Tolerability and acceptability of three alcohol-based hand-rub gel formulations: a randomized crossover study.

BACKGROUND: Healthcare workers often experience skin dryness and irritation from performing hand hygiene frequently. Tolerability and acceptability are barriers to hand hygiene compliance, but there is little in the literature about exactly which types of alcohol-based hand rubs (ABHRs) have a higher dermal tolerance. AIM: To compare the tolerability and acceptability of three different ABHR gel formulations in a population of adult volunteers. METHODS: Thirty-eight participants were randomized to three different sequences, testing three hand-rub gel formulations: isopropanol-based (Hopigel®); ethanol-based (World Health Organization (WHO) gel formulation); and ethanol-based containing superfatting agents (Saniswiss Sanitizer Hands H1). Participants tested each of the formulations over a series of three five-day interventions, followed by a nine-day washout period. At the end of each intervention, skin condition was assessed and feedback was collected. FINDINGS: Whereas no statistically significant difference was observed regarding tolerability between the three ABHR gel formulations tested, there were differences in acceptability. Participants preferred the smell of the H1 and WHO gel formulations (P = 0.003 and P = 0.040, respectively); H1 had a better texture than the WHO gel formulation (P < 0.001); and H1 was considered more pleasant overall than Hopigel (P = 0.037). Overall preference varied, but H1 was rated the favourite most often among participants, and the least favourite least often. CONCLUSION: A high variability was observed in the participants' reactions to the different formulations tested. These results highlight the importance of giving healthcare workers a choice between different high-quality hand rubs to ensure maximum acceptability.

The metal- and substrate-dependences of 2,4'-dihydroxyacetophenone dioxygenase.

While the enzyme, 2,4'-dihydroxyacetophenone dioxygenase (DAD), has been known for decades, very little has been characterized of the mechanism of the DAD-catalyzed oxidative cleavage of its reported substrate, 2,4'-dihydroxyacetophenone (DHA). The purpose of this study was to identify the active metal center and to characterize the substrate-dependence of the kinetics of the reaction to lay the foundation for deeper mechanistic investigation. To this, the DAD V1M mutant (bDAD) was overexpressed, purified, and reconstituted with various metal ions. Kinetic assays evaluating the activity of the reconstituted enzyme as well as the substrate- and product-dependences of the reaction kinetics were performed. The results from reconstitution of the apoprotein with a variety of metal ions support the requirement for an Fe3+ center for enzyme activity. Reaction rates showed simple saturation kinetics for DHA with values for kcat and KDHA of 2.4 s-1 and 0.7 µM, respectively, but no significant dependence on the concentration of O2. A low-level inhibition (KI = 1100 µM) by the 4HB product was observed. The results support a minimal kinetic model wherein DHA binds to resting ferric enzyme followed by rapid addition of O2 to yield an intermediate complex that irreversibly collapses to products.

In silico analysis of a therapeutic target in Leishmania infantum: the guanosine-diphospho-D-mannose pyrophosphorylase.

Leishmaniases are tropical and sub-tropical diseases for which classical drugs (i.e. antimonials) exhibit toxicity and drug resistance. Such a situation requires to find new chemical series with antileishmanial activity. This work consists in analyzing the structure of a validated target in Leishmania: the GDP-mannose pyrophosphorylase (GDP-MP), an enzyme involved in glycosylation and essential for amastigote survival. By comparing both human and L. infantum GDP-MP 3D homology models, we identified (i) a common motif of amino acids that binds to the mannose moiety of the substrate and, interestingly, (ii) a motif that is specific to the catalytic site of the parasite enzyme. This motif could then be used to design compounds that specifically inhibit the leishmanial GDP-MP, without any effect on the human homolog.

Recombinant growth hormone for idiopathic short stature in children and adolescents.

