOST register: 68 years (IQR 59-75). The majority (96.1%) of patients from the UK were treated between 8.00 a.m. and 9.00 p.m., and only 18.4% were treated on weekend days, reflecting the difficulties of maintaining provision of a thrombolytic service out of hours. Median onset-to-treatment-time was 155 min (IQR 130-170 min) for the UK, compared to 140 min (IQR 114-165 min) for the non-UK SITS-MOST group (P < 0.001). UK SITS-MOST patients at baseline had more severe stroke in comparison with non-UK patients [median NIHSS 14.5 (IQR 9-19) vs. 12 (IQR 8-17) (P < 0.001)]. Forty-eight percent of UK patients achieved mRS of 0-2 (independence), compared to 55% of the non-UK SITS-MOST register. There was no significant difference in symptomatic intracerebral haemorrhage rate in the UK compared with the non-UK SITS-MOST patients [2.5% (95% CI 1.3-4.8) vs. 1.7% (95% CI 1.4-2.0) P = 0.28]. In the multivariate analysis, there was no statistically significant difference in any outcome between UK and non-UK SITS-MOST patients. CONCLUSION: Thrombolytic therapy for stroke has been implemented successfully at a small number of UK stroke centres, with patchy provision throughout the country. The low frequency of treatment out with office hours suggests deficient infrastructure to support delivery. UK patients tended to be more severely affected at baseline and to be treated later. Outcomes are comparable to those seen at the non-UK SITS centres.

Agreement between ambulance paramedic- and physician-recorded neurological signs with Face Arm Speech Test (FAST) in acute stroke patients.

BACKGROUND AND PURPOSE: Patients with suspected stroke first assessed by ambulance paramedics require early recognition to facilitate appropriate triage and early treatment. We determined paramedic's accuracy in detecting acute stroke signs by comparing agreement between neurological signs recorded in the Face Arm Speech Test (FAST), a stroke recognition instrument, by paramedics on the scene and by stroke physicians after admission. METHODS: Suspected stroke patients admitted by ambulance paramedics directly to an acute stroke unit through a rapid ambulance protocol were examined by a trainee stroke neurologist or admitting stroke physician over a 1-year period. Recorded neurological signs (facial weakness, arm weakness, speech disturbance) in confirmed acute stroke/transient ischemic attack (TIA) cases were compared between paramedics and the stroke neurologist/physician. RESULTS: Ambulance crews referred 278 suspected stroke patients of whom 217 (78%) had confirmed stroke (n=189) or TIA (n=28); 95% were examined by the stroke neurologist (median 18 hours after paramedic assessment). Recorded signs and agreement between paramedics and stroke physicians in confirmed stroke group were: facial weakness, 68% versus 70% (kappa=0.49; 95% CI: 0.36 to 0.62); arm weakness, 96% versus 95% (kappa=0.77; 95% CI: 0.55 to 0.99); and speech disturbance, 79% versus 77% (kappa=0.69; 95% CI: 0.56 to 0.82). Interrater agreement was complete for arm weakness in 98% cases. CONCLUSIONS: Recognition of neurological deficits by ambulance paramedics using FAST shows good agreement with physician assessment, even allowing for temporal evolution of deficits. The high prevalence and good agreement for arm weakness suggest that this sign may have the greatest usefulness for prehospital ambulance triage and paramedic-based neuroprotective trials.

Comparison of caffeine-induced changes in cerebral blood flow and middle cerebral artery blood velocity shows that caffeine reduces middle cerebral artery diameter.

