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Atypical antipsychotic drugs in the treatment of behavioural and psychological symptoms of dementia: systematic review.

OBJECTIVE: To review the role of oral atypical antipsychotic drugs in the management of the behavioural and psychological symptoms of dementia (BPSD). DATA SOURCES: Medline, Embase, and the Cochrane Library. Reference lists were reviewed and experts were contacted to identify additional trials. STUDY SELECTION: Double blind randomised controlled trials that evaluated the four oral atypical antipsychotic therapies for BPSD. REVIEW METHODS: Two reviewers assessed trial validity independently. DATA EXTRACTION: Demographics of patients, study duration, dose of antipsychotic, primary end points, adverse events. RESULTS: 77 abstracts were reviewed. Five randomised trials (1570 patients) evaluating risperidone and olanzapine were identified. The quality of trials was generally good. Most participants were in an institution (> 96%), elderly (weighted mean 82.3 years), and had Alzheimer's disease (76.3%). Trials lasted 6-12 weeks. Treatment with atypical antipsychotic drugs was superior to placebo for the primary end point in three of the five trials. Two trials comparing risperidone with haloperidol did not find any differences in the primary measures of efficacy. Adverse events were common and included extrapyramidal symptoms, somnolence, and abnormal gait. CONCLUSIONS: Although atypical antipsychotic drugs are being used with increasing frequency, few randomised trials have evaluated their use for BPSD. Limited evidence supports the perception of improved efficacy and adverse event profiles compared with typical antipsychotic drugs.

Administration, Oral↗

Prevention of preeclampsia with low-dose aspirin -- a systematic review and meta-analysis of the main randomized controlled trials.

The purpose of this paper is to evaluate the effectiveness of low-dose aspirin in the prevention of preeclampsia in low-risk and high-risk women. We identified randomized clinical trials of the use of low-dose aspirin to prevent preeclampsia through the PUBMED search engine, and through the Cochran Library database. Twenty-two studies met our inclusion criteria, and were divided according to the studied population into 2 groups: trials with women at low risk for preeclampsia and trials with women at high risk. Effects were measured through the incidence of preeclampsia in women taking either placebo or aspirin, in studies where the relative risks and the 95% confidence intervals were calculated for both groups. A total of 33,598 women were studied, comprising 5 trials with 16,700 women at low-risk and 17 trials including 16,898 women at high risk. The incidence of preeclampsia was 3.75% (626/17,700), in the low-risk group, 9.01% (1,524/16,898) in the high-risk group, and 6.40% (2,150/33,598) overall. Low-dose aspirin had no statistically significantly effect on the incidence of preeclampsia in the low-risk group (RR = 0.95, 95% CI = 0.81-1.11), but had a small beneficial effect in the high-risk group (RR = 0.87, 95% CI = 0.79-0.96). Therefore, low-dose aspirin is mildly beneficial in terms of reducing the incidence of preeclampsia in women at high risk of developing preeclampsia.

Aspirin↗

Importance of pharmacological and physicochemical properties for tolerance of antimuscarinic drugs in the treatment of detrusor instability and detrusor hyperreflexia--chances for improvement of therapy.

BACKGROUND: Antimuscarinic side-effects are relatively frequent problems in oral pharmacotherapy of detrusor instability and neurogenic dysfunction of the urinary bladder. Results of recent clinical trials demonstrate differences in tolerance between antimuscarinic drugs. It is the purpose of this paper to relate the available clinical data to the pharmacological and physicochemical properties of the different antimuscarinic drugs, in order to discuss the reasons for this enhanced tolerance and to make possible modes for improvement of antimuscarinic therapy plainly visible. METHODS: Therefore, we reviewed the available literature using among others the computerized library systems Medline (National Library of Medicine, Bethesda, Maryland, USA) and Embase (Excerpta Medica, Amsterdam, the Netherlands). Differences in tolerance of oral antimuscarinic drugs may result from muscarine-receptor selectivity, organ selectivity, and pharmacokinetic as well as physicochemical properties. While the roles of m-receptor and organ selectivity need more detailed clarification, influences of differences in bioavailability and physicochemical properties on the tolerance of antimuscarinic drugs are more sufficiently investigated. RESULTS: Generally, tolerance as well as efficacy of antimuscarinic drugs seem to be a complex result of a combination of various pharmacological properties distinguishing the individual substances. The enhancement of tolerance of propiverine hydrochloride, tolterodine tartrate and trospium chloride compared to oxybutynin chloride seems to be reached by different modes, from which the molecular structure -- propiverine and tolterodine are tertiary amines, trospium chloride possesses a quarternary ammonium structure -- may be of great importance. First investigations with alternative transdermal and intravesical application routes show interesting possibilities for further improvement of antimuscarinic therapy in urological indications. CONCLUSION: In conclusion, from pharmacological and clinical data it becomes obvious that there are significant differences between antimuscarinic drugs, which are of clinical relevance and include possible starting points for the development of new drugs and application forms.

