Placebo Preparations Research Articles

Plant-Origin Additives from Boswellia Species in Emulgel Formulation for Radiotherapy Skin Care

The research objective of this study was to include plant-origin additives of the Boswellia species in the formulation of topical preparations for skin care after radiotherapy. The main factor damaging the skin during radiotherapy is the free radicals that form from water molecules and granulocytes in the inflammatory area; hence, the use of substances with antioxidant properties, including plant extracts rich in antioxidants, seems to be an alternative therapy in radiodermatitis treatment. A series of cosmetic preparations containing plant-origin additives from Boswellia species and corresponding placebo formulations were prepared. In order to assess the applicability of emulgels as oncocosmetics, their stability, physicochemical properties, rheological properties, and antioxidant capacity were determined. Somatosensory analysis was also performed. An attempt was also made to correlate the effect of plant-derived additives on the functional properties of the product determined via instrumental methods and the sensory properties. The most promising preparation was the emulgel containing the Soxhlet extract and essential oil (Em_SO) due to its high antioxidant properties compared to other preparations (% inhibition of 11.69) and polyphenol content (3.63 mg/dm3). Additionally, probands positively assessed all its features, including consistency (4.00), absorption (4.43), and hydration (4.71). The presence of significant correlations for % inhibition and polyphenols content with sensory and physicochemical characteristics of samples was indicated. There were low ratings for placebo preparations by probands, and the demonstrated correlations of odor with moisturization and distribution, oiliness and hydration with the % inhibition of the sample, and the content of polyphenols with the pH and size of the dispersed phase droplets proved the positive effect of the addition of plant-origin additives from Boswellia to the emulgel formulation on the functional and sensory properties.

Essential oils for agitation in dementia [rELOAD]: A pragmatic, cluster-randomized, placebo-controlled, pilot feasibility trial

BackgroundClinical guidelines recommend non-pharmacological interventions as the first line of treatment for agitation in dementia. One intervention that shows some promise as a treatment for agitation is essential oils. The objective of this study was to provide preliminary evidence of the effectiveness and feasibility of using topically-administered, individualized essential oil preparations for the alleviation of agitation in persons with dementia. MethodsWe conducted a 10-week pragmatic, cluster-randomized, placebo-controlled, pilot feasibility trial to compare the effectiveness of topically-administered, individualized essential oil preparations to control (placebo) preparations. Outcomes included frequency and severity of agitation, quality of life, frequency of antipsychotic medication use and physical restraint, incidence of adverse events, and trial feasibility. Participants with dementia and clinically significant agitation were recruited from five residential aged-care facilities across regional South Australia. ResultsThirty-eight participants were randomized from five sites. Accounting for random effects, we found statistically significant differences between the intervention and control groups in Pittsburgh Agitation Scale (PAS) aberrant vocalization sub score, Cohen Mansfield Agitation Inventory (CMAI) verbally agitated sub score and CMAI total score at week 4, but not at weeks 8 (post-intervention) or 10 (follow-up). No significant time-group interactions were observed for other PAS/CMAI scores or sub scores, quality of life - Alzheimer's disease total score, or frequency of physical restraint or as-needed antipsychotic medication. No adverse events were reported in any group. ConclusionsThe study findings highlight some promising effects of topically-administered, individualized essential oil preparations for agitation in dementia, and indicate that a large multi-center, cluster-randomized controlled trial of this treatment is feasible. Trial registrationAustralian New Zealand Clinical Trial Registry [ACTRN12617001159347].

Pancreatic enzyme replacement therapy for people with cystic fibrosis.

Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. This is an updated version of a published review. To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 15 July 2016.We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 22 July 2016. Randomised and quasi-randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations. Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review. One parallel trial and 12 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 512 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias.We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67; P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, mean difference -0.58 (95% confidence interval -0.85 to -0.30; P < 0.0001); proportion of days with abdominal pain, mean difference -7.96% (95% confidence interval -12.97 to -2.94; P = 0.002); and fecal fat excretion, mean difference -11.79 g (95% confidence interval -17.42 to -6.15; P < 0.0001). Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency, mean difference -0.70 (95% confidence interval -0.90 to -0.50; P < 0.00001). There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed study that can answer these questions.

Effects of oral Enterococcus faecium strain DSM 10663 NCIMB 10415 on diarrhoea patterns and performance of sucking piglets.

