No need for rescue medication (NNR) as an easily interpretable efficacy outcome measure in analgesic trials: validation in an individual-patient meta-analysis of dental pain placebo-controlled trials of naproxen.

WHAT IS KNOWN AND OBJECTIVE: In analgesic trials, pain relief is often assessed using a pain-relief score. We aimed to assess, through a meta-analysis, whether absence of need for rescue medication (NNR) is a reliable outcome measure in the evaluation of acute pain relief. METHODS: Individual-patient meta-analysis of placebo-controlled trials of single-dose naproxen sodium 220 or 440 mg in dental pain. Efficacy estimates were based on NNR and compared with the more commonly used 50% maximum total pain relief score (50% TOTPAR). The trials included were the full set of trials sponsored by one manufacturer. RESULTS AND DISCUSSION: Need for rescue medication and 50% TOTPAR gave comparable estimates of efficacy of naproxen sodium (220 and 440 mg) relative to placebo in dental pain at both 8 and 12 h after dosing. WHAT IS NEW AND CONCLUSION: No need for rescue medication is a reliable outcome measure for use in acute pain trials. As it is more readily understandable than 50% TOTPAR, it should be the preferred primary outcome measure in acute pain trials.

Barking up the wrong genome--we are not alone.

WHAT IS KNOWN AND OBJECTIVE: Pharmacogenetic studies, to help us understand variability in human drug response, have hitherto focussed largely on our own germline mutations, and in the context of anticancer and antimicrobial drugs, also on mutations of the tumour cell or invader microorganism. Here, we wish to draw attention to how our microbiome may contribute to variability in drug effects. COMMENT: Irinotecan, a prodrug which is activated to the topoisomerase I inhibitory metabolite (SN-38), is commonly used for the treatment of a range of cancers. SN-38 is subsequently detoxified by uridine diphosphate-glycosyltransferase 1, encoded by the UGT1A1 gene. It is well known that the variant allele UGT1A*18 is associated with the more common adverse effects of irinotecan. A recent study shows that the potentially dose-limiting irinotecan-induced diarrhoea is due to enterohepatic circulation of SN-38, and its reactivation in the gut by bacterial ß-glucuronidases. Importantly, the authors used specific inhibitors of the microbial enzymes to reduce the gastro-intestinal toxicity in mice. WHAT IS NEW AND CONCLUSION: We draw attention to the increasing range of diseases, including diabetes and obesity, associated with our microbiome. This pharmacogenetic example reminds us that in personalized medicine, there is more than our own genome to take account of.

The clinical effectiveness and cost-effectiveness of newer drugs for children with epilepsy. A systematic review.