Administration, Cutaneous↗

A systematic review for effective management of central venous catheters and catheter sites in acute care paediatric patients.

BACKGROUND: Central venous catheters (CVCs) have provided many benefits in modern-day medical practice; however, they also put patients at risk of catheter-related complications. Numerous studies have been carried out in relation to the management of central venous catheters with conflicting results. While there were several systematic reviews of central venous catheter-related issues, it is clear that there was no systematic review of CVC-related studies specific to the paediatric population in the acute care setting. OBJECTIVE: To present the best available evidence for effective management of central venous catheters and catheter sites in the prevention and/or reduction of catheter-related complications in hospitalised paediatric patients. METHODS: A systematic review was undertaken according to the approach of the Centre for Reviews and Dissemination (CRD; http://www.york.ac.uk/inst/crd). DATA SOURCE: Literature was identified by electronic searching of Cochrane Library, MEDLINE, CINAHL, HealthSTAR, and CancerLit; checking references of all review articles; hand searching of key relevant journals and conference proceedings; and contact with expert informants, medical suppliers, and pharmaceutical companies. INCLUSION/EXCLUSION CRITERIA: The review included randomised and non-randomised controlled trials conducted with hospitalised paediatric patients. Studies that included mixed adult and paediatric populations and mixed hospitalised and home care settings were excluded. DATA EXTRACTION: Two independent reviewers extracted data onto a standard data extraction form, with differences resolved by discussion. QUALITY ASSESSMENT: The quality assessment of retrieved studies included: study design, the degree to which systematic bias was avoided or minimised, the degree to which the assessment was "blind," the degree to which follow up was completed. DATA SYNTHESIS: Quantitative pooling of studies was not feasible due to the diversity of interventions and outcome measures between similar studies. A narrative account of the study characteristics and results was therefore undertaken. RESULTS: Thirty-eight randomised and quasi-randomised controlled trials were retrieved for critical appraisal. Of these, 32 were excluded from the review because the studies did not meet the inclusion criteria and some lacked reporting of appropriate data. Six studies met the criteria with interventions such as antibiotic flushes, antiseptic skin preparations, and dressing materials. CONCLUSION: Quality of reporting was generally lacking. Statistical pooling of results was not possible due to diversity in the reporting of outcomes. There was no evidence to make recommendations on the degree of barrier precautions and the type of aseptic technique to be used at the time of catheter insertion in the paediatric population to prevent catheter-related infection. There was insufficient evidence to support the routine use of an antibiotic flushing solution. There was a lack of randomised controlled trial (RCT) evidence on the benefit of heparin flushes, the use of in-line filters, the frequency of fluid administration set changes, or the type of dressing to use and the frequency of dressing changes. There was some evidence to suggest that chlorhexidine lotion is superior to povidone iodine as a cutaneous antiseptic at the catheter insertion site. However, no recommendation can be made for the use of chlorhexidine in neonates less than 2 weeks old or in premature infants. This systematic review concluded that there is an urgent need for well-designed randomised controlled trials with sufficient power to determine the effectiveness of various interventions in relation to management of CVCs.

Adolescent↗

Oral treatments for fungal infections of the skin of the foot.