Effects of probiotic Enterococcus faecium DMS 10663 NCIMB 10415 on diarrhoea and performance of sucking piglets were evaluated in a double-blind, placebo-controlled study. Piglets from treatment group (TG, n=56) and placebo group (PG, n=53) sows were included in the study. Immediately after birth and at day 2 and 3 post natum, each of the TG piglets received 2.8×10(9) colony forming units (cfu) per os. From day 4 until weaning (day 26), 1.26×10(9) cfu E. faecium/piglet were given twice a day via a liquid additive. Piglets already suffering from diarrhoea additionally got a glucose-electrolyte solution enriched with 2.9×10(8) (week 1) and 5.8×10(8) (week 2) cfu E. faecium/day. PG piglets received corresponding placebo preparations. A score was defined to characterise the severity of diarrhoea, including accompanying symptoms. The counts of viable born, stillborn and weaned piglets were similar in TG and PG litters (P>0.05). The probiotic treatment mitigated incidence and severity of diarrhoea (P<0.05) with no impact on diarrhoea length (P>0.05). Probiotic treatment improved daily weight gain (P<0.05) yet with no provable effect on body weight at weaning (P>0.05). The additional supply of E. faecium in piglets suffering from diarrhoea had no further beneficial effect.

Pancreatic enzyme replacement therapy for people with cystic fibrosis.

Most people with cystic fibrosis (80% to 90%) need pancreatic enzyme replacement therapy to prevent malnutrition. Enzyme preparations need to be taken whenever food is taken, and the dose needs to be adjusted according to the food consumed. A systematic review on the efficacy and safety of pancreatic enzyme replacement therapy is needed to guide clinical practice, as there is variability between centres with respect to assessment of pancreatic function, time of commencing treatment, dose and choice of supplements. To evaluate the efficacy and safety of pancreatic enzyme replacement therapy in children and adults with cystic fibrosis and to compare the efficacy and safety of different formulations of this therapy and their appropriateness in different age groups. Also, to compare the effects of pancreatic enzyme replacement therapy in cystic fibrosis according to different diagnostic subgroups (e.g. different ages at introduction of therapy and different categories of pancreatic function). We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search: 14 August 2014.We also searched an ongoing trials website and the websites of the pharmaceutical companies who manufacture pancreatic enzyme replacements for any additional trials. Most recent search: 12 May 2014. Randomised and quasi-randomised controlled trials in people of any age, with cystic fibrosis and receiving pancreatic enzyme replacement therapy, at any dosage and in any formulation, for a period of not less than four weeks, compared to placebo or other pancreatic enzyme replacement therapy preparations. Two authors independently assessed trials and extracted outcome data. They also assessed the risk of bias of the trials included in the review. One parallel trial and 11 cross-over trials of children and adults with cystic fibrosis were included in the review. The number of participants in each trial varied between 14 and 129 with a total of 426 participants included in the review. All the included trials were for a duration of four weeks. The included trials had mostly an unclear risk of bias from the randomisation process as the details of this were not given; they also mostly had a high risk of attrition bias and reporting bias.We could not combine data from all the trials as they compared different formulations. Findings from individual studies provided insufficient evidence to determine the size and precision of the effects of different formulations. Ten studies reported information on the review's primary outcome (nutritional status); however, we were only able to combine data from two small cross-over studies (n = 41). The estimated gain in body weight was imprecise, 0.32 kg (95% confidence interval -0.03 to 0.67, P = 0.07). Combined data from the same studies gave statistically significant results favouring enteric-coated microspheres over enteric-coated tablets for our secondary outcomes stool frequency, abdominal pain and fecal fat excretion. Data from another single small cross-over study also favoured enteric-coated microspheres over non-enteric-coated tablets with adjuvant cimetidine in terms of stool frequency. There is limited evidence of benefit from enteric-coated microspheres when compared to non-enteric coated pancreatic enzyme preparations up to one month. In the only comparison where we could combine any data, the fact that these were cross-over studies is likely to underestimate the level of inconsistency between the results of the studies due to over-inflation of confidence intervals from the individual studies.There is no evidence on the long-term effectiveness and risks associated with pancreatic enzyme replacement therapy. There is also no evidence on the relative dosages of enzymes needed for people with different levels of severity of pancreatic insufficiency, optimum time to start treatment and variations based on differences in meals and meal sizes. There is a need for a properly designed trial that can answer these questions.

Flupenthixol decanoate (depot) for schizophrenia or other similar psychotic disorders.