Changes in cerebral blood flow (CBF) can be assessed directly with xenon clearance (XeC) or indirectly by measuring changes in middle cerebral artery blood velocity (Vmca) with transcranial Doppler (TCD). The aim of this study was to compare the changes in CBF and Vmca following caffeine ingestion. Nineteen patients (age 48-86, recovering from an acute stroke) and ten controls (age 52-85) were each studied twice. Bilateral measurements of CBF and Vmca were made before and after ingestion of 250 mg caffeine or matched placebo. The percentage change in CBF and Vmca after caffeine was calculated. Full results (CBF and Vmca) were obtained from 14 patients and 9 controls. There was no significant difference between patients and controls, so results were combined. Caffeine reduced CBF by 22% (95% confidence interval (CI) = 17% to 28%) and reduced Vmca by 13% (95% CI = 10% to 17%). The fall in Vmca was significantly less than that in CBF (p = 0.0016), showing that caffeine reduces mca diameter. Analysis based on Poiseuille flow in the arterioles suggests that caffeine reduced arteriole diameter by 5.9% (95% CI = 4.6% to 7.3%) and mca diameter by 4.3% (95% CI = 2.0% to 6.6%). TCD is being used as an alternative to XeC for assessing the effect of vasoconstrictors and vasodilators on CBF. This study has demonstrated that in mca diameter can be changed by the vasoactive agents, and that changes in Vmca do not necessarily reflect changes in CBF.

SK3 is an important component of K(+) channels mediating the afterhyperpolarization in cultured rat SCG neurones.

1. Our aim was to identify the small-conductance Ca(2+)-activated K(+) channel(s) (SK) underlying the apamin-sensitive afterhyperpolarization (AHP) in rat superior cervical ganglion (SCG) neurones. 2. Degenerate oligonucleotide primers designed to the putative calmodulin-binding domain conserved in all mammalian SK channel sequences were employed to detect SK DNA in a cDNA library from rat SCG. Only a single band, corresponding to a fragment of the rSK3 gene, was amplified. 3. Northern blot analysis employing a PCR-generated rSK3 fragment showed the presence of mRNA coding for SK3 in SCG as well in other rat peripheral tissues including adrenal gland and liver. 4. The same rSK3 fragment enabled the isolation of a full-length rSK3 cDNA from the library. Its sequence was closely similar to, but not identical with, that of the previously reported rSK3 gene. 5. Expression of the rSK3 gene in mammalian cell lines (CHO, HEK cells) caused the appearance of a K(+) conductance with SK channel properties. 6. The application of selective SK blocking agents (including apamin, scyllatoxin and newer non-peptidic compounds) showed these homomeric SK3 channels to have essentially the same pharmacological characteristics as the SCG afterhyperpolarization, but to differ from those of homomeric SK1 and SK2 channels. 7. Immunohistochemistry using a rSK3 antipeptide antibody revealed the presence of SK3 protein in the cell bodies and processes of cultured SCG neurones. 8. Taken together, these results identify SK3 as a major component of the SK channels responsible for the afterhyperpolarization of cultured rat SCG neurones.

Synthesis and structure-activity relationships of cetiedil analogues as blockers of the Ca(2+)-activated K+ permeability of erythrocytes.

Cetiedil, [2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1H-azepin-1-yl)ethyl ester], which blocks the intermediate calcium-activated potassium ion permeability (IK(Ca)) in red blood cells, was used as a lead for investigating structure-activity relationships with the aim of determining the pharmacophore and of synthesizing agents of greater potency. A series of compounds having structures related to cetiedil was made and tested on rabbit erythrocytes. Channel blocking activity within the series was found to correlate well with octanol-water partition coefficients but not with the specific chemical structure of the acid moiety. However, whereas log P for the compounds spans a range of values over 4 orders of magnitude, potency only increases by 2 orders. This suggests that hydrophobic interactions with an active site on the channel are probably not the main determinants of activity. It seems more likely that increased lipophilicity enhances access to the channel, probably from within the cell membrane. In keeping with this interpretation, cetiedil methoiodide was found to be inactive. Triphenylethanoic was found to be a more effective acid grouping than 2-cyclohexyl-2-(3-thienyl)ethanoic, and its 2-(hexahydro-1H-azepin-l-yl)ethyl ester (11) was approximately 3 times more potent than cetiedil. The 9-benzylfluoren-9-yl carboxylic acid ester (21) was found to be approximately 9 times more active than cetiedil, and replacing -CO(2)- in 21 by an ethynyl (-C identical to C-) linkage (compound 26, UCL 1608) increased potency by some 15-fold over that of cetiedil.