BACKGROUND: About 15% of the population have fungal infections of the feet (tinea pedis or athlete's foot). Whilst there are many clinical presentations of tinea pedis the most common are between the toes (interdigital) and on the soles, heels and sides of the foot (plantar) which is known as moccasin foot. Once acquired the infection can spread to other sites including the nails, which can be a source of reinfection. Oral therapy is usually used for chronic conditions or when topical treatment has failed. OBJECTIVES: To assess the effects and costs of oral treatments for fungal infections of the skin of the foot (tinea pedis). SEARCH STRATEGY: Randomised controlled trials were identified from MEDLINE, EMBASE and CINAHL from the beginning of these databases to January 2000. We also searched the Cochrane Controlled trials Register (Cochrane Library issue 1, 2000) the Science Citation Index, BIOSIS, CAB-Health, Health star and Economic databases. Bibliographies were searched, podiatry journals hand searched and the pharmaceutical industry and schools of podiatry contacted. SELECTION CRITERIA: Randomised controlled trials including participants who have a clinically diagnosed tinea pedis, confirmed by microscopy and growth of dermatophytes in culture. DATA COLLECTION AND ANALYSIS: Study selection was done by two independent reviewers. Methodological quality assessment and data collection was also assessed by two independent reviewers. MAIN RESULTS: Twelve trials, involving 700 participants, were included. The two trials comparing terbinafine and griseofulvin produced a pooled risk difference of 52% (95% confidence intervals 33% to 71%) in favour of terbinafine's ability to cure infection. No significant difference was detected between terbinafine and itraconazole; fluconazole and either itraconazole and ketoconazole; or between griseofulvin and ketoconazole, although the trials were generally small. Two trials showed that terbinafine and itraconazole were effective compared with placebo. Adverse effects were reported for all drugs, with gastrointestinal effects most commonly reported. REVIEWER'S CONCLUSIONS: The evidence suggests that terbinafine is more effective than griseofulvin and that terbinafine and itraconazole are more effective than no treatment.

Administration, Oral↗

Single dose oral indometacin for the treatment of acute postoperative pain.

BACKGROUND: Indometacin is a non-steroidal anti-inflammatory drug (NSAID) used most commonly for the treatment of inflammation and pain resulting from rheumatic disease (arthritis), and less commonly in postoperative pain management. When taken for chronic pain conditions, indometacin has been associated with a high incidence of adverse events. The benefits and harms of orally-administered indometacin for postoperative pain are not clear. OBJECTIVES: To determine the efficacy of a single dose of oral indometacin compared with placebo in treating acute postoperative pain in adults, and to analyse information relating to adverse events. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 3, 2004), MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were sought from the reference lists of retrieved reports. SELECTION CRITERIA: Studies were included in the review if they were randomised, double blind, placebo-controlled clinical trials using a single oral dose of indometacin in adults with acute postoperative pain. DATA COLLECTION AND ANALYSIS: Trials were assessed independently by two authors. Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. The relative benefit for at least 50% pain relief was calculated. MAIN RESULTS: One trial of 59 women with post-episiotomy pain met the inclusion criteria. The dose of indometacin assessed against placebo was 50 mg, and the results concluded that indometacin was not significantly better than placebo for relieving postoperative pain at four to six hours. There was insufficient information to conduct further efficacy analyses or assess adverse events. REVIEWERS' CONCLUSIONS: Conclusions about the clinical efficacy of indometacin for postoperative cannot be made until more trials are conducted for a variety of surgical procedures, and different doses of indometacin are assessed.

Administration, Oral↗

Integrated oral bioavailability projection using in vitro screening data as a selection tool in drug discovery.

The objective of the analysis described herein is to examine the in vitro/in vivo relationship of estimated bioavailability values and also the applicability of the estimated in vitro bioavailability to lead candidate selection in drug discovery. To this end, in vitro ADME data from screening assays as well as in vivo rat pharmacokinetic (PK) data were compiled for 140 compounds across therapeutic areas from the Pfizer library in Ann Arbor. The compounds span a broad range of structural types, including neutral, basic, and acidic compounds. Solubility and Caco-2 permeability data from in vitro ADME screening were used to calculate the fraction dose absorbed (FDp) using the physiologically based IDEA model. In vitro metabolic stability (t(1/2)) from human and rat liver microsomal incubations was converted to an in vitro intrinsic clearance value (CL(int)'), which was then scaled up to reflect in vivo clearance (CL) and hepatic extraction as described by Obach et al. [J. Pharmcol. Exp. Ther. 283 (1997) 46]. Subsequently, the in vitro/in vivo relationship between the measured bioavailability (F(obs)) in rats and the estimated bioavailability (F(est)) from FDp and predicted CL values was examined. The observed data suggest that compounds with low estimated in vitro bioavailability (F(est)<15%) are more likely to have low in vivo bioavailability (F(obs)<30%). Therefore, the present study indicates that in vitro estimation of bioavailability is an efficient tool to eliminate compounds having low bioavailability prior to in vivo characterization and therefore can be used to reduce attrition due to poor ADME properties in drug development.