Long-acting depot injections of drugs such as flupenthixol decanoate are extensively used as a means of long-term maintenance treatment for schizophrenia. To evaluate the effects of flupenthixol decanoate in comparison with placebo, oral antipsychotics and other depot neuroleptic preparations for people with schizophrenia and other severe mental illnesses, in terms of clinical, social and economic outcomes. We identified relevant trials by searching the Cochrane Schizophrenia Group Trials Register in March 2009 and then for this update version, a search was run in April 2013. The register is based on regular searches of CINAHL, EMBASE, MEDLINE and PsycINFO. References of all identified studies were inspected for further trials. We contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. All randomised controlled trials that focused on people with schizophrenia or other similar psychotic disorders where flupenthixol decanoate had been compared with placebo or other antipsychotic drugs were included. All clinically relevant outcomes were sought. Review authors independently selected studies, assessed trial quality and extracted data. For dichotomous data we estimated risk ratios (RR) with 95% confidence intervals (CI) using a fixed-effect model. Analysis was by intention-to-treat. We summated normal continuous data using mean difference (MD), and 95% CIs using a fixed-effect model. We presented scale data only for those tools that had attained prespecified levels of quality. Using Grading of Recommendations Assessment, Development and Evaluation (GRADE) we created 'Summary of findings tables and assessed risk of bias for included studies. The review currently includes 15 randomised controlled trials with 626 participants. No trials compared flupenthixol decanoate with placebo.One small study compared flupenthixol decanoate with an oral antipsychotic (penfluridol). Only two outcomes were reported with this single study, and it demonstrated no clear differences between the two preparations as regards leaving the study early (n = 60, 1 RCT, RR 3.00, CI 0.33 to 27.23,very low quality evidence) and requiring anticholinergic medication (1 RCT, n = 60, RR 1.19, CI 0.77 to 1.83, very low quality evidence).Ten studies in total compared flupenthixol decanoate with other depot preparations, though not all studies reported on all outcomes of interest. There were no significant differences between depots for outcomes such as relapse at medium term (n = 221, 5 RCTs, RR 1.30, CI 0.87 to 1.93, low quality evidence), and no clinical improvement at short term (n = 36, 1 RCT, RR 0.67, CI 0.36 to 1.23, low quality evidence). There was no difference in numbers of participants leaving the study early at short/medium term (n = 161, 4 RCTs, RR 1.23, CI 0.76 to 1.99, low quality evidence) nor with numbers of people requiring anticholinergic medication at short/medium term (n = 102, 3 RCTs, RR 1.38, CI 0.75 to 2.25, low quality evidence).Three studies in total compared high doses (100 to 200 mg) of flupenthixol decanoate with the standard doses (˜40mg) per injection. Two trials found relapse at medium term (n = 18, 1 RCT, RR 1.00, CI 0.27 to 3.69, low quality evidence) to be similar between the groups. However people receiving a high dose had slightly more favourable medium term mental state results on the Brief Psychiatric Rating Scale (BPRS) (n = 18, 1 RCT, MD -10.44, CI -18.70 to -2.18, low quality evidence). There was also no significant difference in the use of anticholinergic medications to deal with side effects at short term (2 RCTs n = 47, RR 1.12, CI 0.83 to 1.52 very low quality evidence). One trial comparing a very low dose of flupenthixol decanoate (˜6 mg) with a low dose (˜9 mg) per injection reported no difference in relapse rates (n = 59, 1 RCT, RR 0.34, CI 0.10 to 1.15, low quality evidence). In the current state of evidence, there is nothing to choose between flupenthixol decanoate and other depot antipsychotics. From the data reported in clinical trials, it would be understandable to offer standard dose rather than the high dose depot flupenthixol as there is no difference in relapse. However, data reported are of low or very low quality and this review highlights the need for large, well-designed and reported randomised clinical trials to address the effects of flupenthixol decanoate.

Which polyunsaturated fatty acids are active in children with attention-deficit hyperactivity disorder receiving PUFA supplementation? A fatty acid validated meta-regression analysis of randomized controlled trials

Concerns about growth retardation and unknown effects on long-term brain development with stimulants have prompted interest in polyunsaturated fatty acid supplementation (PUFA) as an alternative treatment. However, randomized controlled trials (RCTs) and meta-analyses of PUFA supplementation in ADHD have shown marginal benefit, and uncertainty exists as to which, if any, PUFA might be effective in alleviating symptoms of ADHD. We conducted an updated meta-analysis of RCTs in ADHD together with multivariable meta-regression analyses using data on PUFA content obtained from independent fatty acid methyl ester analyses of each study PUFA regimen. The PubMed, Embase and PsycINFO databases were searched with no start date and up to 28th July 2013. Study inclusion criteria were: randomized design, placebo controlled, PUFA preparation as active intervention, reporting change scores on ADHD rating-scale measures. Rating-scale measures of inattention and hyperactive-impulsive symptoms were extracted, study authors were contacted to obtain missing data, studies not reporting negative findings had these data imputed, and study quality was assessed using the Jadad system plus other indicators. Random-effects models were used for pooled effects and for meta-regression analyses. Standardized mean differences (SMD) in inattention, hyperactive-impulsive and combined symptoms were assessed as rated by parents, teachers or all raters. The influence of study characteristics and PUFA regimen content was explored in multivariable meta-regression analyses. The overall pooled estimate from 18 studies showed that combined ADHD symptoms rated by all raters decreased with PUFA supplementation; SMD −0.192 (95% CI: −0.297, −0.086; P<0.001). However, when analyzed by rater, only parent-rated symptoms decreased significantly. Multivariable meta-regression showed that longer study duration, γ-linolenic acid (GLA), and the interaction between GLA and eicosapentaenoic acid (EPA) were associated with significant decreases in inattention; however, PUFA regimen content was unrelated to changes in hyperactive-impulsive symptoms. Certain fatty acids present in placebo preparations may potentially have been psychoactive. This meta-analysis provides modest evidence of PUFA effectiveness in ADHD, especially GLA and EPA for inattention symptoms; however, evidence of reporting bias, publication bias, variable methodological quality, and use of potentially psychoactive placebos limit the generalizability of these findings.

