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H Powell

Publications and source records attributed to H Powell.

At least 19 recordsLinked to original sources
PubMed2005

Long-acting beta2-agonists as an inhaled corticosteroid-sparing agent for chronic asthma in adults and children.

BACKGROUND: The addition of a long acting beta agonist (LABA) to inhaled corticosteroid (ICS) therapy can improve asthma symptoms and reduce exacerbations. The addition of LABA may also have an ICS-sparing effect and permit a reduction in ICS maintenance dose. OBJECTIVES: To determine the efficacy of adding LABA to maintenance ICS therapy in reducing the requirement for ICS while maintaining control of chronic asthma. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. Date of last search: November 2004 SELECTION CRITERIA: Parallel RCTs that compared reduced dose ICS in combination with LABA vs ICS alone in asthmatics requiring daily ICS. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. Trials were analysed according to the following ICS dose comparisons: a fixed moderate/high dose or a reduced/tapering dose of the same ICS. MAIN RESULTS: 19 publications describing 10 trials of adults were included in the review. Studies that compared reduced dose (mean 60% reduction) ICS/LABA combination to a fixed moderate/high dose ICS found no significant difference in severe exacerbations requiring oral corticosteroids (RR 1.0, 95%CI 0.76 to 1.32), withdrawal due to worsening asthma (RR 0.82, 95%CI 0.5 to 1.35) or airway inflammation. There were also significant improvements in FEV1 (change from baseline WMD 0.10, 95%CI 0.07 to 0.12), morning & evening PEF and percent rescue free days with LABA. Two studies provided outcomes for a reduced/tapering ICS dose comparison. More participants receiving the LABA/reduced ICS combination achieved a reduction in ICS dose reaching significance in one study. A significant reduction of 253 mcg BDP was achieved in one study. AUTHORS' CONCLUSIONS: In adults with asthma, using moderate to high maintenance doses of ICS, the addition of LABA has an ICS-sparing effect. The addition ofLABA permits more participants on minimum maintenance ICS to reduce ICS. The precise magnitude of the ICS dose reduction requires further study.

Administration, Inhalation↗
PubMed2004

High dose versus low dose inhaled corticosteroid as initial starting dose for asthma in adults and children.

BACKGROUND: Inhaled corticosteroids (ICS) form the basis of maintenance therapy in asthma and their efficacy is well established. However, the optimal starting dose of ICS is not clearly established. Recent reviews demonstrate a relatively flat efficacy curve for ICS and increasing side effects with increasing ICS doses. High doses are frequently prescribed and there are now reports of significant side effects occurring with high dose ICS use. These issues demonstrate the need to establish the optimal starting dose of ICS in asthma. OBJECTIVES: To establish the optimal starting dose of ICS by evaluating the efficacy of initial high dose ICS with low dose ICS in subjects with asthma, not currently on ICS. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. Date of last search: January 2003 SELECTION CRITERIA: Randomised controlled trials of two different doses of the same ICS in adults and children with asthma with no concomitant ICS or OCS. DATA COLLECTION AND ANALYSIS: Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. Trials were analysed according to the following ICS dose comparisons: step down vs constant dose ICS (n=7); high vs moderate (n=11); high vs low (n=9); moderate vs low (n=11); fold change in dose (all studies). MAIN RESULTS: 31 papers reporting the results of 26 trials were included in the review. For studies that compared a step down approach to a constant moderate/low ICS dose, there were no significant differences in lung function, symptoms, rescue medications or asthma control between the two treatment approaches. Significant but clinically small improvements in percent predicted FEV(1) ( WMD 5.32, 95% CI 0.65 to 9.99) and non significant improvements in the change in morning PEF were found for high dose ICS compared to moderate dose ICS. There were no significant differences in efficacy between high and low dose ICS. For moderate dose ICS, compared to low dose ICS, there were significant improvements in the change in morning PEF l/min from baseline (WMD 11.14, 95% CI 1.34 to 20.93) and nocturnal symptoms (SMD -0.29, 95% CI -0.53 to -0.06 ). Commencing ICS at double or quadruple a base moderate or low dose had no greater effect than commencing with the base dose. Several studies reported greater improvement in airway hyperresponsiveness for high dose ICS. REVIEWERS' CONCLUSIONS: For patients with asthma who require ICS, commencing with a moderate dose ICS is equivalent to commencing with a high dose ICS and down-titrating. The small significant benefits of commencing with a high ICS dose are not of sufficient clinical benefit to warrant its use when compared to moderate or low dose ICS. Initial moderate ICS dose appears to be more effective than initial low ICS dose. High dose ICS may be more effective than moderate or low dose ICS for airway hyperresponsiveness. There is no benefit in doubling or quadrupling ICS in subjects with stable asthma.

