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Human Vaccines & Immunotherapeutics 2016Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a... (Review)
Review
Montanide ISA™51 (ISA 51) is a vaccine adjuvant which has been tested in therapeutic and prophylactic vaccine trials. The aim of this review is to present a comprehensive examination of the safety and tolerability of ISA 51 containing vaccines. A systematic literature search was conducted in PubMed, EMBASE and clinicaltrials.gov . Eligible studies were categorized into: (A) uncontrolled studies with non-healthy subjects, (B) controlled studies with non-healthy subjects, and (C) controlled studies with healthy subjects. Reported adverse events (AEs) were assessed. 91 studies were included in our review. Generally observed AEs included injection site reaction; injection site pain; myalgia; headache; gastro-intestinal disorders; fatigue and fever - regardless of the administration route and subject characteristic. Specific AEs, e.g. injection site reactions and rash, were more frequently reported from subjects receiving ISA 51-adjuvanted vaccines than from subjects receiving antigen or ISA 51 only. The reported AEs were mainly mild to moderate in intensity. Serious AEs (SAEs) were reported in 27% of the uncontrolled trials and 2 trials conducted with healthy subjects. Notably, 2 other trials conducted with healthy subjects were stopped due to unacceptable AEs. Some studies indicate that the mixing procedure of antigen and adjuvant might influence the occurrence of AEs. Reports on SAEs and premature termination of 2 trials advise caution when using ISA 51. Yet, AEs might be preventable by proper mixing of vaccine and adjuvant to a stable emulsion. Trials including an active control group are needed for a fair evaluation of adjuvant safety.
Topics: Adjuvants, Immunologic; Drug-Related Side Effects and Adverse Reactions; Fatigue; Fever; Gastrointestinal Diseases; Headache; Humans; Mannitol; Oleic Acids; Pain; Skin Diseases; Vaccines
PubMed: 26378866
DOI: 10.1080/21645515.2015.1071455 -
The Cochrane Database of Systematic... Apr 2015Rosacea is a common chronic skin condition affecting the face, characterised by flushing, redness, pimples, pustules and dilated blood vessels. The eyes are often... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rosacea is a common chronic skin condition affecting the face, characterised by flushing, redness, pimples, pustules and dilated blood vessels. The eyes are often involved and thickening of the skin with enlargement (phymas), especially of the nose, can occur in some people. A range of treatment options are available but it is unclear which are most effective.
OBJECTIVES
To assess the efficacy and safety of treatments for rosacea.
SEARCH METHODS
We updated our searches, to July 2014, of: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 6), MEDLINE (from 1946), EMBASE (from 1974) and Science Citation Index (from 1988). We searched five trials registers and checked reference lists for further relevant studies.
SELECTION CRITERIA
Randomised controlled trials in people with moderate to severe rosacea.
DATA COLLECTION AND ANALYSIS
Study selection, data extraction, risk of bias assessment and analyses were carried out independently by two authors.
MAIN RESULTS
We included 106 studies, comprising 13,631 participants. Sample sizes of 30-100 and study duration of two to three months were most common. More women than men were included, mean age of 48.6 years, and the majority had papulopustular rosacea, followed by erythematotelangiectatic rosacea.A wide range of comparisons (67) were evaluated. Topical interventions: metronidazole, azelaic acid, ivermectin, brimonidine or other topical treatments. Systemic interventions: oral antibiotics, combinations with topical treatments or other systemic treatments, i.e. isotretinoin. Several studies evaluated laser or light-based treatment.The majority of studies (57/106) were assessed as 'unclear risk of bias', 37 'high risk ' and 12 'low risk'. Twenty-two studies provided no usable or retrievable data i.e. none of our outcomes were addressed, no separate data reported for rosacea or limited data in abstracts.Eleven studies assessed our primary outcome 'change in quality of life', 52 studies participant-assessed changes in rosacea severity and almost all studies addressed adverse events, although often only limited data were provided. In most comparisons there were no statistically significant differences in number of adverse events, most were mild and transient. Physician assessments including investigators' global assessments, lesion counts and erythema were evaluated in three-quarters of the studies, but time needed for improvement and duration of remission were incompletely or not reported.The quality of the body of evidence was rated moderate to high for most outcomes, but for some outcomes low to very low.Data