OBJECTIVES: To examine the clinical effectiveness and cost-effectiveness of newer antiepileptic drugs (AEDs) for epilepsy in children: gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin. DATA SOURCES: Electronic databases. Drug company submissions. REVIEW METHODS: For the systematic review of clinical and cost-effectiveness, studies were assessed for inclusion according to predefined criteria. Data extraction and quality assessment were also undertaken. A decision-analytic model was constructed to estimate the cost-effectiveness of the newer agents in children with partial seizures, the only condition where there were sufficient trial data to inform a model. RESULTS: The quality of the randomised controlled trial (RCT) data was generally poor. For each of the epilepsy subtypes considered in RCTs identified for this review (partial epilepsy with or without secondary generalisation, Lennox-Gastaut syndrome, infantile spasms, absence epilepsy and benign epilepsy with centrotemporal spikes), there is some evidence from placebo-controlled trials that the newer agents tested are of some value in the treatment of these conditions. Where active controls have been used, the limited evidence available does not indicate a difference in effectiveness between newer and older drugs. The data are not sufficient to inform a prescribing strategy for any of the newer agents in any of these conditions. In particular, there is no clinical evidence to suggest that the newer agents should be considered as a first-choice treatment in any form of epilepsy in children. Annual drug costs of the newer agents ranges from around 400 pound to 1200 pound, depending on age and concomitant medications. An AED that is ineffective or has intolerable side-effects will only be used for a short period of time, and many patients achieving seizure freedom will successfully withdraw from drug treatment without relapsing. The results of the decision-analytic model do not suggest that the use of the newer agents in any of the scenarios considered is clearly cost-effective but, similarly, do not indicate that they are clearly not cost-effective. CONCLUSIONS: The prognosis for children diagnosed with epilepsy is generally good, with a large proportion responding well to the first treatment given. A substantial proportion, however, will not respond well to treatment, and for these patients the clinical goal is to find an optimal balance between the benefits and side-effects of any treatment given. For the newly, or recently, diagnosed population, the key question for the newer drugs is how soon they should be tried. The cost-effectiveness of using these agents early, in place of one of the older agents, will depend on the effectiveness and tolerability of these agents compared with the older agents; the evidence from the available trial data so far suggests that the newer agents are no more effective but may be somewhat better tolerated than the older agents, and so the cost-effectiveness for early use will depend on the trade-off between effectiveness and tolerability, both in terms of overall (long-term) treatment retention and overall utility associated with effects on seizure rate and side-effects. There are insufficient data available to estimate accurately the nature of this trade off either in terms of long-term treatment retention or utility. Better information is required from RCTs before any rational evidence-based prescribing strategy could be developed. Ideally, RCTs should be conducted from a 'public health' perspective, making relevant comparisons and incorporating outcomes of interest to clinicians and patients, with sufficiently long-term follow-up to determine reliably the clinical utility of different treatments, particularly with respect to treatment retention and the balance between effectiveness and tolerability. RCTs should mirror clinical practice with respect to diagnosis, focusing on defined syndromes or, where no syndrome is identified, on groups defined by specific seizure type(s) and aetiology. Epilepsy in children is a complex disease, with a variety of distinct syndromes and many alternative treatment options and outcomes. Diagnosis-specific decision-analytic models are required; further research may be required to inform parameter values adequately with respect to epidemiology and clinical practice.

Stability and in vitro absorption of captopril, enalapril and lisinopril across the rat intestine.

In vitro absorption of three angiotensin converting enzyme (ACE) inhibitors, captopril, enalapril and lisinopril, and their stabilities in aqueous buffer as well as their resistance to intestinal and dermal tissue homogenates were investigated. The results demonstrate that the spontaneous oxidation of captopril, enalapril and lisinopril followed first-order degradation kinetics in McIlvaine's citrate-phosphate buffer. The degradation rates for enalapril and lisinopril were much slower than that for captopril. With the former two ACE inhibitors, the first-order rate constants of breakdown in the presence of dermal homogenate were not significantly different from the control values. Intestinal homogenate increased the decomposition of both of these inhibitors when compared to the enzyme-free control systems. On the other hand, the first-order rates of disappearance of captopril in the presence of both dermal and intestinal homogenates were lower than in the enzyme-free system. The extent of reduction was proportional to the amount of homogenate added. This suggests that tissue homogenates prevent the oxidation of captopril to its disulphide dimer. Transport experiments show that the amounts of ACE inhibitors transferred from solution on the mucosal side increased linearly with incubation time over the 2 hr of study. The rates of transfer from the mucosal side to the serosal side had the following rank order: captopril > enalapril > lisinopril roughly in the ratio 1:1.13:1.27. Addition of harmaline caused a significant reduction in the transfer rate of captopril compared to the control system, which strongly suggests that captopril is transported by a sodium-dependent carrier-mediated process across intestinal tissue.

Systematic review of treatments for atopic eczema.