Administration, Inhalation↗
PubMed2004

Written action plans for asthma: an evidence-based review of the key components.

BACKGROUND: Written action plans for asthma facilitate the early detection and treatment of an asthma exacerbation. Several versions of action plans have been published but the key components have not been determined. A study was undertaken to determine the impact of individual components of written action plans on asthma health outcomes. METHODS: Randomised controlled trials (n=26) that evaluated asthma action plans as part of asthma self-management education were identified. Action plans were classified as being individualised and complete if they specified when and how to increase treatment (n=17), and as incomplete (n=4) or non-specific (n=5) if they did not include these instructions. RESULTS: For individualised complete written action plans the use of 2-4 action points and the use of both inhaled (ICS) and oral (OCS) corticosteroid consistently improved asthma outcomes. Action points based on personal best peak expiratory flow (PEF) consistently improved health outcomes while those based on percentage predicted PEF did not. The efficacy of incomplete action plans was inconclusive because of insufficient data. Non-specific action plans led to improvements in knowledge and symptoms. CONCLUSION: Individualised written action plans based on personal best PEF, using 2-4 action points, and recommending both ICS and OCS for treatment of exacerbations consistently improve asthma health outcomes. Other variations appear less beneficial or require further study. These observations provide a guide to the types of variations possible with written action plans, and strongly support the use of individualised complete written action plans.

Adult↗
PubMed2004

Initial starting dose of inhaled corticosteroids in adults with asthma: a systematic review.

BACKGROUND: Asthma guidelines vary in their recommendations for the initial dose of inhaled corticosteroid (ICS) in asthma. A systematic review of the literature was conducted to establish the optimal starting dose of ICS for asthma in adults. METHODS: Randomised controlled trials comparing two doses of the same ICS in adults with asthma and no concomitant inhaled or oral corticosteroid were assessed. Included trials were analysed according to the following ICS dose comparisons: high (> or =800 microg/day beclomethasone (BDP)) versus moderate (400<800 microg/day BDP) (n = 7); moderate versus low (<400 microg/day BDP) (n = 6); step down versus constant dose (n = 4). RESULTS: Fourteen publications describing 13 trials were included in the review. Studies (n = 4) that compared a step down approach with a constant moderate/low dose of ICS found no difference in lung function, symptoms, or rescue medications between the two treatment approaches (p>0.05). There was no difference in the change in morning peak flow after treatment with high compared with moderate dose ICS. When compared with low dose ICS, moderate dose ICS significantly improved morning peak flow (change from baseline WMD 11.14 l/min, 95% CI 1.34 to 20.93) and nocturnal symptoms (SMD -0.29, 95% CI -0.53 to -0.06). CONCLUSIONS: For patients with asthma who require ICS, starting with a moderate dose is equivalent to starting with a high dose and stepping down. The small non-significant benefits of starting with a high ICS dose are not of sufficient clinical benefit to warrant its use. Initial moderate ICS doses appear to be more effective than an initial low ICS dose.

Administration, Inhalation↗
PubMed2003

Options for self-management education for adults with asthma.