BACKGROUND: Idiopathic short stature (ISS) refers to children who are very short compared with their peers for unknown or hereditary reasons. Recombinant human growth hormone (GH) has been used to increase growth and final height in children with ISS. OBJECTIVES: To assess the effects of recombinant human GH on short-term growth and final height in children with ISS. SEARCH STRATEGY: Studies were obtained from computerised searches of MEDLINE, EMBASE, The Cochrane Library, Science Citation Index, BIOSIS and Current Controlled Trials. Article reference lists were assessed for trials and experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with ISS with normal GH secretion. GH had to be administered for a minimum of six months and be compared with placebo or no treatment. A growth or height outcome measure had to be assessed. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. Data were extracted by one reviewer and checked by a second. The primary outcome was final height and secondary outcomes included short term growth, health related quality of life and adverse effects. To estimate summary treatment effects, data were pooled, when appropriate using a random effects model. MAIN RESULTS: Ten RCTs were included. One trial reported near final height in girls and found that girls treated with GH were 7.5 cm taller than untreated controls (GH group, 155.3 cm +/- 6.4; control, 147.8 cm +/- 2.6; P = 0.003); another trial which reported adult height standard deviation score found that children treated with GH were 3.7 cm taller than children in a placebo-treated group (95% confidence intervals 0.03 to 1.10; P < 0.04). The other trials reported short term outcomes. Results suggest that short-term height gains can range from none to approximately 0.7 SD over one year. One study reported health related quality of life and showed no significant improvement in GH treated children compared with those in the control group, whilst another found no significant evidence that GH treatment impacts psychological adaptation or self-perception in children with ISS. No serious adverse effects of treatment were reported. AUTHORS' CONCLUSIONS: GH therapy can increase short-term growth and improve (near) final height. Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature. Large, multicentre RCTs are required which should focus on final height and address quality of life and cost issues.

Recombinant growth hormone for children and adolescents with Turner syndrome.

BACKGROUND: Turner syndrome (TS) affects about one in 1500 to 2500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Untreated women are approximately 20 to 21 cm shorter than normal women within their respective populations. Recombinant human growth hormone (hGH) has been used to increase growth and final height in girls who have Turner syndrome. OBJECTIVES: To assess the effects of recombinant growth hormone in children and adolescents with TS. SEARCH STRATEGY: MEDLINE, EMBASE, The Cochrane Library, LILACS, BIOSIS, Science Citation Index and reference lists were used to identify relevant trials. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with TS before achieving final height. Growth hormone had to be administered for a minimum of six months and compared with a placebo or no treatment control condition. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. The primary outcomes were final height and growth. Secondary outcomes included bone age, quality of life, cognitive performance, and adverse effects. MAIN RESULTS: Four RCTs that included 365 participants after one year of treatment were included. Only one trial reported final height in 61 treated women to be 148 cm and 141 cm in 43 untreated women (mean difference (MD) seven cm, 95% CI 6 to 8). Short-term growth velocity was greater in treated than untreated girls after one year (two trials, MD three cm per year, 95% CI 2 to 4) and after two years (one trial, MD two cm per year, 95% CI 1 to 2.3). Skeletal maturity was not accelerated by treatment with recombinant growth hormone (hGH). Adverse effects were minimally reported. AUTHORS' CONCLUSIONS: Recombinant human growth hormone (hGH) doses between 0.3 to 0.375 mg/kg/wk increase short-term growth in girls with Turner syndrome by approximately three (two) cm in the first (second) year of treatment. Treatment in one trial increased final height by approximately six cm over an untreated control group. Despite this increase, the final height of treated women was still outside the normal range. Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.

Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context. DATA SOURCES: Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies. RESULTS: The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis. CONCLUSIONS: Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.