BACKGROUND: Atopic eczema is the commonest inflammatory skin disease of childhood, affecting 15-20% of children in the UK at any one time. Adults make up about one-third of all community cases. Moderate-to-severe atopic eczema can have a profound effect on the quality of life for both sufferers and their families. In addition to the effects of intractable itching, skin damage, soreness, sleep loss and the social stigma of a visible skin disease, other factors such as frequent visits to doctors, special clothing and¿the need to constantly apply messy topical applications all add to the burden of disease. The cause of atopic eczema is unknown, though a genetic pre-disposition and a combination of allergic and non-allergic factors appear to be important in determining disease expression. Treatment of atopic eczema in the UK is characterised by a profusion of treatments aimed at disease control. The evidential basis of these treatments is often unclear. Most people with atopic eczema are managed in primary care where the least research has been done. OBJECTIVES: The objectives of this scoping review are two-fold. To produce an up-to-date coverage 'map' of randomised controlled trials (RCTs) of treatments of atopic eczema. To assist in making treatment recommendations by summarising the available RCT evidence using qualitative and quantitative methods. DATA SOURCES: Data sources included electronic searching of MEDLINE, EMBASE, the Cochrane Controlled Clinical Trials Register, the Cochrane Skin Group specialised register of trials, hand-searching of atopic eczema conference proceedings, follow-up of references in retrieved articles, contact with leading researchers and requests to relevant pharmaceutical companies. INCLUSION/EXCLUSION CRITERIA: Only RCTs of therapeutic agents used in the prevention and treatment of people with atopic eczema of any age were considered for inclusion. Only studies where a physician diagnosed atopic eczema or atopic dermatitis were included. DATA EXTRACTION: Data extraction was conducted by two observers onto abstraction forms, with discrepancies resolved by discussion. QUALITY ASSESSMENT: The quality assessment of retrieved RCTs included an assessment of: a clear description of method and concealment of allocation of randomisation, the degree to which assessors and participants were blinded to the study interventions, and whether all those originally randomised were included in the final main analysis. DATA SYNTHESIS: Where possible, quantitative pooling of similar RCTs was conducted using the Cochrane Collaboration's methods. Where statistical heterogeneity was found, sources of heterogeneity in terms of study participants, formulation or posology of intervention, and use of co-treatments were explored. Where pooling was not deemed to be appropriate, detailed descriptions of the study characteristics and main reported results were presented along with comments on study quality. RESULTS: A total of 1165 possible RCTs were retrieved in hard copy form for further scrutiny. Of these, 893 were excluded from further analysis because of lack of appropriate data. The 272 remaining RCTs of atopic eczema covered at least 47 different interventions, which could be broadly categorised into ten main groups. Quality of reporting was generally poor, and limited statistical pooling was possible only for oral cyclosporin, and only then after considerable data transformation. There was reasonable RCT evidence to support the use of oral cyclosporin, topical corticosteroids, psychological approaches and ultraviolet light therapy. There was insufficient evidence to make recommendations on maternal allergen avoidance for disease prevention, oral antihistamines, Chinese herbs, dietary restriction in established atopic eczema, homeopathy, house dust mite reduction, massage therapy, hypnotherapy, evening primrose oil, emollients, topical coal tar and topical doxepin. (ABSTRACT TRUNCATED)

Combination regimens of topical calcipotriene in chronic plaque psoriasis: systematic review of efficacy and tolerability.

OBJECTIVE: To examine the efficacy and tolerability of calcipotriene combined with phototherapy or systemic therapies compared with monotherapy for the treatment of chronic plaque psoriasis. DESIGN: Quantitative systematic review of 11 randomized controlled trials involving a total of 756 patients with plaque psoriasis. MAIN OUTCOME MEASURES: Rate ratios (RRs) for marked improvement or clearance in patient and investigator overall assessments of response; mean difference in percentage change in Psoriasis Area and Severity Index; and RRs for clearance in patient and investigator overall assessments of response. Adverse effects were estimated with the RR and the rate difference in terms of withdrawal rate, proportion of patients experiencing adverse events, and proportion of patients with cutaneous and noncutaneous adverse effects. RESULTS: Antipsoriatic effects of acitretin, cyclosporine, and psoralen-UV-A phototherapy were enhanced with the addition of topical calcipotriene using the Psoriasis Area and Severity Index as the outcome, but this is not translated into an increase in the number of patients who achieve at least marked improvement. At the end of treatment, the RRs for marked improvement or clearance in patient assessments were as follows: calcipotriene plus acitretin vs acitretin alone (12 weeks), 1.4 (95% confidence interval [CI], 1.0-1. 9); calcipotriene plus cyclosporine vs cyclosporine alone (6 weeks), 1.2 (95% CI, 0.9-1.6); and calcipotriene plus psoralen-UV-A vs psoralen-UV-A alone (12 weeks), 1.2 (95% CI, 0.9-1.6). Patients were also no more likely to obtain marked improvement or better with calcipotriene plus UV-B therapy than with UV-B therapy alone (RR, 1. 0; 95% CI, 0.8-1.1 at 8 weeks in the patient assessment). There is limited evidence that use of calcipotriene might reduce the cumulative exposure to phototherapy and systemic treatment. During the short duration of these trials, there were no significant differences in withdrawal rates or adverse effects between the combined regimens and their corresponding monotherapy control interventions. CONCLUSIONS: Overall, there is insufficient evidence to support any large effects in favor of combination treatment. In the patient assessments, the results do not show an adjuvant effect, but there is some evidence that use of calcipotriene might reduce cumulative exposure to systemic therapy to obtain clearance. There were no long-term morbidity data on the effectiveness of any of the combinations studied. Given that psoriasis is a chronic recurrent disease for most patients, longer trials are needed to determine whether the addition of topical calcipotriene to systemic therapy improves the risk-benefit ratio by reducing the long-term risk of toxic effects. Equally important is the need to examine the impact of such combinations on the duration of remission after treatment.