BACKGROUND: Asthma education and self-management are key recommendations of asthma management guidelines because they improve health outcomes. There are several different modalities for the delivery of asthma self-management education. OBJECTIVES: We evaluated programmes that: 1) Optimised asthma control through inhaled corticosteroid use by regular medical review or optimised asthma control by individualised written action plans 2) Used written self-management plans based on peak expiratory flow self-monitoring compared with symptom self-monitoring 3) Compared different options for the delivery of optimal self-management programmes. SEARCH STRATEGY: We searched the Cochrane Airways Group trials register and reference lists of articles. SELECTION CRITERIA: Randomised trials of asthma self-management education interventions in adults over 16 years of age with asthma. DATA COLLECTION AND ANALYSIS: Fifteen trials met the inclusion criteria. Trial quality was assessed and data were extracted independently by two reviewers. Study authors were contacted for confirmation. MAIN RESULTS: 1) Six studies compared optimal self-management allowing self-adjustment of medications according to an individualised written action plan to adjustment of medications by a doctor. These two styles of asthma management gave equivalent effects for hospitalisation, ER visits, unscheduled doctor visits and nocturnal asthma. 2) Self-management using a written action plan based on PEF was found to be equivalent to self-management using a symptoms based written action plan in the six studies which compared these interventions. 3) Three studies compared self-management options. In one, that provided optimal therapy but tested the omission of regular review, the latter was associated with more health centre visits and sickness days. In another, comparing high and low intensity education, the latter was associated with more unscheduled doctor visits. In a third, no difference in health care utilisation or lung function was reported between verbal instruction and written action plans. REVIEWER'S CONCLUSIONS: Optimal self-management allowing for optimisation of asthma control by adjustment of medications may be conducted by either self-adjustment with the aid of a written action plan or by regular medical review. Individualised written action plans based on peak expiratory flow are equivalent to action plans based on symptoms. Reducing the intensity of self-management education or level of clinical review may reduce its effectiveness.

Adult↗
PubMed2003

Relationship between induced sputum eosinophils and the clinical pattern of childhood asthma.

BACKGROUND: The relationship between the clinical pattern of asthma and airway inflammation in childhood asthma is poorly characterised, yet underpins the treatment recommendations in current asthma guidelines. A study was undertaken to examine the relationship between airway inflammation and clinical asthma in children. METHODS: Children with asthma (n=146) and healthy controls (C, n=37) were recruited from primary and specialist clinics. Sputum induction and hypertonic saline challenge were performed. RESULTS: As the frequency of asthma episodes in the past 12 months increased, there were significant increases in sputum eosinophils (median; infrequent episodic (IE) 1.5%, frequent episodic (FE) 2.3%, persistent (P) 3.8%, control (C) 1.0%; p=0.002), sputum eosinophil cationic protein (ECP) (IE 113 ng/ml, FE 220, P 375, C 139; p=0.003), and desquamated bronchial epithelial cells (IE 2.0%, FE 6.0%, P 5.0%, C 2.5%; p=0.04). Treatment intensity was also associated with increased sputum eosinophils (p=0.005). The relationships between other severity markers (current symptoms, lung function) were less strong. CONCLUSION: Children with more frequent episodes of clinical asthma exhibit increasing airway inflammation that is characterised by sputum eosinophilia and bronchial epithelial desquamation. The results support clinical assessment by frequency of wheezing episodes over the past 12 months when determining anti-inflammatory treatment requirements, and indicate that current symptoms are determined by mechanisms in addition to sputum eosinophilia.

Adolescent↗
PubMed2001

Randomised controlled trial to change the hospital management of unstable angina.