Ultrastructure of the hyperhidrotic eccrine sweat gland.

BACKGROUND: Hyperhidrosis is the secretion of inappropriately large amounts of sweat by eccrine glands; it can be very debilitating. Little is known of the causes of primary hyperhidrosis. OBJECTIVES: To determine whether the glands exhibit any structural abnormality in primary hyperhidrosis. METHODS: Skin biopsies were obtained from the axilla (n = 6) or neck (n = 2) of individuals aged 26-62 years with primary hyperhidrosis and from five age- and sex-matched normal individuals, with informed consent and ethical committee approval. Samples were prepared by standard methods for light and electron microscopic examination. RESULTS: All characteristics observed in the hyperhidrotic specimens were consistent with the changes seen in normal glands following strong activation: degranulation of the granular (dark) cells, dilatation of the basolateral infoldings and the canaliculi of the non-granular (clear) cells, contraction of the myoepithelial cells and thickening of the basal lamina, and presence of cellular debris including lipid droplets in the gland lumen. Pathological changes were not observed. CONCLUSIONS: The present finding of the absence of structural defects in the glands indicates that future studies should concentrate on the investigation of neurohumoral or secretory cell metabolic abnormalities.

Transcranial Doppler blood velocity measurement--the effect of changes in velocity profile.

Transcranial Doppler (TCD) units measure blood velocity in the middle cerebral artery (MCA) and are used to examine the effects of pharmacological agents. The units actually measure the average of the maximum blood velocity envelope (aveV(max)) and it is assumed that changes in aveV(max) follow changes in the true mean velocity (aveV(mean)). This may not be true if there are changes in velocity profile. Results from previous TCD studies using acetazolamide (ACZ) and caffeine were examined for evidence for changes in velocity profile. ACZ increased aveV(max) by 21% (95% CI 13 to 29%) and aveV(mean) by 14% (95% CI 9 to 19%). Caffeine decreased aveV(max) by 8% (95% CI 4 to 12%) and aveV(mean) by 5% (95% CI 4% increase to 13% decrease). In both cases, the true change, measured using aveV(mean) was lower, indicating possible changes in velocity profile. We conclude that the possibility of changes in velocity profile must be considered when using TCD to quantify changes in blood velocity.

Compounds that block both intermediate-conductance (IK(Ca)) and small-conductance (SK(Ca)) calcium-activated potassium channels.

1. Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to block apamin-sensitive small conductance Ca(2+)-activated K(+) channels (SK(Ca)), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca(2+)-activated K(+) channels (IK(Ca)) in rabbit blood cells. 2. In most experiments, a K(+)-sensitive electrode was employed to monitor the IK(Ca)-mediated net loss of cell K(+) that followed the addition of the Ca(2+) ionophore A23187 (2 microM) to red cells suspended at an haematocrit of 1% in a low K(+) (0.12 - 0.17 mM) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying A23187 (0.4 or 2 microM) to a very dilute suspension of red cells (haematocrit 0.02%). 3. Of the compounds tested, the most potent IK(Ca) blocker was 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL 1407) which had an IC(50) of 0.85+/-0.06 microM (mean+/-s.d. mean). 4. The inhibitory action of UCL 1407 and its three most active congeners was characterized by (i) a Hill slope greater than unity, (ii) sensitivity to an increase in external [K(+)], and (iii) a time course of onset that suggested use-dependence. Also, the potency of the nonquaternary compounds tested increased with their predicted lipophilicity. These findings suggested that the IK(Ca) blocking action resembles that of cetiedil rather than of clotrimazole. 5. Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1-[N-[1-(3, 5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino]-10-[N'-(2-me thylqu inolinium-4yl)amino] decane (trifluoroacetate) which had an IC(50) of 1.8+/-0.1 microM. The corresponding bisquaternary UCL 1438 (1, 10-bis[N-[1-(3,5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino] decane bis(trifluoroacetate) was almost as active (IC(50) 2.7+/-0.3 microM). 6. A bis-aminoquinolium cyclophane (UCL 1684) had little IK(Ca) blocking action despite its great potency at SK(Ca) channels (IC(50) 4.1+/-0.2 nM). 7. The main outcome is the identification of new intermediate-conductance Ca(2+)-activated K(+) channel blockers with a wide range of IK(Ca)/SK(Ca) selectivities.