Safety, effectiveness, and cost of long-acting versus intermediate-acting insulin for type 1 diabetes: Protocol for a systematic review and network meta-analysis

BackgroundType 1 diabetes mellitus (T1DM) causes progressive destruction of pancreatic beta cells leading to absolute insulin deficiency. Treatment of T1DM requires insulin, and some evidence suggests that longer acting insulin analogues might have a higher effectiveness and greater safety profile compared to intermediate-acting insulin. Our objective is to evaluate the comparative effectiveness, safety, and cost of long-acting insulin versus intermediate-acting insulin through a systematic review and network meta-analysis.Design/methodsStudies examining long-acting versus intermediate-acting insulin or placebo preparations for adult T1DM patients will be included. The primary outcome is glycosylated hemoglobin (A1C), and secondary outcomes include emergency department and physician visits, hospital admissions, weight gain, quality of life, microvascular complications (e.g., retinopathy), macrovascular complications (e.g., cardiovascular disease), all-cause mortality, incident cancers, and cost. We will include experimental [randomized clinical trials (RCTs), quasi-RCTs, non-RCTs], quasi-experimental (controlled before-after, interrupted time series), observational (cohort), and cost studies, of any duration of follow-up, conducted during all time periods, and disseminated in any language.We will conduct comprehensive searches of electronic databases from inception onwards, including MEDLINE, Cochrane Central Register of Controlled Trials, and EMBASE. We will also search for difficult to locate and unpublished literature by searching dissertation databases, public health organization websites, and trial registries. After a calibration exercise using our eligibility criteria and data abstraction forms, two reviewers will screen all citations, full-text articles, and abstract data in duplicate. Conflicts will be resolved by team discussion. Using a similar process, the Cochrane Effective Practice and Organization of Care Risk of Bias tool will be used to appraise the risk of bias of experimental and quasi-experimental studies, while the Newcastle Ottawa Scale will be used to assess the methodological quality of cohort studies. If feasible and appropriate, we will conduct a random effects meta-analysis, as well as a network meta-analysis.DiscussionOur systematic review will be of utility to healthcare providers, policy-makers, T1DM patients and family members regarding treatment options of long-acting versus intermediate-acting insulin preparations.Trial registrationPROSPERO registry number: CRD42013003610

Granulocyte colony stimulating factor therapy for acute myocardial infarction

Acute myocardial infarction (AMI) is the leading cause of death in developed countries, and current treatment modalities have failed to regenerate the dead myocardium resulting from the ischemic damage. Stem cells have the potential to regenerate the damaged myocardium. These cells can be mobilized from the bone marrow by factors such as granulocyte colony stimulating factor (G-CSF). To assess the effects of stem cell mobilization following granulocyte colony stimulating factor therapy in patients with acute myocardial infarction. We searched CENTRAL (The Cochrane Library Issue 4, 2010), MEDLINE (1950 to November week 3, 2010), EMBASE (1980 to 2010 week 48), BIOSIS Previews (1969 to 30 November 2010), ISI Science Citation Index Expanded (1970 to 4 December 2010) and ISI Conference Proceedings Citation Index - Science (1990 to 4 December 2010). We also checked reference lists of articles. We included randomized controlled trials including participants with a clinical diagnosis of AMI who were randomly allocated to the subcutaneous administration of G-CSF through a daily dose of 2.5, 5 or 10 microgram/kg for four to six days or placebo. No age or other restrictions were applied for the selection of patients. Two authors independently selected trials, assessed trials for eligibility and methodological quality, and extracted data regarding the clinical efficacy and adverse outcomes. Disagreements were resolved by the third author. We included seven trials reported in 30 references in the review (354 participants). In all trials, G-CSF was compared with placebo preparations. Dosage of G-CSF varied among studies, ranging from 2.5 to 10 microgram/kg/day. Regarding overall risk of bias, data regarding the generation of randomization sequence and incomplete outcome data were at a low risk of bias; however, data regarding binding of personnel were not conclusive. The rate of mortality was not different between the two groups (RR 0.64, 95% CI 0.15 to 2.80, P = 0.55). Regarding safety, the limited amount of evidence is inadequate to reach any conclusions regarding the safety of G-CSF therapy. Moreover, the results did not show any beneficial effects of G-CSF in patients with AMI regarding left ventricular function parameters, including left ventricular ejection fraction (RR 3.41, 95% CI -0.61 to 7.44, P = 0.1), end systolic volume (RR -1.35, 95% CI -4.68 to 1.99, P = 0.43) and end diastolic volume (RR -4.08, 95% CI -8.28 to 0.12, P = 0.06). It should also be noted that the study was limited since the trials included lacked long enough follow up durations. Limited evidence from small trials suggested a lack of benefit of G-CSF therapy in patients with AMI. Since data of the risk of bias regarding blinding of personnel were not conclusive, larger RCTs with appropriate power calculations and longer follow up durations are required in order to address current uncertainties regarding the clinical efficacy and therapy-related adverse events of G-CSF treatment.