OBJECTIVES: To examine the benefits of a guideline-based educational program to improve management of unstable angina pectoris (UAP) in hospital patients. DESIGN: Randomised controlled trial. SETTING: 37 public hospitals across New South Wales. PATIENTS: 1,872 patients admitted with a diagnosis of UAP between 1 February and 30 June 1996 (baseline survey), and 1,368 patients with the same diagnosis admitted between 1 July and 31 December 1998 (follow-up survey). INTERVENTION: Educational sessions run by local opinion leaders, presenting guidelines on management of UAP from the National Health and Medical Research Council and feedback on local practice using data from the baseline survey. Sessions were run between March and June 1998. MAIN OUTCOME MEASURES: Use of evidence-based practice, identified by review of medical records. RESULTS: Use of beta-blockers increased in intervention and control hospitals, although the increase was significant only in the former. Use of calcium-channel blockers decreased significantly in both intervention and control hospitals. However, the change in drug use between baseline and follow-up did not differ significantly between intervention and control hospitals. CONCLUSIONS: Despite some appropriate changes in drug use for UAP management between 1996 and 1998, there was no evidence that a guideline-based educational program was of benefit in changing management. This reaffirms the difficulty of changing doctors' behaviour through practice guidelines. Alternative methods of encouraging evidence-based practice should be considered.

Adrenergic beta-Antagonists↗
PubMed2001

Fast ignition by intense laser-accelerated proton beams.

The concept of fast ignition with inertial confinement fusion (ICF) is a way to reduce the energy required for ignition and burn and to maximize the gain produced by a single implosion. Based on recent experimental findings at the PETAWATT laser at Lawrence Livermore National Laboratory, an intense proton beam to achieve fast ignition is proposed. It is produced by direct laser acceleration and focused onto the pellet from the rear side of an irradiated target and can be integrated into a hohlraum for indirect drive ICF.

Journal Article↗
PubMed2001

Accuracy of administrative data to assess comorbidity in patients with heart disease. an Australian perspective.

The objective of this study was to determine the accuracy of administrative data (by use of hospital discharge codes) for measuring comorbidity in patients with heart disease. One thousand seven hundred and sixty-five medical records of subjects admitted to hospital for AMI, unstable angina, angina pectoris, chronic IHD or heart failure were reviewed. The number and types of comorbidities were determined from the medical records (regarded as the "gold standard"). These were compared with the 10 discharge codes obtained from the hospital administrative records (referred to as the "administrative data"). The rate of false-negative and false-positive comorbidity diagnoses were determined. Twenty of the 21 comorbidities studied were underreported in the administrative data. For these 20 comorbidities, the median false-negative rate was 49.5% and ranged from 11% for diabetes to 100% for dementia. False-positive rates were low, less than 1.5%, except for chronic arrythmia (4.8%) and hypertension (4.2%). Mean percent agreement was high, ranging from 88% for hypertension to 100% for AIDS/HIV. Administrative data based on hospital discharge codes consistently underestimate the presence of comorbid conditions in our population. This has implications for administrators when estimating mortality, length of stay and disability. Researchers also need to be aware when using administrative data based on hospital discharge codes to assess subject's comorbidities that they may be widely underreported.

Aged↗
PubMed2001

COL4A4 mutation in thin basement membrane disease previously described in Alport syndrome.

BACKGROUND: Carriers of autosomal-recessive and X-linked Alport syndrome often have a thinned glomerular basement membrane (GBM) and have mutations in the COL4A3/COL4A4 and COL4A5 genes respectively. Recently, we have shown that many individuals with thin basement membrane disease (TBMD) are also from families where hematuria segregates with the COL4A3/COL4A4 locus. This study describes the first COL4A4 mutation in an individual with biopsy-proven TBMD who did not have a family member with autosomal-recessive or X-linked Alport syndrome, inherited renal failure, or deafness. METHODS: The index case and all available family members were examined for dysmorphic hematuria> 50,000/mL using phase contrast microscopy and for segregation of hematuria with the COL4A3/COL4A4 and COL4A5 loci using DNA satellite markers. COL4A4 exons from the index case were then studied using the enzyme mismatch cleavage method, and exons that demonstrated abnormal cleavage products were sequenced. RESULTS: Hematuria in this family segregated with a haplotype at the COL4A3/COL4A4 locus (P = 0.031) but not with haplotypes at the COL4A5 locus. A mutation in COL4A4 that changed C to T resulting in an arginine residue being replaced by a stop codon (R1377X) was demonstrated in exon 44, which encodes part of the alpha 4(IV) collagen sequence close to the junction with the noncollagenous domain. This mutation was present in all five family members with hematuria, but not in the four unaffected family members, 33 unrelated individuals with TBMD, or 22 nonhematuric normals. CONCLUSIONS: R1377X has been described previously in a compound heterozygous form of autosomal-recessive Alport syndrome. Our observation is evidence that TBMD can represent a carrier state for autosomal-recessive Alport syndrome in at least some individuals.