Pegylated interferon alpha-2a and -2b in combination with ribavirin in the treatment of chronic hepatitis C: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical-effectiveness and cost-effectiveness of pegylated interferon-alpha combined with ribavirin in the treatment of chronic hepatitis C. DATA SOURCES: Electronic databases, reference lists of retrieved reports, and the industry submissions to the National Institute for Clinical Excellence. REVIEW METHODS: Sources were rigorously searched and studies were selected that met the inclusion criteria of being randomised controlled trials (RCTs) involving comparisons between pegylated interferon-alpha plus ribavirin and non-pegylated interferon plus ribavirin (two trials) or pegylated interferon alone and non-pegylated interferon alone (four trials). The primary outcome in all trials was sustained virological response (SVR) at follow-up. The trials were generally of good quality, although reporting of methodological details could have been more thorough in places. A cost-effectiveness model followed a hypothetical cohort of 1000 individuals with chronic hepatitis C over a 30-year period. RESULTS: In the two trials that tested pegylated interferon plus ribavirin against non-pegylated interferon plus ribavirin the combined percentage of sustained virological response was 55%. The relative risk (RR) for remaining infected was reduced by 17% for pegylated interferon plus ribavirin compared with non-pegylated interferon plus ribavirin. Response to therapy varied according to viral genotype. Patients with genotype 1 had the lowest levels of sustained virological response and patients with genotype 2 or 3 had the highest. In the four trials that evaluated pegylated interferon monotherapy against non-pegylated interferon the combined sustained virological response rates were 31% for pegylated interferon and 14% for non-pegylated interferon. The RR for remaining infected with hepatitis C was reduced by 20% with the use of pegylated interferon. Patients with genotype 1 had the lowest levels of sustained virological response. There were also variations in sustained virological response according to other prognostic variables such as baseline viral load. Regimens involving pegylated interferon appear to be fairly well tolerated. Adverse events were been reported, but they did not differ substantially from levels of adverse events in regimens involving non-pegylated interferon. The incremental discounted cost per QALY for comparing no active treatment to 48 weeks of dual therapy with pegylated interferon and ribavirin (PEG + RBV) was 6045 pounds sterling. When moving from 48 weeks of dual therapy with non-pegylated interferon and ribavirin (IFN + RBV) to 48 weeks of dual therapy with PEG + RBV the figure was 12,123 pounds sterling. Subgroup analyses for dual PEG + RBV therapy demonstrated that the most favourable incremental discounted cost per QALY estimates were for patients infected with genotypes 2 and 3, and with low baseline viral load (3921 pounds sterling) compared with no active treatment. Results of one-way sensitivity analyses showed that the estimates varied according to differences in SVRs, drug costs and discount rates. In general estimates remained under 30,000 pounds sterling per QALY. The incremental discounted cost per QALY when moving from no active treatment to 48 weeks of monotherapy with pegylated interferon was 6484 pounds sterling. When moving from 48 weeks of monotherapy with IFN to 48 weeks of monotherapy with PEG the figure was 8404 pounds sterling. As with dual therapy, the lowest incremental cost per QALY was for patients with genotypes 2 and 3 and low baseline viral load, in the range 2641-4194 pounds sterling. The highest estimates were for patients with genotype 1 and high baseline viral load, around 30,000 pounds sterling. CONCLUSIONS: Well-designed RCTs show that patients treated with pegylated interferon, both as dual therapy and as monotherapy, experience higher sustained viral response rates than those treated with non-pegylated interferon. Patients with genotypes 2 and 3 experience the highest response, with rates in excess of 80%. Patients with the harder to treat genotype 1 nevertheless benefit, with up to 46% of patients experiencing an SVR in one of the trials. Pegylated interferon also appears to be relatively cost-effective in both monotherapy and dual therapy, with cost per QALY estimates remaining generally under 30,000 pounds sterling. The most favourable estimates were for patients with genotypes 2 and 3. Pegylated interferon is a relatively new intervention in the treatment of hepatitis C and therefore there are areas where further research is needed. These include: efficacies of therapy with PEG-alpha-2a vs PEG-alpha-2b; retreatment of previous non-responders using pegylated interferon; efficacy of treatments and long-term outcomes in patients who have other co-morbidities; prospective tests of rules governing stopping treatment; treating patients with acute hepatitis C; problems that may occur in a minority of patients with hepatitis C, such as cryoglobulinaemia and vasculitis; additional psychological effects on quality of life due to hepatitis C and also on the treatment of children and adolescents with hepatitis C.