Dietary strawberries increase the proliferative response of CD3/CD28-activated CD8+ T cells and the production of TNF-α in lipopolysaccharide-stimulated monocytes from obese human subjects

Obesity increases the risk of developing bacterial and viral infections compared with normal weight. In a 7-week double-blind, randomised, cross-over trial, twenty obese volunteers (BMI between 30 and 40 kg/m²) were fed freeze-dried strawberry powder or strawberry-flavoured placebo preparations to determine the effects of dietary strawberries on immune function. Blood was collected at six time points during the study and peripheral blood mononuclear cells (PBMC) were isolated at each time point and activated with CD3 plus CD28 antibodies (T-lymphocyte activation) or lipopolysaccharide (LPS, monocyte activation). Interferon-γ, TNF-α, IL-4 and IL-10 were measured in supernatants from the activated T cells. Supernatants from the activated monocytes were analysed for the production of TNF-α, IL-1β, IL-6 and IL-8. PBMC were pre-stained with PKH (Paul Karl Horan) dye and activated with CD3 plus CD28 antibodies to determine the proliferative responses of CD4⁺ and CD8⁺ T-lymphocytes by flow cytometry. To detect global changes in gene expression, microarray analysis was performed on LPS- and vehicle-treated PBMC from two subjects before and after the strawberry intervention. No difference was observed for the production of T-cell cytokines between the intervention groups. The production of TNF-α was increased in the supernatants from LPS-activated PBMC in the group consuming strawberries compared with the placebo. A modest increase in the proliferation of the CD8⁺ T-lymphocyte population was observed at 24 h post-activation. These data suggest that dietary strawberries may increase the immunological response of T-lymphocytes and monocytes in obese people who are at greater risk for developing infections.

Cochrane Review: Topical treatments for cutaneous warts

AbstractBackgroundViral warts are common and usually harmless but very troublesome. A very wide range of local treatments are used.ObjectivesTo assess the effects of different local treatments for cutaneous, non‐genital warts in healthy people.Search strategyWe searched the Cochrane Skin Group Specialised Register (March 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to March 2005), EMBASE (1980 to March 2005) and a number of other biomedical databases. The references of all trials and selected review articles were also searched. In addition, we contacted pharmaceutical companies involved in local treatments for warts and experts in the fieldSelection criteriaRandomised controlled trials of local treatments for cutaneous non‐genital viral warts in immunocompetent (healthy) people.Data collection and analysisData was extracted and two authors independently selected the trials and assessed methodological quality.Main resultsSixty trials were identified that fulfilled the criteria for inclusion. The evidence provided by these studies was generally weak due to poor methodology and reporting.In 21 trials with placebo groups that used participants as the unit of analysis, the average cure rate of placebo preparations was 27% (range 0 to 73%) after an average period of 15 weeks (range 4 to 24 weeks).The best available evidence was for simple topical treatments containing salicylic acid, which were clearly better than placebo. Data pooled from five placebo‐controlled trials showed a cure rate of 117/160 (73%) compared with 78/162 (48%) in controls, which translates to a risk ratio of 1.60 (95% confidence interval 1.16 to 2.23), using a random effects model.Evidence for the absolute efficacy of cryotherapy was surprisingly lacking. Two trials comparing cryotherapy with salicylic acid and one comparing duct tape with cryotherapy showed no significant difference in efficacy.Evidence for the efficacy of the remaining treatments reviewed was limited.Authors' conclusionsThere is a considerable lack of evidence on which to base the rational use of topical treatments for common warts. The reviewed trials are highly variable in method and quality. Cure rates with placebo preparations are variable but nevertheless considerable. There is certainly evidence that simple topical treatments containing salicylic acid have a therapeutic effect. There is less evidence for the efficacy of cryotherapy, but reasonable evidence that it is only of equivalent efficacy to simpler and safer treatments. The benefits and risks of topical dinitrochlorobenzene and 5‐fluorouracil, intralesional bleomycin and interferons, photodynamic therapy and other miscellaneous treatments remain to be determined.Plain Language SummaryTopical treatments for skin wartsViral warts are one of the most common skin diseases. They are caused by the human papilloma virus and most commonly found on the hands and feet. While warts are not harmful and usually go away in time without any treatment, they are unattractive and can be painful. Warts can be removed with wart paints containing salicylic acid. These are cheap and readily available, but slow to work. Cryotherapy, usually using liquid nitrogen, is often considered more effective than wart paints but is more expensive. The review of trials found that there was not enough evidence to compare treatments and that there was not enough evidence to support the use of cryotherapy (freezing) over wart paints as initial treatment for viral warts. More research is needed.