Basement Membrane↗
PubMed2001

A comparison of the clinical, histopathologic, and ultrastructural phenotypes in carriers of X-linked and autosomal recessive Alport's syndrome.

Previous series that described phenotypes in carriers of Alport's syndrome did not distinguish genetically between carriers of X-linked and autosomal recessive disease. In this study, modes of inheritance in unselected families with Alport's syndrome associated with two city and two provincial hospitals were determined using microsatellite markers, and carriers of disease haplotypes were identified within these families. All 47 carriers (100%) from 18 families with X-linked Alport's syndrome had dysmorphic hematuria on phase-contrast microscopy, but few developed renal failure (3 of 40 carriers; 8%), clinical hearing loss (2 of 45 carriers; 4%), retinopathy (1 of 30 carriers; 3%), or lenticonus (0 of 30 carriers; 0%). Eleven of the 14 carriers (79%) from 2 families with autosomal recessive disease had dysmorphic hematuria, but none had renal failure, clinical hearing loss, retinopathy, or lenticonus. Urinary red blood cell counts in carriers of X-linked Alport's syndrome were greater than those in carriers of autosomal recessive disease (P < 0.0001), but the frequency of proteinuria and hypertension and levels of proteinuria were not different. There was more tubulointerstitial damage in carriers of X-linked disease (P = 0.012); however, carriers of autosomal recessive disease had more widespread and more uniform thinning of the glomerular basement membrane (P < 0.0001) and less lamellation (P < 0.04).

Adolescent↗
PubMed2001

Expression of chemokine receptors CXCR1 and CXCR2 during cardiopulmonary bypass.

OBJECTIVE: This study investigated the effects of cardiopulmonary bypass on neutrophil expression of chemokine receptors, CXCR1 and CXCR2, and the beta2 integrin CD11b. METHODS: Ten patients undergoing coronary artery grafting with cardiopulmonary bypass were studied. Blood samples were collected preoperatively, before bypass, at termination of bypass, and 12 to 18 hours postoperatively. In vitro studies were performed on control subjects to determine changes in the surface expression of CXCR1, CXCR2, and CD11b on stimulation with interleukin 8. Receptor expression was measured by flow cytometry. Plasma levels of interleukin 8 from the patients were determined by enzyme-linked immunoassay. RESULTS: After bypass, CXCR2 expression fell by 66% (P <.0001) and remained low postoperatively (P <.0001). CXCR1 expression persisted at preoperative levels. CD11b expression increased significantly after bypass (P <.0001), returning to prebypass levels postoperatively. In vitro studies showed a dose-related fall of both CXCR1 (P <.0001) and CXCR2 expression (P <.0001) and a significant rise in CD11b expression (P <.0001). Plasma interleukin 8 increased significantly after bypass (P <.0001), remaining elevated 12 to 18 hours postoperatively (P =.02). Correlations between interleukin 8 levels and CXCR2 expression (P <.0001) and CD11b expression (P <.03) were demonstrated. CONCLUSIONS: CXCR2 expression is significantly down-regulated after bypass; in contrast, CXCR1 expression remains unchanged. In addition, whereas interleukin 8 is an important determinant of both CXCR1 and CXCR2 expression in vitro, it only correlates with CXCR2 and CD11b expression in vivo. This has implications in the search for antagonists against CXC chemokines and their receptors.

Cardiopulmonary Bypass↗
PubMed2001

Allele and genotype frequencies of polymorphic cytochromes P4502D6, 2C19 and 2E1 in aborigines from western Australia.

