Combined oral lysine acetylsalicylate and metoclopramide in the acute treatment of migraine: a multicentre double-blind placebo-controlled study

This multicentre, double-blind, randomized, placebo-controlled, parallel study was designed to evaluate the efficacy of combined oral lysine acetylsalicylate and metoclopramide (LAS-MCP) in the acute treatment of migraine attacks. A total of 266 patients, 18–65 years old, with two to six attacks of migraine with or without aura (IHS criteria) per month were included. The patients had to treat two migraine attacks with LAS-MCP (1620 mg lysine acetylsalicylate-the equivalent of 900 mg aspirin- combined with 10 mg metoclopramide) or placebo. The main outcome measure was headache relief (reduction in headache severity from grade 3 or 2-severe or moderate-to grade 1 or 0-mild or none) 2 h after treatment. LAS-MCP was superior to placebo for headache relief (56% vs 28%) and for the following secondary outcome measures: complete headache relief (18% vs 7%; p < 0.001), nausea (28% vs 44%; p < 0.001), vomiting (3% vs 11%; p = 0.001), use of rescue medication (47% vs 68%; p < 0.001), global efficacy judged as good or excellent (32% vs 14%; p < 0.001). The tolerability was considered as good in 94% of treated attacks in both groups. Combined oral lysine acetylsalicylate and metoclopramide is an effective and well-tolerated acute treatment of migraine attacks.     

Transmission of hepatitis G virus in patients with angioedema treated with steam-heated plasma concentrates of C1 inhibitor

BACKGROUND: Hepatitis G virus (HGV) is a blood-borne flavivirus that may cause acute and chronic transfusion-transmitted infections. Patients with complement component 1 (C1) inhibitor (C1-INH) deficiency may acquire blood-borne infections through infusion of plasma concentrates. STUDY DESIGN AND METHODS: Serum samples from 84 patients with C1-INH deficiency (19 who received unmodified C1-INH concentrates, 23 who received steam-heated concentrates, and 42 untreated patients) were tested for HGV RNA and hepatitis C virus (HCV) RNA by a nested polymerase chain reaction (PCR). The samples were also tested for antibodies to the E2 envelope protein of HGV (anti-HGV) and to HCV with enzyme-linked immunosorbent assays. RESULTS: Nine (11%) patients had serum HGV RNA; that is, 7 (17%) of 42 patients previously treated with C1-INH concentrates and 2 of 42 previously untreated patients. HGV RNA was as common in the 19 patients treated with unmodified concentrates as in the 23 given steam-heated concentrates (16 vs. 17%, p = 0.60). Anti-HGV was more common among the recipients of unmodified concentrates than among those given steam-heated concentrates (26 vs. 0%, p = 0.014). HCV RNA was more frequently detected in treated patients than in untreated patients (33 vs. 7%, p = 0.005) and in the 19 recipients of unmodified concentrates than in the 23 treated with steam-heated concentrates (58 vs. 16%, p = 0.003). Only one HGV RNA- seropositive patient had elevated serum aminotransferase activity, compared to 11 with HCV RNA. CONCLUSION: HGV was transmitted by both unmodified and steam-heated concentrates, but it caused persistent viremia in a minority of the cases and was rarely associated with liver disease.     

Health system costs of in-hospital cardiac arrest

This paper reports on the health system resources used in the treatment of in-hospital cardiac arrests in a British district general hospital. The resources used in resuscitation attempts were recorded prospectively by observation of a convenience sample of 30 cardiac arrests. The post-resuscitation resource use by survivors was collected through a retrospective record review (n = 37) and by following survivor members in the prospective sample (n = 6). Financial data were used to translate resource use into costs (1999 prices). There was a non-significant trend for more resources to be used in daytime resuscitations than at night. Survivors had significantly fewer diagnostic tests during resuscitation than those who died (P = 0.004). Length of resuscitation attempt was positively and significantly related to resource use (P < 0.05). The average variable cost per resuscitation attempt (1999 prices) was 195.66 pounds sterling; 76.5% was for staff, and 13.1% for drugs and fluids. Emergency calls were attended by an average of 10.11 staff. The average fixed cost per resuscitation attempt was 928.81 pounds sterling; 12% for capital equipment and 73% for staff training. The average post-resuscitation costs attributable to the cardiac arrest of the 29 people surviving more than 24 h after cardio-pulmonary resuscitation (CPR) were estimated to be 1,589.72 pounds sterling. This is lower than other studies which estimated total costs of post-CPR lengths of stay. Reducing avoidable cardiac arrests would generate in-hospital savings in direct resuscitation care of survivors. Scope for reducing capital and training costs is discussed.     