Effect of hyaluronic acid in symptomatic hip osteoarthritis: A multicenter, randomized, placebo‐controlled trial

To evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA). A multicenter, randomized, parallel-group, placebo-controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment. Eighty-five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent-to-treat analysis (mean +/- SD decrease 7.8 +/- 24.9 mm with HA versus 9.1 +/- 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events. Our findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.

Effect of remifentanil on postoperative pain in gynecologic surgery with sevoflurane anesthesia

Background: Rapid development of acute opioid tolerance and hyperalgesia is well established in animal studies and is more likely to occur with large doses of short-acting drugs. Several experimental and clinical studies of varied design that have been conducted in humans comparing remifentanil with other routinely used anesthetics or placebo preparations have produced conflicting results. The aim of this study was to investigate whether remifentanil had any impact on postoperative pain after gynecologic surgery. Methods: Sixty patients undergoing gynecological surgery were randomly allocated into three groups (each n=20): N group with normal saline, L group with target-controlled infusion (TCI) of 1 ng/ml remifentanil, and H group with TCI of 3 ng/ml remifentanil. All patients were anesthetized with sevoflurane to maintain mean arterial pressure within 20% of basal values. Thirty minutes before the end of surgery, patients received morphine sulfate through a patient-controlled infusion device. Pain scores, sedation scores, and analgesic requirements were recorded for 48 hours postoperatively. Results: The mean remifentanil infusion dose of the H group was significantly higher than that of the L group. The VAS scores of the L and H groups were significantly higher than those of the N group only at the postanesthetic care unit and not at the ward. Conclusions: Intraoperative use of remifentanil with sevoflurane may be related to increased postoperative pain during early postanesthetic period. Provision for effective preventive and therapeutic management strategies in case of intraoperative remifentanil use may be reasonable.

Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels

Background/Aims : Mechanisms by which synbiotic treatment improves liver function in patients with cirrhosis are unknown. This study was performed to address this important issue. Patients and methods: Thirty cirrhotic patients were randomized to receive synbiotic or placebo preparations for 7 days. Viable faecal counts of Lactobacillus species, Child-Pugh class, plasma retention rate of indocyanine green (ICG R15 ), whole blood tumour necrosis factor alpha (TNF- α ) mRNA and interleukin-6 (IL-6) mRNA, serum TNF-a, soluble TNF receptor (sTNFR)I, sTNFRII and IL-6 and plasma endotoxin levels were measured pre- and post-treatment. Results : Synbiotic treatment was associated with significantly increased faecal lactobacilli counts and significant improvements in ICGR15 and Child-Pugh class. Significant increases in whole blood TNF-a mRNA and IL-6 mRNA, along with serum levels of sTNFRI and sTNFRII, also occurred. TNF- α and IL-6 levels correlated significantly, both at baseline and post-synbiotic treatment. Synbiotic-related improvement in ICGR15 was significantly associated with changes in IL-6, both at mRNA and protein levels, and unrelated to plasma endotoxin values. No significant changes in any study parameter followed placebo treatment. Conclusions : Short-term synbiotic treatment proven to modulate gut flora significantly improves liver function in patients with cirrhosis. Benefit is unrelated to reduction in endotoxaemia and may be mediated, at least in part, by treatment-related induction of IL-6 synthesis by TNF- α . Key words: Cirrhosis, synbiotics, cytokines

Synbiotic-associated improvement in liver function in cirrhotic patients: Relation to changes in circulating cytokine messenger RNA and protein levels

Background/Aims : Mechanisms by which synbiotic treatment improves liver function in patients with cirrhosis are unknown. This study was performed to address this important issue. Patients and methods: Thirty cirrhotic patients were randomized to receive synbiotic or placebo preparations for 7 days. Viable faecal counts of Lactobacillus species, Child-Pugh class, plasma retention rate of indocyanine green (ICG R15 ), whole blood tumour necrosis factor alpha (TNF- α ) mRNA and interleukin-6 (IL-6) mRNA, serum TNF-a, soluble TNF receptor (sTNFR)I, sTNFRII and IL-6 and plasma endotoxin levels were measured pre- and post-treatment. Results : Synbiotic treatment was associated with significantly increased faecal lactobacilli counts and significant improvements in ICGR15 and Child-Pugh class. Significant increases in whole blood TNF-a mRNA and IL-6 mRNA, along with serum levels of sTNFRI and sTNFRII, also occurred. TNF- α and IL-6 levels correlated significantly, both at baseline and post-synbiotic treatment. Synbiotic-related improvement in ICGR15 was significantly associated with changes in IL-6, both at mRNA and protein levels, and unrelated to plasma endotoxin values. No significant changes in any study parameter followed placebo treatment. Conclusions : Short-term synbiotic treatment proven to modulate gut flora significantly improves liver function in patients with cirrhosis. Benefit is unrelated to reduction in endotoxaemia and may be mediated, at least in part, by treatment-related induction of IL-6 synthesis by TNF- α . Key words: Cirrhosis, synbiotics, cytokines