Administration, Oral↗

Strain-Promoted mRNA Transdermal Delivery by Lipoic Lipid Nanoparticles for Therapeutic Skin Genome Editing.

Lipid nanoparticle (LNP)-mRNA formulations have revolutionized the field of nucleic acid therapeutics, yet their broader clinical application is constrained by inflammatory side effects and oxidative stress, particularly in the context of inflammatory diseases. Herein, we report the rational design and synthesis of a lipoic acid-based ionizable lipid library to address these limitations. By leveraging the antioxidant properties and thiol-mediated uptake potential of lipoic acid, we identified LA-A2B2CD3 as an optimal candidate through a structure-activity relationship study and design of experiment (DOE) optimization. LA-A2B2CD3 LNPs exhibited superior reactive oxygen species scavenging, enhanced mRNA translation, and reduced inflammatory cytokine production in vitro and in vivo. Mechanistic studies revealed that the efficient cellular uptake and the transdermal delivery capacity of LA-A2B2CD3 heavily rely on the reducible disulfide ring of lipoic acid. Application of LA-A2B2CD3 LNPs for the localized transdermal delivery of Cas9 mRNA and CD93 sgRNA in a murine model of psoriasis resulted in effective CD93 genome editing and the inhibition of the CD93-p38 MAPK-AKT-SMAD2/3 pathway, leading to significant therapeutic improvement. This work presents a robust, biocompatible LNP platform with minimized immunogenicity and strong potential for genome-editing therapies in inflammatory conditions, offering a transformative approach for the mRNA-based treatment of skin and other inflammation-related disorders.

Animals↗

Combined use of alpha-adrenergic and muscarinic antagonists for the treatment of voiding dysfunction.

PURPOSE: We provide an overview of the medical literature supporting the combined use of muscarinic and alpha-adrenergic antagonist therapy for the treatment of voiding dysfunction. MATERIALS AND METHODS: The MEDLINE database (1966 to 2004) of the United States National Library of Medicine was searched for pertinent studies. RESULTS: Although the mechanism of action of alpha-adrenergic antagonist therapy for voiding dysfunction has traditionally been assumed to be relaxation of the periurethral, prostatic and bladder neck smooth muscle, substantial evidence supports action at extraprostatic sites involved in micturition, including the bladder dome smooth muscle, peripheral ganglia, spinal cord and brain. Likewise the mechanism of action of anticholinergic therapy has been traditionally assumed to be inhibition of the M3 muscarinic receptor subtypes that mediate normal bladder contractions. However, M2 receptor mediates hypertrophied bladder contractions and there is evidence for an M2 component to the suprasacral control of voiding. CONCLUSIONS: Based on the physiology of alpha-adrenergic and muscarinic receptors the inhibition of each one would be expected to be more beneficial than that of either alone because they would work on 2 components of detrusor function. Patients who would likely benefit from this combination therapy are men with lower urinary tract symptoms, women with urgency/frequency syndrome (overactive bladder), patients with uninhibited bladder contractions due to neurogenic bladder, and patients with pelvic pain and voiding symptoms, ie interstitial cystitis and chronic prostatitis/chronic pelvic pain syndrome.

Adrenergic alpha-Antagonists↗

Thrombolysis in acute ischaemic stroke: a guide to patient selection.