for several outcomes could only be pooled for topical metronidazole and azelaic acid. Both were shown to be more effective than placebo in papulopustular rosacea (moderate quality evidence for metronidazole and high for azelaic acid). Pooled data from physician assessments in three trials demonstrated that metronidazole was more effective compared to placebo (risk ratio (RR) 1.98, 95% confidence interval (CI) 1.29 to 3.02). Four trials provided data on participants' assessments, illustrating that azelaic acid was more effective than placebo (RR 1.46, 95% CI 1.30 to 1.63). The results from three studies were contradictory on which of these two treatments was most effective.Two studies showed a statistically significant and clinically important improvement in favour of topical ivermectin when compared to placebo (high quality evidence). Participants' assessments in these studies showed a RR of 1.78 (95% CI 1.50 to 2.11) and RR of 1.92 (95% CI 1.59 to 2.32),which were supported by physicians' assessments. Topical ivermectin appeared to be slightly more effective than topical metronidazole for papulopustular rosacea, based on one study, for improving quality of life and participant and physician assessed outcomes (high quality evidence for these outcomes).Topical brimonidine in two studies was more effective than vehicle in reducing erythema in rosacea at all time points over 12 hours (high quality evidence). At three hours the participants' assessments had a RR of 2.21 (95% CI 1.52 to 3.22) and RR of 2.00 (95% CI 1.33 to 3.01) in favour of brimonidine. Physicians' assessments confirmed these data. There was no rebound or worsening of erythema after treatment cessation.Topical clindamycin phosphate combined with tretinoin was not considered to be effective compared to placebo (moderate quality evidence).Topical ciclosporin ophthalmic emulsion demonstrated effectiveness and improved quality of life for people with ocular rosacea (low quality evidence).Of the comparisons assessing oral treatments for papulopustular rosacea there was moderate quality evidence that tetracycline was effective but this was based on two old studies of short duration. Physician-based assessments in two trials indicated that doxycycline appeared to be significantly more effective than placebo (RR 1.59, 95% CI 1.02 to 2.47 and RR 2.37, 95% CI 1.12 to 4.99) (high quality evidence). There was no statistically significant difference in effectiveness between 100 mg and 40 mg doxycycline, but there was evidence of fewer adverse effects with the lower dose (RR 0.25, 95% CI 0.11 to 0.54) (low quality evidence). There was very low quality evidence from one study (assessed at high risk of bias) that doxycycline 100 mg was as effective as azithromycin. Low dose minocycline (45 mg) was effective for papulopustular rosacea (low quality evidence).Oral tetracycline was compared with topical metronidazole in four studies and showed no statistically significant difference between the two treatments for any outcome (low to moderate quality evidence).Low dose isotretinoin was considered by both the participants (RR 1.23, 95% CI 1.05 to 1.43) and physicians (RR 1.18, 95% CI 1.03 to 1.36) to be slightly more effective than doxycycline 50-100 mg (high quality evidence).Pulsed dye laser was more effective than yttrium-aluminium-garnet (Nd:YAG) laser based on one study, and it appeared to be as effective as intense pulsed light therapy (both low quality evidence).
AUTHORS' CONCLUSIONS
There was high quality evidence to support the effectiveness of topical azelaic acid, topical ivermectin, brimonidine, doxycycline and isotretinoin for rosacea. Moderate quality evidence was available for topical metronidazole and oral tetracycline. There was low quality evidence for low dose minocycline, laser and intense pulsed light therapy and ciclosporin ophthalmic emulsion for ocular rosacea. Time needed to response and response duration should be addressed more completely, with more rigorous reporting of adverse events. Further studies on treatment of ocular rosacea are warranted.
Topics: Anti-Infective Agents; Brimonidine Tartrate; Cyclosporine; Dermatologic Agents; Dicarboxylic Acids; Doxycycline; Female; Humans; Ivermectin; Male; Metronidazole; Middle Aged; Ophthalmic Solutions; Quinoxalines; Randomized Controlled Trials as Topic; Rosacea; Tetracycline
PubMed: 25919144
DOI: 10.1002/14651858.CD003262.pub5 -
Clinical Toxicology (Philadelphia, Pa.) Nov 2014Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. (Review)
Review
CONTEXT
Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion.
OBJECTIVE
To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations.
METHODS
Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types.
RESULTS
The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5-2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue.
CONCLUSIONS
The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.