The polymorphisms of the important xenobiotic metabolizing enzymes CYP2D6, CYP2C19 and CYP2E1 have been studied extensively in a large number of populations and show significant heterogeneity in the frequency of different alleles/genotypes and in the prevalence of the extensive and poor metabolizer phenotypes. Understanding of inter-ethnic differences in genotypes is important in prediction of either beneficial or adverse effects from therapeutic agents and other xenobiotics. Since no data were available for Australian Aborigines, we investigated the frequencies of alleles and genotypes for CYP2D6, CYP2C19 and CYP2E1 in a population living in the far north of Western Australia. Because of its geographical isolation, this population can serve as a model to study the impact of evolutionary forces on the distribution of different alleles for xenobiotic metabolizing enzymes. Twelve CYP2D6 alleles were analysed. The wild-type allele *1 was the most frequent (85.81%) and the non-functional alleles (*4, * 5, * 16) had an overall frequency of less than 10%. Only one subject (0.4%) was a poor metabolizer for CYP2D6 because of the genotype *5/*5. For CYP2C19, the frequencies of the *1 (wild-type) and the non-functional (*2 and *3) alleles were 50.2%, 35.5% and 14.3%, respectively. The combined CYP2C19 genotypes (*2/*2, *2/*3 or *3/*3) correspond to a predicted frequency of 25.6% for the CYP2C19 poor metabolizer phenotype. For CYP2EI, only one subject had the rare c2 allele giving an overall allele frequency of 0.2%. For CYP2D6 and CYP2C19, allele frequencies and predicted phenotypes differed significantly from those for Caucasians but were similar to those for Orientals indicating a close relationship to East Asian populations. Differences between Aborigines and Orientals in allele frequencies for CYP2D6* 10 and CYP2E1 c2 may have arisen through natural selection, or genetic drift, respectively.

Alleles↗
PubMed2001

Nationwide study of haemolytic uraemic syndrome: clinical, microbiological, and epidemiological features.

AIMS: To establish the incidence and aetiology of haemolytic uraemic syndrome (HUS) in Australia and compare clinical and microbial characteristics of sporadic and outbreak cases. METHODS: National active surveillance through the Australian Paediatric Surveillance Unit with monthly case notification from paediatricians, July 1994 to June 1998. Children under 15 years presenting with microangiopathic haemolytic anaemia, thrombocytopenia, and acute renal impairment were identified. RESULTS: Ninety eight cases were identified (incidence 0.64 per 10(5) children <15 years/annum and 1.35 per 10(5) children <5 years/annum). Eighty four were associated with diarrhoea (64 sporadic, 20 constituting an outbreak) and 14 were atypical. Shiga toxin producing Escherichia coli (STEC) O111:H- was the most common isolate in sporadic HUS and caused the outbreak. However O111:H- isolates from outbreak and sporadic cases differed in phage type and subtyping by DNA electrophoresis. STEC isolates from sporadic cases included O26:H-, O113:H21, O130:H11, OR:H9, O157:H-, ONT:H7, and ONT:H-. STEC O157:H7 was not isolated from any case. Only O111:H- isolates produced both Shiga toxins 1 and 2 and possessed genes encoding E coli attaching and effacing gene (intimin) and enterohemolysin. Outbreak cases had worse gastrointestinal and renal disease at presentation and more extrarenal complications. CONCLUSIONS: Linking national surveillance with a specialised laboratory service allowed estimation of HUS incidence and provided information on its aetiology. In contrast to North America, Japan, and the British Isles, STEC O157:H7 is rare in Australia; however, non-O157:H7 STEC cause severe disease including outbreaks. Disease severity in outbreak cases may relate to yet unidentified virulence factors of the O111:H- strain isolated.

Adolescent↗
PubMed2001

Trends in the hospital management of unstable angina.