Thrombolysis should be a routine treatment for selected patients with acute ischaemic stroke and shows promise in a much larger group of patients. This recommendation is based on data from two completed meta-analyses: the Cochrane Library and the rt-PA Study Group individual patient meta-analysis. In patients with ischaemic stroke, treatment with alteplase (recombinant tissue plasminogen activator; rt-PA) is associated with a non-significant excess of deaths, equivalent to about 19 extra deaths per 1000 treated. Furthermore, thrombolysis, regardless of which drug is used, definitely increases the odds of fatal intracranial haemorrhage by 4-fold. However, despite these risks, thrombolysis with alteplase reduces the odds of death or disability, with the benefit being equivalent to about 55 extra independent survivors per 1000 treated. Unfortunately, there are currently too few data to provide a comprehensive guide to patient selection. The available data suggest that younger patients (<80 years of age) who can be treated with alteplase within 3 hours of stroke onset have the most to gain, equivalent to about 100 more independent survivors per 1000 treated. The role of thrombolysis beyond 3 hours, in those with more extensive CT scan ischaemic change, and patients >80 years of age needs further evaluation. In summary, thrombolysis with alteplase is now an established treatment for acute ischaemic stroke, but clinicians need to cooperate in terms of enrolling more patients in further trials if we are to get the most out of this important treatment.

Drug Administration Routes↗

Prevention of and therapies for nipple pain: a systematic review.

OBJECTIVE: To review the literature on nipple pain and to delineate effective strategies for the prevention and treatment of nipple pain in breastfeeding mothers. DATA SOURCES: Computerized searches on MEDLINE, Pre-MEDLINE, CINAHL, and the Cochrane Library. STUDY SELECTION: Articles from indexed journals relevant to the objective were reviewed from January 1983 to April 2004. Preference was given to research-based studies in English. DATA EXTRACTION: Data were extracted and organized under two headings: prevention of nipple pain or trauma and treatment of nipple pain or trauma. The Critical Appraisal Form by J. Briggs was used to extract the data from research-based articles. DATA SYNTHESIS: The health benefits of breastfeeding for mother and infant are well documented; however, nipple pain is a common reason reported by women for the early termination of breastfeeding. Several studies have compared various treatments for either the prevention of or treatment for nipple pain. These treatments include warm water compresses, tea bag compresses, heat, application of expressed mother's milk, lanolin, vitamin A, collagenase, dexpanthenol, hydrogel therapy, glycerin gel therapy, moist occlusive dressing, education regarding proper latch-on and positioning, and no treatment. CONCLUSIONS: No one topical agent showed superior results in the relief of nipple discomfort. The most important factor in decreasing the incidence of nipple pain is the provision of education in relation to proper breastfeeding technique and latch-on as well as anticipatory guidance regarding the high incidence of early postpartum nipple pain.

Administration, Cutaneous↗

Cilomilast: orally active selective phosphodiesterase-4 inhibitor for treatment of chronic obstructive pulmonary disease.

OBJECTIVE: To review available literature evaluating the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of cilomilast, a selective phosphodiesterase-4 (PDE4) inhibitor. DATA SOURCES: Literature was accessed through MEDLINE (1966-May 2006), Current Contents Clinical Medicine (1998-May 2006), and The Cochrane Library Database (1st quarter 2006) using the terms cilomilast, Ariflo, and SB 207 499. Reference lists from retrieved articles and information from the manufacturer were manually reviewed. STUDY SELECTION AND DATA EXTRACTION: All clinical trials evaluating cilomilast and published in English were included in this review. In addition, articles evaluating the pharmacology, pharmacokinetics, and safety of cilomilast in humans were reviewed. DATA SYNTHESIS: Cilomilast is a second-generation PDE4 inhibitor with antiinflammatory effects that target bronchoconstriction, mucus hypersecretion, and airway remodeling associated with chronic obstructive pulmonary disease (COPD). Selective PDE4 inhibition is proposed to maximize the antiinflammatory effects of PDE inhibition while minimizing the adverse effects of nonselective agents. To date, 4 clinical trials have evaluated the efficacy of cilomilast and demonstrated improvement in lung function (forced expiratory volume in 1 second) and quality of life and reduction in the occurrence of COPD exacerbations compared with placebo. Cilomilast is generally well tolerated, with adverse effects being overall mild and self-limiting. CONCLUSIONS: COPD is a progressive disease, and available treatment options provide limited efficacy. Given its unique mechanism of action and improved adverse effect profile compared with previous agents, cilomilast may have a promising role for the management of COPD.