Recombinant growth hormone for idiopathic short stature in children and adolescents.

BACKGROUND: Idiopathic short stature (ISS) refers to children who are very short compared with their peers for unknown or hereditary reasons. Recombinant human growth hormone has been used to increase growth and final height in children with idiopathic short stature. OBJECTIVES: To assess the effects of recombinant human growth hormone on short-term growth and final height in children with idiopathic short stature. SEARCH STRATEGY: Randomised controlled trials (RCTs) were sought by searching The Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, PubMed, Science Citation Index, BIOSIS and Current Controlled Trials (date of last search 10 December 2002). Article reference lists were assessed for trials and experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with ISS with normal growth hormone secretion. Growth hormone (GH) had to be administered for a minimum of six months and be compared with placebo or no treatment. A growth or height outcome measure had to be assessed. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. Data were extracted by one reviewer and checked by a second. The primary outcome was final height and secondary outcomes included short term growth, health related quality of life and adverse effects. To estimate summary treatment effects, data were pooled, when appropriate using a random effects model. MAIN RESULTS: Nine randomised controlled trials were included. One trial reported near final height in girls and found that girls treated with growth hormone were 7.5 cm taller than untreated controls (GH group, 155.3 cm +/- 6.4; control, 147.8 cm +/- 2.6; p = 0.003). The other trials reported short term outcomes. Results suggest that short-term height gains can range from none to approximately 0.7 SD over one year. One study reported health related quality of life and showed no significant improvement in growth hormone treated children compared with those in the control group. No serious adverse effects of treatment have been reported. REVIEWER'S CONCLUSIONS: Results suggest that growth hormone therapy can increase short-term growth and improve (near) final height. Increases in height are such that treated individuals remain relatively short when compared with peers of normal stature. Further research in the form of large, multicentre RCTs are required. These should focus on final height, which is the best outcome for assessing the effects of growth hormone, and address quality of life and cost issues.

The clinical and cost-effectiveness of patient education models for diabetes: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of educational interventions for patients with diabetes, compared with usual care or other educational interventions. DATA SOURCES: Electronic databases, reference lists and experts were all consulted in this study. Sponsor submissions to the National Institute of Clinical Excellence were also reviewed. REVIEW METHODS: Electronic databases were searched, references of all retrieved articles were checked for relevant studies, and experts were contacted for advice and peer review and to identify additional published and unpublished references. Randomised clinical trials (RCTs) and controlled clinical trials (CCTs) were included if they fulfilled pre-specified criteria, among which was follow-up from inception for 12 months or longer. Data were synthesised through a narrative review because the diversity of studies prevented a meta-analysis. RESULTS: Twenty-four studies (18 RCTs and six CCTs) that compared education with either a control group or with another educational intervention were included. The quality of reporting and methodology was generally found to be poor by today's standards. As part of treatment intensification, education in Type 1 diabetes (four studies) resulted in significant and long-lasting improvements in metabolic control and reductions in complications. In Type 2 diabetes (16 studies) a diversity of educational programmes did not yield consistent results on measures of metabolic control. Inconsistent results on metabolic control were also found in studies of diabetes of either type (four studies), with studies of lower quality producing significant effects. Few studies evaluated quality of life. Economic evaluations comparing education with usual care or other educational interventions were not identified. CONCLUSIONS: Education as part of intensification of treatment produces improvement in diabetic control in Type 1 diabetes. Mixed results in Type 2 diabetes mean that no clear characterisation is possible as to what features of education may be beneficial. Cost analysis and information from sponsor submissions indicated that where costs associated with patient education were in the region of 500-600 pounds sterling per patients, the benefits over time would have to be very modest to offer an attractive cost-effectiveness profile. Further research should focus on RCTs with clear designs based on explicit hypotheses and with a range of outcomes evaluated after long follow-up intervals.