Antimicrobial efficacy of silver ions in combination with tea tree oil against Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans

Tea tree oil (TTO) and silver ions (Ag(+)), either alone or in combination with other antimicrobial compounds, have been used in the treatment of topical infections. However, there appears to be little data on the efficacy of TTO combined with silver in the absence of any other agents. TTO and Ag(+) were added, alone and in combination, to suspension cultures of Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Treatment of these cultures with TTO and Ag(+) at sub-minimal lethal concentrations resulted in an enhanced loss of viability compared with treatment with individual agents. The order of sensitivity to the combined agents was P. aeruginosa>S. aureus>C. albicans. The fractional lethal concentration index (FLCI) showed that these combinations of TTO and Ag(+) exerted a synergistic effect against P. aeruginosa (FLCI=0.263) and an indifferent effect against S. aureus and C. albicans (FLCI=0.663 and 1.197, respectively). The results indicate that combining these antimicrobial agents may be useful in decreasing the concentration of antimicrobial agents required to achieve an effective reduction in opportunistic pathogenic microorganisms that typically infect wounds.     

Doubly robust and multiple-imputation-based generalized estimating equations

Generalized estimating equations (GEE), proposed by Liang and Zeger (1986), provide a popular method to analyze correlated non-Gaussian data. When data are incomplete, the GEE method suffers from its frequentist nature and inferences under this method are valid only under the strong assumption that the missing data are missing completely at random. When response data are missing at random, two modifications of GEE can be considered, based on inverse-probability weighting or on multiple imputation. The weighted GEE (WGEE) method involves weighting observations by the inverse of their probability of being observed. Imputation methods involve filling in missing observations with values predicted by an assumed imputation model, multiple times. The so-called doubly robust (DR) methods involve both a model for the weights and a predictive model for the missing observations given the observed ones. To yield consistent estimates, WGEE needs correct specification of the dropout model while imputation-based methodology needs a correctly specified imputation model. DR methods need correct specification of either the weight or the predictive model, but not necessarily both. Focusing on incomplete binary repeated measures, we study the relative performance of the singly robust and doubly robust versions of GEE in a variety of correctly and incorrectly specified models using simulation studies. Data from a clinical trial in onychomycosis further illustrate the method.     

Effect of tecarfarin,a novel vitamin K epoxide reductase inhibitor,on coagulation in beagle dogs

Background and purpose:

Tecarfarin (ATI-5923) is a novel vitamin K epoxide reductase inhibitor that is metabolized by esterase (mainly human carboxylesterase 2) to a single major metabolite, ATI-5900, in rats, dogs and humans. Tecarfarin is not significantly metabolized by CYP450 enzymes. The objective of this study was to test and compare the efficacy of tecarfarin with that of warfarin, when administered either intravenously or once a day orally, to produce stable anticoagulation in beagle dogs.

Experimental approach:

Effects on coagulation were assessed by measuring the activity levels of Factor VII and Factor X and thromboplastin-induced coagulation times, reported as prothrombin time (PT).

Key results:

Continuous intravenous infusions and oral administration of tecarfarin and warfarin caused a dose-dependent decrease in activity of Factor VII and Factor X, and associated increase in PT. Intravenous fresh frozen canine plasma or subcutaneous vitamin K₁ treatment reversed the anticoagulant effects of orally administered tecarfarin. Consistent with the inhibitory effects of amiodarone on CYP2C9, co-administration of amiodarone significantly increased the anticoagulation effect of warfarin and plasma warfarin concentrations. In contrast, amiodarone had no effect on the anticoagulation induced by tecarfarin or tecarfarin plasma concentrations in this model.

Conclusions and implications:

Overall, the data presented herein indicate that tecarfarin, via a vitamin K-dependent mechanism, causes changes in key parameters of haemostasis in beagle dogs that are consistent with effective anticoagulation. Compared to warfarin it has a decreased potential to interact metabolically with drugs that inhibit CYP450 enzymes and, therefore, may offer an improved safety profile for patients.     

Last Observation Carried Forward: A Crystal Ball?

In spite of widespread criticism and notwithstanding the availability of flexible, broadly valid, and conveniently implemented methods like direct-likelihood and direct-Bayesian analyses, last observation carried forward (LOCF), baseline observation carried forward (BOCF), and complete case analysis remain popular for handling incomplete clinical trial data. To the well-known criticisms toward LOCF and BOCF, namely, that they can be either conservative or liberal depending on the context, that they can violate the intention-to-treat principle, and so on, we add that, with the exception of certain degenerate and unrealistic special cases, these methods are incompatible with the sensible requirement that the mechanism governing dropout be independent of future, unobserved measurements, given covariates, past observed measurements, and the current possibly missing measurement.