Cost-effectiveness analysis of topical calcipotriol versus short-contact dithranol. In the treatment of mild to moderate plaque psoriasis.

OBJECTIVE: To examine the relative cost effectiveness of topical calcipotriol and short-contact dithranol in the treatment of mild to moderate plaque psoriasis. DESIGN AND SETTING: This was a modelling study from the perspective of the UK National Health Service as payer. METHODS: The interventions were compared using 2 decision-analytic models: one using a short term horizon (12 weeks) and the other using a longer term horizon (up to 1 year). Clinical success of treatment and relapse rates were obtained from the results of randomised controlled trials. MAIN OUTCOME MEASURES AND RESULTS: The outcome measure used was the degree of improvement in psoriasis as judged by the patient. In the short term comparison, calcipotriol was the most effective treatment (60.8% success), but it was also the most expensive (96.03 Pounds; 2000 values). The incremental cost per success was 577.50 Pounds using a 12-week course of calcipotriol compared with short-contact dithranol. Over the long term horizon, first-line treatment with calcipotriol still had the highest expected cost per successful treatment (164.91 Pounds), but the incremental cost using this strategy was 38.66 Pounds compared with short-contact dithranol. In terms of cost per successful day's treatment (i.e. the cost for a day in which the patient reported a marked improvement or cleared lesions), the cost of each additional successful day's treatment was 19.93 Pounds when using calcipotriol as first-line treatment rather than short-contact dithranol. CONCLUSION: The combination of differences in drug acquisition costs and relapse rates can lead to large differences in the comparative cost effectiveness of topical treatments for plaque psoriasis. From the perspective of the prescriber, the results of this analysis suggest that selecting short-contact dithranol as first-line treatment was the most cost-effective strategy.

Kinetics of decomposition and formulation of hydrocortisone butyrate in semiaqueous and gel systems.

The stability of hydrocortisone butyrate in semiaqueous and formulated gel systems has been investigated. It was shown that hydrocortisone butyrate underwent reversible isomerization to the C-21 ester of butyric acid. This ester then hydrolyzed to hydrocortisone, which in turn degraded to a complex mixture of compounds. This step is metal catalyzed and can be inhibited by the addition of EDTA [disodium(ethylenedinitrilo)tetraacetate]. The kinetics of decomposition is modeled using nonlinear regression analysis, and the rate constants for the various decomposition pathways are quantified.

Flupenthixol dihydrochloride decomposition in aqueous solution.

Flupenthixol dihydrochloride in aqueous solution oxidized to trifluoromethylthioxanthone, ethanol, and piperazine via aldehydic and epoxidic intermediates in the presence of air. The formation rate of trifluoromethylthioxanthone increased with increases in pH and oxygen concentration. Buffer ions also affected the decomposition rate. Micelle formation by the drug markedly influenced its oxidation rate.

Solid-state stability of aspirin in the presence of excipients: kinetic interpretation, modeling, and prediction.

Salicylsalicylic acid and acetylsalicylsalicylic acid were identified as decomposition products of aspirin when mixtures of the drug, with magnesium stearate, were stored in the solid state of 60 degrees and 75% relative humidity. The effect of increasing the concentration of magnesium stearate and the addition of other alkali stearates on the rate of decomposition of aspirin were studied. The validity of the theory that pH changes induced by the alkali stearates account for the catalytic effect of the lubricants on the decomposition was tested. The changes observed were modeled and the mechanism involved elucidated. The potential use of the melting points of aspirin mixtures in predicting the stability of the drug in such drug-excipient mixtures is demonstrated.