Depot perphenazine decanoate and enanthate for schizophrenia

Antipsychotic drugs are usually given orally but compliance with medication given by this route may be difficult to quantify. The development of depot injections in the 1960s gave rise to extensive use of depots as a means of long-term maintenance treatment. Perphenazine decanoate and enanthate are depot antipsychotics that belong to the phenothiazine family and have a piperazine ethanol side chain. To assess the effects of depot perphenazine decanoate and enanthate versus placebo, oral antipsychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. We updated previous searches of the Cochrane Schizophrenia Group Register (June 1998), Biological Abstracts (1982-1998), the Cochrane Library (Issue 2, 1998), EMBASE (1980-1998), MEDLINE (1966-1998), and PsycLIT (1974-1998) by searching the Cochrane Schizophrenia Group Register (March 2004). References of all identified trials were also inspected for more studies and industry contacted. We compared randomised clinical trials focusing on people with schizophrenia where depot perphenazine decanoate and enanthate, oral antipsychotics or other depot preparations. We reliably selected studies, quality rated them and extracted data. For dichotomous data we estimated the Relative Risk (RR) with the 95% confidence intervals (CI). Where possible, we calculated the number needed to treat statistic (NNT). Analysis was by intention-to-treat. Only four studies (Ahlfors 1980, Eufe 1979, Knudsen 1985c, Tegeler 1979), randomising a total 313 people could be included in this review and this combined with an overall lack of usable data limits any interpretation of results. Perphenazine enanthate was not significantly any better or worse than other depot antipsychotics in most of the main outcomes such as global state, relapse or leaving the study early. We found some differences favouring the control groups for adverse effects. One study (Ahlfors 1980) of six months' duration (n=172), compared perphenazine enanthate to clopenthixol decanoate. There were no differences between the two groups for outcomes of global improvement, relapse and leaving the study early. More people in the perphenazine enanthate group, however, required anticholinergic drugs than those allocated to clopenthixol decanoate (RR 1.12 CI 1.0 to 1.2, NNT 10).A single study (n=64, duration six weeks) compared perphenazine enanthate and its longer acting decanoate ester. Data on relapse and leaving the study early failed to show convincing differences. The enanthate group, however, experienced more movement disorders (RR 1.36, CI 1.1 to 1.8 NNT 5) than those allocated the decanoate ester of the same drug and required more anticholinergic drugs (RR 1.47 CI 1.1 to 2.0, NNT 4). Depot perphenazine is in clinical use in the Nordic countries, Belgium, Portugal and the Netherlands. At a conservative estimate, a quarter of a million people suffer from schizophrenia in those countries and could be treated with depot perphenazine. The total number of participants in the four trials with useful data is 313. None of the studies observed the effects of oral versus depot antipsychotic drugs. Until well conducted and reported randomised trials are undertaken clinicians will be in doubt as to the effects of perphenazine depots and people with schizophrenia should exercise their own judgement or ask to be randomised.

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

Sublingual immunotherapy for allergic rhinitis: systematic review and meta‐analysis*

Allergic rhinitis is a common condition which, at its most severe, can significantly impair quality of life despite optimal treatment with antihistamines and topical nasal corticosteroids. Allergen injection immunotherapy significantly reduces symptoms and medication requirements in allergic rhinitis but its use is limited by the possibility of severe systemic reactions. There has therefore been considerable interest in alternative routes for delivery of allergen immunotherapy, particularly the sublingual route. The objective was to evaluate the efficacy of sublingual immunotherapy (SLIT), compared with placebo, for reductions in symptoms and medication requirements. The Cochrane Controlled Clinical Trials Register, MEDLINE (1966-2002), EMBASE (1974-2002) and Scisearch were searched, up to September 2002, using the terms (Rhin* OR hay fever) AND (immunotherap* OR desensiti*ation) AND (sublingual). All studies identified by the searches were assessed by the reviewers to identify Randomized Controlled Trials involving participants with symptoms of allergic rhinitis and proven allergen sensitivity, treated with SLIT or corresponding placebo. Data from identified studies was abstracted onto a standard extraction sheet and subsequently entered into RevMan 4.1. Analysis was performed by the method of standardized mean differences (SMD) using a random effects model. P-values < 0.05 were considered statistically significant. Subgroup analyses were performed according to the type of allergen administered, the age of participants and the duration of treatment. Twenty-two trials involving 979 patients, were included. There were six trials of SLIT for house dust mite allergy, five for grass pollen, five for parietaria, two for olive and one each for, ragweed, cat, tree and cupressus. Five studies enrolled exclusively children. Seventeen studies administered the allergen by sublingual drops subsequently swallowed, three by drops subsequently spat out and two by sublingual tablets. Eight studies involved treatment for less than 6 months, 10 studies for 6-12 months and four studies for greater than 12 months. All included studies were double-blind placebo-controlled trials of parallell group design. Concealment of treatment allocation was considered adequate in all studies and the use of identical placebo preparations was almost universal. There was significant heterogeneity, most likely due to widely differing scoring systems between studies, for most comparisons. Overall there was a significant reduction in both symptoms (SMD -0.42, 95% confidence interval -0.69 to -0.15; P = 0.002) and medication requirements [SMD -0.43 (-0.63, -0.23); P = 0.00003] following immunotherapy. Subgroup analyses failed to identify a disproportionate benefit of treatment according to the allergen administered. There was no significant reduction in symptoms and medication scores in those studies involving only children but total numbers of participants was too small to make this a reliable conclusion. Increasing duration of treatment does not clearly increase efficacy. The total dose of allergen administered may be important but insufficient data was available to analyse this factor.