3',5'-Cyclic-AMP Phosphodiesterases↗

Antileukotrienes in the treatment of asthma and allergic rhinitis.

OBJECTIVES: To compare leukotriene antagonists (LTA) to other groups of drugs used in asthma and allergic rhinitis treatment. SOURCES: MEDLINE, LILACS and Cochrane Library. KEYWORDS: leukotrienes, antileukotrienes, asthma treatment, allergic rhinitis treatment, asthma and allergic rhinitis. An attempt was made to group the main studies and reviews about this topic. SUMMARY OF THE FINDINGS: LTA are more efficient than placebo and enhance the effects of inhaled corticosteroids. The association of inhaled corticosteroids with long-acting Beta2 agonists is more efficient than the association of inhaled corticosteroids + LTA. Although use of LTA in acute asthma attacks and allergic rhinitis seems reasonable, more studies are needed to confirm this benefit. LTA reduce hospitalization time and the number of wheezing attacks in infants with acute viral bronchiolitis caused by respiratory syncytial virus, as well as recurrent wheezing after acute viral bronchiolitis. LTA are less efficient than intranasal corticosteroids for allergic rhinitis management. LTA are efficient in exercise-induced asthma, although they are not the first-line treatment. CONCLUSION: Controlled and randomized studies show that inhaled corticosteroids are the drugs of choice to treat persistent asthma and allergic rhinitis. There is not enough evidence to recommend the use of LTA as first-line drug (monotherapy) in children with asthma (level I). For children who cannot use inhaled corticosteroids, LTA may be a good alternative (level II).

Acute Disease↗

Systemic therapy for treating locoregional recurrence in women with breast cancer.

BACKGROUND: Between 10% and 35% of women with operable breast cancer will experience an isolated locoregional recurrence following their primary treatment. There is currently no good evidence that adjuvant systemic treatment is effective in this situation and there is no standard treatment for women who have such a recurrence. OBJECTIVES: To investigate whether additional systemic treatment will improve the result of local therapy in regard to relapse-free and overall survival in women with potentially curatively resected loco-regional recurrence following breast cancer, who have not had a previous or synchronous distant metastases. SEARCH STRATEGY: Searches were done, in the first half of 2001, of the specialised register of the Cochrane Breast Cancer Collaborative Review Group, The Cochrane Library, MEDLINE and EMBASE. In addition, the records of the Early Breast Cancer Trialists' Collaborative Group were checked for any relevant trials. The citations in articles reviewing the treatment of locoregional recurrence of breast cancer were checked. SELECTION CRITERIA: Randomised controlled trials or trials in which women were allocated to treatment or observation by a quasi-random process (such as alternation or date of birth) were eligible. Our aim was to consider separately women with a first incidence of isolated loco-regional recurrence in the treated breast, the chest wall or the regional lymphnode areas (except clavicular nodes) which can be resected without (R0) or with (R1) microscopically demonstrable residual disease. Women with previous or synchronous distant metastases were to be excluded from this part of the review. The second part of the review was to consider women with inoperable loco-regional recurrence and / or clavicular lymphnode involvement, regardless of previous or synchronous metastases. DATA COLLECTION AND ANALYSIS: We identified three closed studies in which there were a total of four randomised comparisons of systemic therapy versus observation for women who have received radiotherapy for loco-regional recurrence of breast cancer. One trial assessed Actinomyicin-D and randomised 32 patients in the 1960s and another randomised the same number of women to alpha-interferon versus observation in the early 1980s. The Swiss SAKK trial assessed tamoxifen for "good risk" patients and combination chemotherapy (Vincristine, Doxorubicin and Cyclophosphamide) for "poor risk" patients. It randomised 178 and 50 women respectively during 1982-1991. Where possible, data on relapse-free and overall survival were extracted for these trials and analysed using RevMan 4.1. No attempt was made to pool the results of the studies because of clinical heterogeneity and the small number of randomised patients. Three ongoing trials of chemotherapy versus observation have been identified. MAIN RESULTS: The trial of 32 women who received either radiotherapy alone or in combination with systemic administration of Actinomycin-D found that chemotherapy improved the local control rate but had no apparent effect on overall survival. The interferon trial, which also included a total of only 32 patients, showed that the addition of alpha-Interferon to local treatment of locoregional recurrent breast cancer had no apparent effect on the further course of the disease. The Swiss SAKK trial of tamoxifen (178 women randomized) found an improvement in disease-free survival but not in overall survival and no results are available for the 50 women randomized into the concurrent trial of chemotherapy. The three ongoing trials of chemotherapy have a total target accrual of nearly 2000 patients. REVIEWER'S CONCLUSIONS: This systematic review of randomised trials provides insufficient evidence to do other than conclude that the most appropriate form of practice for women with loco-regional recurrence of breast cancer is participation in randomised trials of systemic treatment versus observation.