Factors influencing decomposition rate of amitriptyline hydrochloride in aqueous solution.

The degradation rate of amitriptyline hydrochloride in buffered aqueous solution containing various additives was determined. The oxidation was a free radical-mediated process, and the rate was accelerated by the presence of metal-ion contaminants. Glass ampuls, particularly amber ones, in which the solutions were stored were the major source of these contaminants. Edetate disodium stabilized the solution, but the primary antioxidants propyl gallate and hydroquinone were less effective. Sodium metabisulfite accelerated the decomposition, and it is postulated that there was direct attack by metabisulfite at the olefinic double bond in the drug molecule.

Nonisothermal kinetics using a microcomputer: a derivative approach to the prediction of the stability of penicillin formulations.

A procedure is described for the determination of the shelf-life of pharmaceutical preparations using nonisothermal kinetics. A BASIC computer program, which enables the data analysis to be undertaken rapidly and automatically on a microcomputer, is presented.

Decomposition of amitriptyline hydrochloride in aqueous solution: identification of decomposition products.

The decomposition of amitriptyline hydrochloride upon autoclaving in a buffered solution (pH 6.8) was investigated. Three major decomposition products [3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, dibenzosuberone, and 3-(2-oxoethylidene)-1,2:4,5-dibenzocyclohepta-1,4-diene] were detected and identified by chromatographic and spectroscopic techniques. Evidence is presented that the latter two compounds are formed by further oxidation of 3-(propa-1,3-dienyl)-1,2:4,5-dibenzocyclohepta-1,4-diene, and a possible decomposition pathway is outlined.

Human albumin solution for resuscitation and volume expansion in critically ill patients.

BACKGROUND: Human albumin solutions are used in a range of medical and surgical problems. Licensed indications are the emergency treatment of shock and other conditions where restoration of blood volume is urgent, burns, and hypoproteinaemia. Human albumin solutions are more expensive than other colloids and crystalloids. OBJECTIVES: To quantify the effect on mortality of human albumin and plasma protein fraction (PPF) administration in the management of critically ill patients. SEARCH STRATEGY: We searched the Cochrane Injuries Group trials register, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE and BIDS Index to Scientific and Technical Proceedings. Reference lists of trials and review articles were checked, and authors of identified trials were contacted. The search was last updated in August 2004. SELECTION CRITERIA: Randomised controlled trials comparing albumin/PPF with no albumin/PPF, or with a crystalloid solution, in critically ill patients with hypovolaemia, burns or hypoalbuminaemia. DATA COLLECTION AND ANALYSIS: We collected data on the participants, albumin solution used, mortality at the end of follow up, and quality of allocation concealment. Analysis was stratified according to patient type. MAIN RESULTS: We found 32 trials meeting the inclusion criteria and reporting death as an outcome. There were 1632 deaths among 8452 trial participants. For hypovolaemia, the relative risk of death following albumin administration was 1.01 (95% confidence interval 0.92, 1.10). This estimate was heavily influenced by the results of the SAFE trial which contributed 91% of the information (based on the weights in the meta-analysis). For burns, the relative risk was 2.40 (1.11, 5.19) and for hypoalbuminaemia the relative risk was 1.38 (0.94, 2.03). There was no substantial heterogeneity between the trials in the various categories (chi-square = 21.86, df = 25, p =0.64). The pooled relative risk of death with albumin administration was 1.04 (0.95, 1.13). REVIEWERS' CONCLUSIONS: For patients with hypovolaemia there is no evidence that albumin reduces mortality when compared with cheaper alternatives such as saline. There is no evidence that albumin reduces mortality in critically ill patients with burns and hypoalbuminaemia. The possibility that there may be highly selected populations of critically ill patients in which albumin may be indicated remains open to question. However, in view of the absence of evidence of a mortality benefit from albumin and the increased cost of albumin compared to alternatives such as saline, it would seem reasonable that albumin should only be used within the context of well concealed and adequately powered randomised controlled trial.