New ursolic and betulinic derivatives as potential cytotoxic agents.

Fifteen new ursolic and betulinic triterpenoids, bearing various functionalities at C-3 and C-28 were synthesized as potential cytotoxic agents. All compounds were obtained by a hemisynthetic route via ursolic and betulinic acids. Preliminary screening of these compounds on human HT 29 colon cancer cells revealed inhibitory activity for three of them. Beta-D-Glucopyranosyl-3beta-hydroxyurs-12(13)-en-28-oate 1c, 3beta-3-(3-pyridyl)-prop-2-enoyloxyurs-12(13)-en-28-oic acid 1i and the potassium salt of 3beta-cinnamoyloxylup-20(29)-en-28-oic acid 2d demonstrated cytotoxic activity in the micromolar range: 8.0, 45.0 and 8.0 microM, respectively.

Recombinant growth hormone in children and adolescents with Turner syndrome.

BACKGROUND: Turner syndrome (TS) affects about one in 1,500 to 2,500 live-born females. One of the most prevalent and salient features of the syndrome is extremely short stature. Untreated women are approximately 20-21 cm shorter than normal women within their respective populations. Recombinant human growth hormone (hGH) has been used to increase growth and final height in women who have Turner syndrome. OBJECTIVES: To assess the effects of recombinant growth hormone on short-term growth and final height in children and adolescents with Turner syndrome. SEARCH STRATEGY: Published and unpublished randomised-controlled trials (RCTs) were sought by searching the Cochrane Central Register of Controlled Trials (Central) (2002, Issue 3), Medline (1981 to July 2002), Embase (1980 to June 2002), PubMed (search 30 July, 2002 for entries in last 180 days), Science Citation Index (search 30 July, 2002), BIOSIS (search 30 July, 2002) and Current Controlled Trials (search 30 July, 2002). Article reference lists were assessed for trials and experts and pharmaceutical companies were contacted. SELECTION CRITERIA: Randomised controlled trials were included if they were carried out in children with Turner Syndrome before achieving final height. Growth hormone had to be administered for a minimum of six months and compared with a placebo or no treatment control condition. A growth or height outcome measure must have been assessed. In addition, in the context of a growth assessment other outcomes reflecting psychological adjustment were also included. DATA COLLECTION AND ANALYSIS: Two reviewers assessed studies for inclusion criteria and for methodological quality. Data were extracted by one reviewer and checked by a second. The main outcomes were final height (in cm or standard deviation score), growth (in velocity or velocity standard deviation score). Additional outcomes included bone age, quality of life, cognitive performance, and adverse effects. To estimate summary treatment effects, data were pooled using a random effects model (when data were sufficient and appropriate to combine) with calculation of weighted mean differences (WMD) for continuous outcomes. MAIN RESULTS: Four RCTs that included 211 participants after one year of treatment were included. These were described in six publications. Three studies were included in the analyses of growth outcomes (one study did not report any data). Only one trial reported results on final height. This trial reported that average final height in 40 treated women was 146.2 cm and 141.4 cm in 29 untreated women (mean difference (MD) 4.8 cm, 95% CI 2.2 to 7.4). Short-term growth velocity was greater in treated than untreated girls after one year (two trials, weighted mean difference (WMD) 3.3 cm/yr, 95% CI 2.4 to 4.3) after 18 months (one trial, MD 2.6 cm/yr, 95% CI 2.1 to 3.1) and after two years (one trial, MD 1.8 cm/yr, 95% CI 1.3 to 2.3). Results were similar when reported as growth velocity standard deviation scores. Skeletal maturity was not accelerated by treatment with recombinant growth hormone (hGH). Bone age divided by chronological age was approximately one in both treated and untreated groups in one trial after both one and two years of treatment. One trial selectively reported psychological outcomes that suggested that psychological adjustment was better in girls treated with hGH, but selective reporting leaves these results in some doubt. Adverse effects were minimally reported. There is little evidence of serious short-term adverse effects in these trials, but they are underpowered to detect rare adverse effects. REVIEWER'S CONCLUSIONS: Recombinant human growth hormone (hGH) doses between 0.3 - 0.375 mg/kg/wk increase short-term growth in girls with Turner Syndrome (TS) by approximately 3 cm in the first year of treatment and by approximately 2 cm per year after 2 years of treatment. There is little evidence on the effects of hGH on final height. Treatment in one trial increased final height by approximately 5 cm over an untreated control group. Despite this increase, the fated control group. Despite this increase, the final height of treated women was still outside the normal range (more than two standard deviations below the normal population mean). Additional trials of the effects of hGH carried out with control groups until final height is achieved would allow better informed decisions about whether the benefits of hGH treatment outweigh the requirement of treatment over several years at considerable cost.