Antineoplastic Agents↗

Effectiveness and safety of ginger in the treatment of pregnancy-induced nausea and vomiting.

OBJECTIVE: Conventional antiemetics are burdened with the potential of teratogenic effects during the critical embryogenic period of pregnancy. Thus, a safe and effective medication would be a welcome addition to the therapeutic repertoire. This systematic review was aimed at assessing the evidence for or against the efficacy and safety of ginger (Zingiber officinale) therapy for nausea and vomiting during pregnancy. DATA SOURCES: Systematic literature searches were conducted in 3 computerized databases (MEDLINE, EMBASE, and Cochrane Library), and the reference lists of all papers located were checked for further relevant publications. METHODS OF STUDY SELECTION: For the evaluation of efficacy, only double-blind, randomized controlled trials (RCTs) were included. All retrieved clinical data, including uncontrolled trials, case reports, observational studies, and RCTs, were included in the review of safety. TABULATION, INTEGRATION, AND RESULTS: Six double-blind RCTs with a total of 675 participants and a prospective observational cohort study (n = 187) met all inclusion criteria. The methodological quality of 4 of 5 RCTs was high. Four of the 6 RCTs (n = 246) showed superiority of ginger over placebo; the other 2 RCTs (n = 429) indicated that ginger was as effective as the reference drug (vitamin B6) in relieving the severity of nausea and vomiting episodes. The observational study retrieved and RCTs (including follow-up periods) showed the absence of significant side effects or adverse effects on pregnancy outcomes. There were no spontaneous or case reports of adverse events during ginger treatment in pregnancy. CONCLUSION: Ginger may be an effective treatment for nausea and vomiting in pregnancy. However, more observational studies, with a larger sample size, are needed to confirm the encouraging preliminary data on ginger safety. LEVEL OF EVIDENCE: I.

Administration, Oral↗

[Medical treatment of respiratory emergencies].

Of the four treatments that can be used to treat respiratory insufficiency due to laryngitis, two, nebulized adrenaline and O2 therapy, are undoubtedly effective. The inhalation of water vapour appears to be increasingly useless and may be also harmful. The use of steroids is still under debate. In recent literature, however, the utility of steroids seems to be confirmed, especially if administered per Os, and even at a relatively low single oral dose (1-2 mg/kg of prednisone). According to the official organs (see Red Book) and according to the Evidence Based Medicine (see Cochrane Library) the treatment of bronchiolitis should be limited to an eventual support therapy, i.e. O2 therapy and rehydration. However, the approach adopted by North American Hospitals and European specialists in infectious diseases is in contrast and consists in the use of beta 2 agonists and steroids in 90-100% and 40-80% of patients, respectively. This contrast could be due to a deficiency in the researches of the Evidenced Based Medicine which is obliged to retrieve studies done over 10-15 years in order to obtain a sufficient number of data for a statistically valid investigation. These studies unfortunately are not updated with regard to the dose of individual drugs and the immediate association of drugs. In particular, with regard to nebulized beta 2 agonists, the absence of a positive effect could be due to an excessively low dose in relation to the age of the patient. According to the most recent knowledge, in fact, reduced doses are no longer required for babies in consideration of age and weight. In reality an equal and even higher dose than that used in adults would be best. The other reason for a lack of response could be the absence of the association of a steroid with a beta 2 agonists at the right moment. The lack of timing in associating these two drugs could also account for the absent response to the steroid. On the basis of these considerations it would be a mistake to give up the use of beta 2 agonists and steroids. Considering also the severity and frequency of a disease as bronchiolitis. To follow the "fashion" of the Evidence Based Medicine. Recently, magnesium sulphate, ketamine and the association elium-O2 have been suggested as marginal and not revolutionary medical interventions for the treatment of asthma. Among bronchodilators, the subordinate role of anticholinergics (for ex. ipratropium bromide), and of adrenaline has been defined with respect to beta 2 agonists, in particular salbutamol. The optimisation of the administration by nebulizers of the latter has been fundamental as it has a key role in the treatment of acute severe asthma. In detail, traditional nebulizers tend to be substituted by Metered Dose Inhaler + spacer with a ratio in the dose of 5/1. The venous route is used only in very severe cases and is used late and in intensive care although a single initial intravenous administration could determine a more rapid reduction of bronchoconstriction and reduce the number of nebulized bronchodilatators that can become extremely frequent in most severe cases. For steroids, instead, the only safe therapeutic route is by PO, i.v., i.m.: nebulized steroids although used with a definitely higher dose than that used for chronic asthma, can be used only in the milder forms.