Human albumin solution for resuscitation and volume expansion in critically ill patients. The Albumin Reviewers.

BACKGROUND: Human albumin solutions are used in a range of medical and surgical problems. Licensed indications are the emergency treatment of shock and other conditions where restoration of blood volume is urgent, burns, and hypoproteinaemia. Human albumin solutions are more expensive than other colloids and crystalloids. OBJECTIVES: To quantify the effect on mortality of human albumin and plasma protein fraction (PPF) administration in the management of critically ill patients. SEARCH STRATEGY: We searched the Cochrane Injuries Group trials register, Cochrane Controlled Trials Register, Medline, Embase and BIDS Index to Scientific and Technical Proceedings. Reference lists of trials and review articles were checked, and authors of identified trials were contacted. The search was last updated in November 1999. SELECTION CRITERIA: Randomised controlled trials comparing albumin/PPF with no albumin/PPF, or with a crystalloid solution, in critically ill patients with hypovolaemia, burns or hypoalbuminaemia. DATA COLLECTION AND ANALYSIS: We collected data on the participants, albumin solution used, mortality at the end of follow up, and quality of allocation concealment. Analysis was stratified according to patient type. We assessed publication bias using the regression test for funnel plot asymmetry. MAIN RESULTS: We found 30 trials meeting the inclusion criteria and reporting death as an outcome. There were 156 deaths among 1419 trial participants. For each patient category the risk of death in the albumin treated group was higher than in the comparison group. For hypovolaemia the relative risk of death following albumin administration was 1.46 (95% confidence interval 0.97 to 2.22), for burns the relative risk was 2.40 (1.11 to 5.19), and for hypoalbuminaemia the relative risk was 1.69 (1.07 to 2.67). The pooled relative risk of death with albumin administration was 1.68 (1.26 to 2.23). Overall, the risk of death in patients receiving albumin was 14% compared to 8% in the control groups, an increase in the risk of death of 6% (3% to 9%). These data suggest that for every 17 critically ill patients treated with albumin there is one additional death. REVIEWER'S CONCLUSIONS: There is no evidence that albumin administration reduces the risk of death in critically ill patients with hypovolaemia, burns or hypoalbuminaemia, and a strong suggestion that it may increase the risk of death. These data suggest that the use of human albumin in critically ill patients should be urgently reviewed and that it should not be used outside the context of a rigorously conducted randomised controlled trial.

Minocycline for acne vulgaris: efficacy and safety.

BACKGROUND: Minocycline is a tetracycline antibiotic that is commonly used in the treatment of moderate to severe acne vulgaris. Although it is more convenient for patients to take than first-generation tetracyclines, as it only needs to be taken once or twice a day and can be taken with food, it is more expensive. Concerns have also been expressed over its safety following the deaths of two patients taking the drug. There is a lack of consensus among dermatologists over the relative risks and benefits of minocycline. As most acne prescribing is undertaken by general practitioners, it is important that guidelines issued to them are based on the best available evidence rather than personal judgements. OBJECTIVES: To collate and evaluate the evidence on the clinical efficacy of minocycline in the treatment of inflammatory acne vulgaris. Specific objectives were to compare the efficacy of minocycline with other drug treatments for acne and to collate information on the incidence of adverse drug reactions. SEARCH STRATEGY: Randomised controlled trials (RCTs) of minocycline for acne vulgaris were identified by searching the following electronic databases; MEDLINE, EMBASE, Biosis, Biological Abstracts, International Pharmaceutical Abstracts, Cochrane Skin Group's Trial Register, Theses Online, BIDS ISI Science Citation Index and Bids Index to Scientific and Technical Proceedings. Other strategies used were scanning the references of articles retrieved, hand-searching of major dermatology journals and personal communication with trialists and drug companies. SELECTION CRITERIA: To be eligible for the review, studies had to be RCTs comparing the efficacy of minocycline at any dose to active or placebo control, in subjects with inflammatory acne vulgaris. Diagnoses of papulo-pustular, polymorphic and nodular acne were also accepted. Trials were not excluded on the basis of language. DATA COLLECTION AND ANALYSIS: 27 randomised controlled trials met the inclusion criteria and were included in this review. The comparators used were placebo (2 studies), oxytetracycline (1), tetracycline (6), doxycycline (7), lymecycline (2), topical clindamycin (3), topical erythromycin/zinc (1), cyproterone acetate/ ethinyloestradiol (1), oral isotretinoin (2), topical fusidic acid (1) and there was one dose response study. One study is ongoing and it remains to be clarified whether one further study is a RCT. Major outcome measures used in the trials included lesion counts, acne grades/severity scores, doctors' and patients' global assessments, adverse drug reactions and drop out rates. The quality of each study was assessed independently by two assessors and an effect size calculated where possible. MAIN RESULTS: The trials were generally small and of poor quality and in many cases the published reports were inadequate for our purpose. Pooling of the studies was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data. Although minocycline was shown to be an effective treatment for acne vulgaris, in only two studies was it found to be superior to other tetracyclines. Both of these were conducted under open conditions and had serious methodological problems. A third study showed it to be more effective than 2% fusidic acid, applied topically, against inflammatory lesions in mild to moderate acne. Differences in the way adverse drug reactions were identified could have accounted for the wide variation between studies in numbers of events reported. This meant that no overall evaluation could be made of incidence rates of adverse events associated with minocycline therapy. No RCT evidence was found to support the benefits of minocycline in acne resistant to other therapies and the dose response has only been evaluated up to eight weeks of therapy. (ABSTRACT TRUNCATED)