A review of natural and modified betulinic, ursolic and echinocystic acid derivatives as potential antitumor and anti-HIV agents.

The aim of this review is to update current knowledge on the betulinic, ursolic and echinocystic acids and their natural and semisynthetic analogs, focussing on their cytotoxic and anti-HIV activities. Then, the last results of the authors' team on unusual semisynthetic derivatives of these triterpenoids will be presented in order to establish structure/activity relationships.

Endocrinology trial design: adverse event reporting in randomised controlled trials of recombinant human GH in GH-deficient adults.

We have evaluated the reporting of withdrawals due to adverse effects and specific adverse effects in randomised controlled trials of recombinant human GH in adults. A systematic review was carried out of randomised controlled trials of the clinical effectiveness of recombinant human GH in adults with GH deficiency in relation to impact on quality of life. Trials were identified from searching electronic databases, bibliographies of related articles and consulting experts. There was reporting of withdrawals due to adverse effects and specific adverse effects. Rates of oedema and arthralgia were reported in included trials. Seventeen randomised controlled trials, published between 1990 and 1999, met the inclusion criteria for the review. Nine trials reported data on the effectiveness of GH on quality of life in adults. Only five trials (29%) reported both withdrawals from the study because of adverse events and specific adverse events with numbers per study arm and per type. Six further trials (35%) reported either withdrawal details or specific adverse event details or partial data on specific adverse events. Six trials (35%), however, did not report information on either withdrawals or specific adverse events. Ten of the 17 studies (59%) reported the number of patients who withdrew from the study due to adverse events per study arm and type of adverse event per study arm. Seven of the 17 trials (41%) reported the number of specific adverse events per study arm and six (35%) reported the type per study arm. The reporting of adverse events in randomised controlled trials of GH is variable and not consistent across trials. It is not possible to assess the impact that adverse events may have had on unblinding patients, and therefore the extent to which the effects of GH may have been overestimated. Therefore those conducting endocrinology trials in the future need to pay attention to the reporting of withdrawals due to adverse events and specific adverse events.

A rapid and systematic review of the effectiveness of temozolomide for the treatment of recurrent malignant glioma.

A rapid and systematic review of the effectiveness and cost-effectiveness of temozolomide in the treatment of recurrent malignant glioma was commissioned by the NHS HTA Programme on behalf of NICE. The full report has been published elsewhere. This paper summarizes the results for the effectiveness of temozolomide in people with recurrent glioblastoma multiforme and anaplastic astrocytoma. The review was conducted using standard systematic review methodology involving a systematic literature search, quality assessment of included studies with systematic data extraction and data synthesis. One randomized controlled trial and four uncontrolled studies were identified for inclusion. The key results were that temozolomide may increase progression-free survival but has no significant impact on overall length of survival. The main effect from temozolomide may have been in those patients who had not received any prior chemotherapy regimens, however further randomized controlled trials are required to confirm this suggestion. Temozolomide appears to produce few serious adverse effects and may also have a positive impact on health-related quality of life. Overall the evidence-base is weak and few strong conclusions can be drawn regarding the effectiveness of temozolomide. Large, well-designed randomized controlled trails conducted in a wider patient population are needed.