Acute Disease↗

Pharmacotherapy of ectoparasitic infections.

Epizoonoses such as scabies, lice and cimicosis are common, vexing disorders that occur worldwide. Historically, many treatment modalities have been employed in the management of these disorders, and most of the drugs described in this review are of historical interest and no longer recommended or in widespread use because of their wide spectrum of adverse effects. More recently, reports documenting resistance against various antiectoparasite drugs, complicated and severe courses of the diseases, and adverse effects of drug therapy have prompted the development of new treatment strategies and drugs for optimal disease management. Because the strategies currently recommended for the treatment of ectoparasites differ worldwide, this review proposes a rational approach to selecting the best therapeutic agent by comparing the pharmacokinetics, pharmacodynamics, drug efficacy and adverse effects. A literature search of the currently Internet accessible libraries PubMed, Medline and Ideal library, of citations of articles found there, and from communications with the Federal Institute for Drugs and Medical Devices, Germany, was conducted based on this approach. One major observation of this literature search is that permethrin is the treatment of choice for lice and scabies in the US and in Great Britain, whereas lindane is still recommended for scabies in most other European countries because of its longer-standing record of effectiveness. Although permethrin has not yet been proven to be more effective than lindane in treating infections with these ectoparasites, it currently appears to have the best efficacy versus safety profile of topical treatments for scabies and lice. Ivermectin is a newer oral drug for the treatment of ectoparasites, which has been used with great success in the treatment of onchocercosis and other endoparasites. Although ivermectin appears to be a promising drug, its role in the treatment of ectoparasitic infections will be clarified as more study data become available. Finally, it is important to emphasise the clinical aspects of ectoparasite therapy and that providing the patient with optimal instructions on the use of topical therapeutics is of great importance in avoiding adverse effects and assuring complete removal of the ectoparasite, thereby avoiding the development of drug-resistance.

Administration, Oral↗

Targeted gene delivery to vascular tissue in vivo by tropism-modified adeno-associated virus vectors.

BACKGROUND: Gene therapy offers an unprecedented opportunity to treat diverse pathologies. Adeno-associated virus (AAV) is a promising gene delivery vector for cardiovascular disease. However, AAV transduces the liver after systemic administration, reducing its usefulness for therapies targeted at other sites. Because vascular endothelial cells (ECs) are in contact with the bloodstream and are heterogeneous between organs, they represent an ideal target for site-specific delivery of biological agents. METHODS AND RESULTS: We isolated human venous EC-targeting peptides by phage display and genetically incorporated them into AAV capsids after amino acid 587. Peptide-modified AAVs transduced venous (but not arterial) ECs in vitro, whereas hepatocyte transduction was significantly lower than with native AAV. Intravenous infusion of engineered AAVs into mice produced reduced vector accumulation in liver measured 1 hour and 28 days after injection and delayed blood clearance rates compared with native AAV. Peptide-modified AAVs produced enhanced uptake of virions in the vena cava with selective transgene expression. Retargeting was dose dependent, and coinfusion of either heparin or free competing peptides indicated that uptake was principally independent of native AAV tropism and mediated via the peptide. CONCLUSIONS: AAV tropism can be genetically engineered by use of phage display-derived peptides to generate vectors that are selective for the vasculature.

Animals↗