Human albumin solution for resuscitation and volume expansion in critically ill patients.

BACKGROUND: Human albumin solutions are used in a range of medical and surgical problems. Licensed indications are the emergency treatment of shock and other conditions where restoration of blood volume is urgent, burns, and hypoproteinaemia. Human albumin solutions are more expensive than other colloids and crystalloids. OBJECTIVES: To quantify the effect on mortality of human albumin and plasma protein fraction (PPF) administration in the management of critically ill patients. SEARCH STRATEGY: We searched the Cochrane Injuries Group trials register, Cochrane Controlled Trials Register, Medline, Embase and BIDS Index to Scientific and Technical Proceedings. Reference lists of trials and review articles were checked, and authors of identified trials were contacted. The search was last updated in November 2001. SELECTION CRITERIA: Randomised controlled trials comparing albumin/PPF with no albumin/PPF, or with a crystalloid solution, in critically ill patients with hypovolaemia, burns or hypoalbuminaemia. DATA COLLECTION AND ANALYSIS: We collected data on the participants, albumin solution used, mortality at the end of follow up, and quality of allocation concealment. Analysis was stratified according to patient type. MAIN RESULTS: We found 31 trials meeting the inclusion criteria and reporting death as an outcome. There were 177 deaths among 1519 trial participants. For each patient category the risk of death in the albumin treated group was higher than in the comparison group. For hypovolaemia the relative risk of death following albumin administration was 1.46 (95% confidence interval 0.97 to 2.22), for burns the relative risk was 2.40 (1.11 to 5.19), and for hypoalbuminaemia the relative risk was 1.38 (0.94 to 2.03). The pooled relative risk of death with albumin administration was 1.52 (1.17 to 1.99). Overall, the risk of death in patients receiving albumin was 14% compared to 9% in the control groups, an increase in the risk of death of 5% (2% to 8%). These data suggest that for every 20 critically ill patients treated with albumin there is one additional death. REVIEWER'S CONCLUSIONS: There is no evidence that albumin administration reduces the risk of death in critically ill patients with hypovolaemia, burns or hypoalbuminaemia, and a strong suggestion that it may increase the risk of death. These data suggest that the use of human albumin in critically ill patients should be urgently reviewed and that it should not be used outside the context of a rigorously conducted randomised controlled trial.

Transesterification: an analytical and formulation problem.

A range of esters including salicylates, nicotinates and parabens have been shown to undergo reversible, base-catalysed transesterification in hydroalcoholic solutions. In non-alcoholic solution phenyl salicylate undergoes a concentration-dependent oligomerization which yields salsalate and other products. The transesterification reactions also occur in products formulated for topical use, which have vehicles based upon alcohol, glycol or glycol polymers. Without recognition, such reactions may compromise stability assessments, pharmaceutical integrity and delivery profiles.