Mechanisms of human neutrophil oxidant production after severe injury.

BACKGROUND: The purpose of this study was to determine the mechanisms of enhanced oxidant production after severe injury. METHODS: Neutrophils were harvested from patients within 24 hours of admission who had an injury severity score greater than 16. Nonadherent and adherent neutrophil oxidant production was measured after N-formyl-methionyl-leucyl-phenylalanine (fMLP) stimulation. Translocation of cytochrome b558 and cytosolic components p47phox and p67phox were determined by oxidation-reduction spectroscopy and immunoblotting, respectively. Flow cytometry measured integrin expression. Integrin and p47phox colocalization was examined by confocal microscopy. RESULTS: Eighteen patients were studied within 15 +/- 1.4 hours. Four women and 14 men suffered a blunt injury and had a mean injury severity score of 22 (range, 16 to 34). Nonadherent patient neutrophils showed a decrease in fMLP-stimulated oxidant production, whereas adherent neutrophil oxidant production was increased in both the vehicle control and fMLP-stimulated groups. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components p47phox and cytochrome b558 were mobilized to the plasma membrane, whereas p67phox showed minimal change. Integrin CD11b a chain showed a significant increase in expression. Confocal microscopy showed colocalization of p47phox and a chain CD11b on the plasma membrane of patient neutrophils. CONCLUSIONS: Colocalization of NADPH oxidase components and integrins may regulate the enhanced oxidant production in human neutrophils after severe injury.

CXCR2 regulation of tumor necrosis factor-alpha adherence-dependent peroxide production is significantly diminished after severe injury in human neutrophils.

BACKGROUND: Primed neutrophils are thought to play a key role in inflammatory pathology. We have shown though in vitro studies that interleukin (IL)-8 and growth-related oncogene-alpha (GROalpha) (CXCR2-specific chemokines) regulate the respiratory burst via the CXCR2 receptor. We have also shown in vivo, CXCR2 receptors are down-regulated in severely injured patients. Our hypothesis is that regulation of the respiratory burst by CXCR2 is lost after severe injury. METHODS: Patient neutrophils were studied within 24 hours of admission to the hospital; excluded were severe head injury and patients with Injury Severity Score < 16. Patient and normal neutrophils were isolated by Ficoll-Hypaque centrifugation after dextran sedimentation. Neutrophils were plated with buffer, 50 nmol/L IL-8 or GROalpha on fibronectin-coated plates for 15 minutes, then stimulated with 10 ng/mL of TNFalpha. CXCR2 expression was measured by flow cytometry. Receptor function was assessed by calcium mobilization. RESULTS: One female and 10 male patients with an average age of 37 +/- 3 and Injury Severity Score of 24 +/- 5 suffered blunt injury. CXCR2 showed a 32% +/- 7% loss, whereas CXCR1 showed 15% +/- 6% reduction. GROalpha stimulation of patient neutrophils showed 60% +/- 16% decrease in calcium mobilization, whereas IL-8 showed no decline. At 40 minutes, IL-8 and GROalpha significantly inhibited TNFalpha adherence-dependent peroxide production in normal neutrophils (35% +/- 4% and 45% +/- 3%, respectively; p < 0.05). Both IL-8 and GROalpha lost the ability to suppress the respiratory burst in severely injured patients, but GROalpha had a significantly greater loss of this suppression (p = 0.004). CONCLUSION: IL-8 and GROalpha lose the ability to regulate the TNFalpha-induced respiratory burst. This may contribute to neutrophil dysregulation after injury and result in organ injury.