Depot pipotiazine palmitate and undecylenate for schizophrenia.

Antipsychotic drugs are usually given orally but compliance may be problematic. The development of depot injections in the 1960s gave rise to their extensive use as a means of long-term maintenance treatment. Pipotiazine palmitate is a depot from the phenothiazine family of antipsychotic drugs. To assess the clinical, social and economic effects of depot pipotiazine palmitate and undecylenate compared with placebo, oral antipsychotics and other depot antipsychotic preparations for people with schizophrenia. For this update we searched the Cochrane Schizophrenia Group's Register (June 2003). We also inspected references of all identified trials for more studies and contacted relevant industries. We included all randomised clinical trials comparing depot pipotiazine palmitate and undecylenate to oral antipsychotics or other depot preparations for people with schizophrenia. We reliably selected, quality rated and independently extracted data from relevant studies. We calculated the random effects relative risk (RR), the 95% confidence intervals (CI) and, where possible the number needed to treat (NNT) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). We only presented scale data for those tools that had attained pre-specified levels of quality. When pipotiazine palmitate was compared with 'standard' oral antipsychotic no differences were found for outcomes of global impression (n=53, 1 RCT, RR 2.57, CI 0.8 to 8.6), relapse (n=124, 1 RCT, RR 1.55 CI 0.76 to 3.2), study attrition (n=219, 3 RCTs, RR 1.37 CI 0.8 to 2.4) and behaviour (n=124, 1 RCT, WMD 4.65, CI -1.1 to 10.4). There was also no reported difference in adverse effects such as tardive dyskinesia or the need for anticholinergic drugs. Sixteen studies compared pipotiazine palmitate with other depot preparations (n=1123). Pipotiazine palmitate was consistently equivalent to other depots in terms of a range of outcomes, including global impression (n=217, 4 RCTs, RR not improved 0.99 CI 0.91 to 1.07), relapse (n=239, 5 RCTs, RR relapse by 1 year 0.98 CI 0.55 to 1.75), and adverse effects (n=337, 5 RCTs, RR needing anticholinergic medication 0.98 CI 0.84 to 1.15). Although well-conducted and reported randomised trials are still needed to fully inform practice (no trial data exists reporting hospital and services outcomes, satisfaction with care and economics) pipotiazine palmitate is a viable choice for both clinician and recipient of care.

Influence of synbiotic containing Lactobacillus acidophilus La5 , Bifidobacterium lactis Bb 12 , Streptococcus thermophilus, Lactobacillus bulgaricus and oligofructose on gut barrier function and sepsis in critically ill patients: a randomised controlled trial

Background & aims: Infective complications are a common cause of mortality and morbidity in critically ill patients. Many factors affect sepsis, one of which is gut barrier function. The aim of this study was to determine whether the oral administration of a synbiotic preparation could alter gut barrier function in critically ill patients and thus reduce sepsis. Methods: A total of 90 patients admitted to an intensive care unit (ICU) were randomised to receive either synbiotic or placebo preparations (45 into each group). The synbiotic preparation consisted of Lactobacillus acidophilus La5, Bifidobacterium lactis Bb 12, Streptococcus thermophilus and Lactobacillus bulgaricus (probiotics) with oligofructose (prebiotic ). Gut barrier function was assessed by measurement of intestinal permeability (lactulose/rhamnose test) and culture of nasogastric aspirate on days 1 and 8. All septic complications and mortality were recorded. Results: There were no differences between the groups in terms of age, sex, APACHE II or POSSUM scores. After 1 week of therapy, patients in the synbiotic group had a significantly lower incidence of potentially pathogenic bacteria (43% versus 75%, P=0.05) and multiple organisms (39% versus 75%, P=0.01) in their nasogastric aspirates than controls. There were no significant differences between the groups in terms of intestinal permeability, septic complications or mortality. Conclusions: The administration of synbiotic in critically ill patients favourably altered the microbial composition of the upper gastrointestinal tract but had no effect on intestinal permeability and was not associated with measurable clinical benefit.