STUDY OBJECTIVE: To examine the hospital management of unstable angina (UAP) in 1996 and 1998, according to patient demographic variables and disease severity. DESIGN: Medical record review. SETTING: 37 hospitals across New South Wales, Australia, representative of the secondary and tertiary care hospitals in the State. PARTICIPANTS: All patients (or a random sample of patients) with UAP admitted to these hospitals during five months in 1996 and six months in 1998 (1872 and 1368 patients respectively). MAIN RESULTS: In the two years between 1996 and 1998, there was an increase in the use of beta blockers and a corresponding decrease in the use of calcium channel blockers, as well as a decrease in the use of intravenous nitrates. Those aged 75 or more were roughly half as likely as those aged less than 65 to be prescribed heparin, aspirin and heparin, beta blockers, intravenous nitrates, and only one third as likely to be offered coronary angiography in hospital. They were one and a half times as likely to be prescribed calcium channel blockers compared with the youngest age group. A similar pattern was seen for gender, where men were more likely than women to be given aspirin, aspirin and heparin, and coronary angiography, and less likely to be given calcium channel blockers. Those with a past history were less likely, and those with more severe disease were more likely than others to be given most interventions. CONCLUSIONS: In view of the low use of evidence-based management of UAP among women and the elderly, it would seem appropriate for disease management guidelines to target these groups.

Adrenergic beta-Antagonists↗
PubMed2001

Excretion of sweat and urine pyridinoline crosslinks in healthy controls and subjects with established metabolic bone disease.

Convenient techniques for measuring rates of bone turnover have been developed in recent years with the advent of biochemical markers of bone metabolism. One recent of these techniques is a collection method and quantitative enzyme immunoassay for free pyridinoline crosslinks in human sweat. The concentrations of pyridinoline crosslinks in 5-day sweat collections and first morning void and 24-hour urine collections from healthy subjects and subjects with established metabolic bone disorders were determined. T-scores were higher in the sweat system than in the urine system by up to 10-fold in postmenopausal subjects, women with hyperparathyroidism, and subjects with postmenopausal osteoporosis. For subjects with postmenopausal osteoporosis, receiver-operating characteristic curve analysis yielded areas under the curve of 0.699, 0.629, and 0.520 for sweat pyridinoline, first morning void urine pyridinoline, and 24 hour urine pyridinoline respectively. The areas under the curve of the sweat and first morning void urine measurements were significantly greater (p<0.05) than the 24-hour pyridinoline measurements. Healthy postmenopausal subjects and subjects with postmenopausal osteoporosis were monitored before and during estrogen replacement therapy or alendronate therapy. Sweat pyridinoline values declined by 49.0 +/- 12.4% and 19.4 +/- 19.9% for estrogen and alendronate subjects respectively. We conclude that this non-invasive technique is a sensitive and specific measure of bone resorption and is appropriate as an adjunct to techniques such as bone density and may also be useful in monitoring of response to anti-resorptive therapies.

Adult↗
PubMed2000

Advances in molecular toxicology-towards understanding idiosyncratic drug toxicity.

Idiosyncratic drug toxicity is a major complication of drug therapy and drug development. Such adverse drug reactions (ADRs) include anaphylaxis, blood dyscrasias, hepatotoxicity and severe cutaneous reactions. They are usually serious and can be fatal. At present, prediction of idiosyncratic ADRs at the preclinical stage of drug development is not possible because there are no suitable animal models and we do not understand the basic mechanisms involved in the toxicity when it does occur in man. Many idiosyncratic reactions appear to have an immunological aetiology. For example, there is increasing evidence for the role of T lymphocytes in severe skin reactions. Nevertheless, the sequence of events by which a simple chemical can elicit severe tissue damage remains poorly understood and alternative novel mechanisms of toxicity must also be explored. The purpose of this article will be to review the currently accepted mechanisms of idiosyncratic drug toxicity at the chemical and the molecular levels. In particular, we will consider how recent advances in cellular immunology and molecular biology can improve our understanding of both the chemical and clinical aspects of drug hypersensitivity. Recent advances in the role of both inter- and intra-cellular signalling in the regulation of the immune response to drugs and their metabolites will be discussed. The long-term aim of such research is to provide test systems for the evaluation of drug safety and patient susceptibility to idiosyncratic drug toxicity.

Animals↗