Incidence of exercise-induced bronchospasm in Olympic winter sport athletes.

PURPOSE: The purpose of this project was to determine the incidence of exercise-induced bronchospasm (EIB) among U.S. Olympic winter sport athletes. METHODS: Subjects included female and male members of the 1998 U.S. Winter Olympic Team from the following sports: biathlon, cross-country ski, figure skating, ice hockey, Nordic combined, long-track speedskating, and short-track speedskating. Assessment of EIB was conducted in conjunction with an "actual competition" (Olympic Trials, World Team Trials, World Cup Event, U.S. National Championships) or a "simulated competition" (time trial, game), which served as the exercise challenge. Standard spirometry tests were performed preexercise and at 5, 10, and 15 min postexercise. An athlete was considered EIB-positive based on a postexercise decrement in FEV1 > or = 10%. RESULTS: For the seven sports evaluated on the 1998 U.S. Winter Olympic Team, the overall incidence of EIB across all sports and genders was 23%. The highest incidence of EIB was found in cross-country skiers, where 50% of the athletes (female = 57%; male = 43%) were diagnosed with EIB. Across the seven sports evaluated, the prevalence of EIB among the female and male athletes was 26% and 18%, respectively. Among those individuals found to be EIB-positive were athletes who won a team gold medal, one individual silver medal, and one individual bronze medal at the Nagano Winter Olympics. CONCLUSIONS: These data suggest that: 1) EIB is prevalent in several Olympic winter sports and affects nearly one of every four elite winter sport athletes; 2) the winter sport with the highest incidence of EIB is cross-country skiing; 3) in general, EIB is more prevalent in female versus male elite winter sport athletes; and 4) athletes may compete successfully at the international level despite having EIB.

Anterior knee pain: a clinical comparison of rehabilitation methods.

OBJECTIVE: To compare different types of rehabilitation for anterior knee pain. DESIGN: Prospective, randomized, blinded, and controlled study of 64 participants with anterior knee pain. SETTING: Outpatient rehabilitation clinic and testing laboratory. PARTICIPANTS: Participants were assigned in randomized fashion to three rehabilitation groups: traditional home rehabilitation (n = 20); physical therapy (n = 21); and home rehabilitation with a modified vastus medialis obliquis (VMO) specific straight leg raise (Muncie method; n = 23). INTERVENTIONS AND MAIN OUTCOME MEASURES: Clinical data was obtained at 0, 2, 6, and 12 weeks. Cybex testing was performed at 0, 6, and 12 weeks. RESULTS: Clinical outcome for the Muncie method indicated a statistically significant improvement in subjective pain and functional impairment ratings. Cybex testing in patients using the Muncie method demonstrated a statistically significant improvement in pain-free isometric contractions and maximum voluntary contraction. There were no significant differences between traditional home therapy and physical therapy. CONCLUSION: Findings suggest that the Muncie method results in improved clinical outcome at a lower cost than traditional home and physical therapy and possibly improved VMO/quadriceps muscle balance. Patients with anterior knee pain may benefit from applying the Muncie method in a home therapy program.