Topics: Animals; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Overdose; Guidelines as Topic; Hospitalization; Humans; Insulin; Length of Stay; Observational Studies as Topic; Treatment Outcome; Vasoconstrictor Agents
PubMed: 25283255
DOI: 10.3109/15563650.2014.965827 -
Intensive Care Medicine Oct 2013Parenteral lipid emulsions (LEs) are commonly rich in long-chain triglycerides derived from soybean oil (SO). SO-containing emulsions may promote systemic inflammation... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Parenteral lipid emulsions (LEs) are commonly rich in long-chain triglycerides derived from soybean oil (SO). SO-containing emulsions may promote systemic inflammation and therefore may adversely affect clinical outcomes. We hypothesized that alternative oil-based LEs (SO-sparing strategies) may improve clinical outcomes in critically ill adult patients compared to products containing SO emulsion only. The purpose of this systematic review was to evaluate the effect of parenteral SO-sparing strategies on clinical outcomes in intensive care unit (ICU) patients.
METHODS
We searched computerized databases from 1980 to 2013. We included randomized controlled trials (RCTs) conducted in critically ill adult patients that evaluated SO-sparing strategies versus SO-based LEs in the context of parenteral nutrition.
RESULTS
A total of 12 RCTs met the inclusion criteria. When the results of these RCTs were statistically aggregated, SO-sparing strategies were associated with clinically important reductions in mortality (risk ratio, RR 0.83; 95 % confidence intervals, CI 0.62, 1.11; P = 0.20), in duration of ventilation (weighted mean difference, WMD -2.57; 95 % CI -5.51, 0.37; P = 0.09), and in ICU length of stay (LOS) (WMD -2.31; 95 % CI -5.28, 0.66; P = 0.13) but none of these differences were statistically significant. SO-sparing strategies had no effect on infectious complications (RR 1.13; 95 % CI 0.87, 1.46; P = 0.35).
CONCLUSION
Alternative oil-based LEs may be associated with clinically important reductions in mortality, duration of ventilation, and ICU LOS but lack of statistical precision precludes any clinical recommendations at this time. Further research is warranted to confirm these potential positive treatment effects.
Topics: Adult; Critical Illness; Databases, Bibliographic; Emulsions; Fat Emulsions, Intravenous; Fish Oils; Humans; Immune System; Inflammation; Intensive Care Units; Lecithins; Oxidative Stress; Parenteral Nutrition; Phospholipids; Plant Oils; Randomized Controlled Trials as Topic; Safflower Oil; Soybean Oil; Treatment Outcome; Triglycerides
PubMed: 23812404
DOI: 10.1007/s00134-013-2999-4 -
Academic Emergency Medicine : Official... Sep 2009The objective was to asses the efficacy of lipid emulsion as antidotal therapy outside the accepted setting of local anesthetic toxicity. (Review)
Review
OBJECTIVES
The objective was to asses the efficacy of lipid emulsion as antidotal therapy outside the accepted setting of local anesthetic toxicity.
METHODS
Literature was accessed through PubMed, OVID (1966-February 2009), and EMBASE (1947-February 2009) using the search terms "intravenous" AND ["fat emulsion" OR "lipid emulsion" OR "Intralipid"] AND ["toxicity" OR "resuscitation" OR "rescue" OR "arrest" OR "antidote"]. Additional author and conference publication searches were undertaken. Publications describing the use of lipid emulsion as antidotal treatment in animals or humans were included.
RESULTS
Fourteen animal studies, one human study, and four case reports were identified. In animal models, intravenous lipid emulsion (ILE) has resulted in amelioration of toxicity associated with cyclic antidepressants, verapamil, propranolol, and thiopentone. Administration in human cases has resulted in successful resuscitation from combined bupropion/lamotrigine-induced cardiac arrest, reversal of sertraline/quetiapine-induced coma, and amelioration of verapamil- and beta blocker-induced shock.
CONCLUSIONS
Management of overdose with highly lipophilic cardiotoxic medications should proceed in accord with established antidotal guidelines and early poisons center consultation. Data from animal experiments and human cases are limited, but suggestive that ILE may be helpful in potentially lethal cardiotoxicity or developed cardiac arrest attributable to such agents. Use of lipid emulsion as antidote remains a nascent field warranting further preclinical study and systematic reporting of human cases of use.
Topics: Adrenergic beta-Antagonists; Animals; Antidepressive Agents; Antidotes; Cardiotoxins; Drug Overdose; Fat Emulsions, Intravenous; Heart Arrest; Humans
PubMed: 19845549
DOI: 10.1111/j.1553-2712.2009.00499.x