Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in nonimmune populations: a safety, efficacy, and pharmacokinetic study.

The efficacy and safety of artemether-lumefantrine for the treatment of malaria in nonimmune populations are not well defined. In this study, 165 nonimmune patients from Europe and non-malarious areas of Colombia with acute, uncomplicated falciparum malaria or mixed infection including P. falciparum were treated with the six-dose regimen of artemether-lumefantrine. The parasitologic cure rate at 28 days was 96.0% for the per protocol population (119/124 patients). Median times to parasite clearance and fever clearance were 41.5 and 36.8 hours, respectively. No patient had gametocytes after Day 7. Treatment was well tolerated; most adverse events were mild to moderate and seemed to be related to malaria. There were few serious adverse events, none of which were considered to be drug-related. No significant effects on ECG or laboratory parameters were observed. In conclusion, the six-dose regimen of artemether-lumefantrine was effective and well tolerated in the treatment of acute uncomplicated falciparum malaria in nonimmune patients.

The inhibition of MAPK potentiates the anti-angiogenic efficacy of mTOR inhibitors.

The mammalian target of rapamycin (mTOR) which is part of two functionally distinct complexes, mTORC1 and mTORC2, plays an important role in vascular endothelial cells. Indeed, the inhibition of mTOR with an allosteric inhibitor such as rapamycin reduces the growth of endothelial cell in vitro and inhibits angiogenesis in vivo. Recent studies have shown that blocking mTOR results in the activation of other prosurvival signals such as Akt or MAPK which counteract the growth inhibitory properties of mTOR inhibitors. However, little is known about the interactions between mTOR and MAPK in endothelial cells and their relevance to angiogenesis. Here we found that blocking mTOR with ATP-competitive inhibitors of mTOR or with rapamycin induced the activation of the mitogen-activated protein kinase (MAPK) in endothelial cells. Downregulation of mTORC1 but not mTORC2 had similar effects showing that the inhibition of mTORC1 is responsible for the activation of MAPK. Treatment of endothelial cells with mTOR inhibitors in combination with MAPK inhibitors reduced endothelial cell survival, proliferation, migration and tube formation more significantly than either inhibition alone. Similarly, in a tumor xenograft model, the anti-angiogenic efficacy of mTOR inhibitors was enhanced by the pharmacological blockade of MAPK. Taken together these results show that blocking mTORC1 in endothelial cells activates MAPK and that a combined inhibition of MAPK and mTOR has additive anti-angiogenic effects. They also provide a rationale to target both mTOR and MAPK simultaneously in anti-angiogenic treatment.

Efficacy of the barbecue manoeuvre in benign paroxysmal vertigo of the horizontal canal

Five to ten percent of benign paroxysmal positional vertigo are caused by the horizontal semi-circular variant (h-BPPV). In this study, we reviewed the efficacy of the Barbecue repositioning manoeuvre in h-BPPV, and we assessed the possible effect of different factors on the outcome. Barbecue manoeuvre consists in turning the supine patient around his longitudinal axis toward the unaffected side until 360 degrees are accomplished. After every 90 degrees step the patient is maintained in the new position for 30 s. We reviewed 46 patients with h-BPPV, treated by barbecue rotation from 2003 to 2005. After the first Barbecue manoeuvre, the patients were followed-up at intervals of approximately 1 week and the rotation was repeated if h-BPPV persisted (up to three rotations). Factors assessed were age, gender, duration of symptoms before treatment and type of h-BPPV (canalolithiasis vs. cupulolithiasis). Fisher's exact test was used for the analysis. Results: 85% of patients (39/46) were cured after a maximum of 3 rotations. 74% (34/46) were cured after the first manoeuvre and 80% (37/46) after the second one. None of the evaluated factors did significantly affect the efficacy (P > 0.05). The Barbecue manoeuvre is an efficient treatment of h-BPPV demonstrating 85% cure rate after a maximum of three sessions. 74% of the patients are healed after one manoeuvre. The efficacy is not affected by the evaluated factors.

Positional therapy for obstructive sleep apnea: an objective measurement of patients' usage and efficacy at home.

BACKGROUND: Positional therapy that prevents patients from sleeping supine has been used for many years to manage positional obstructive sleep apnea (OSA). However, patients' usage at home and the long term efficacy of this therapy have never been objectively assessed.¦METHODS: Sixteen patients with positional OSA who refused or could not tolerate continuous positive airway pressure (CPAP) were enrolled after a test night study (T0) to test the efficacy of the positional therapy device. The patients who had a successful test night were instructed to use the device every night for three months. Nightly usage was monitored by an actigraphic recorder placed inside the positional device. A follow-up night study (T3) was performed after three months of positional therapy.¦RESULTS: Patients used the device on average 73.7 ± 29.3% (mean ± SD) of the nights for 8.0 ± 2.0 h/night. 10/16 patients used the device more than 80% of the nights. Compared to the baseline (diagnostic) night, mean apnea-hypopnea index (AHI) decreased from 26.7 ± 17.5 to 6.0 ± 3.4 with the positional device (p<0.0001) during T0 night. Oxygen desaturation (3%) index also fell from 18.4 ± 11.1 to 7.1 ± 5.7 (p = 0.001). Time spent supine fell from 42.8 ± 26.2% to 5.8 ± 7.2% (p < 0.0001). At three months (T3), the benefits persisted with no difference in AHI (p = 0.58) or in time spent supine (p = 0.98) compared to T0 night. The Epworth sleepiness scale showed a significant decrease from 9.4 ± 4.5 to 6.6 ± 4.7 (p = 0.02) after three months.¦CONCLUSIONS: Selected patients with positional OSA can be effectively treated by a positional therapy with an objective compliance of 73.7% of the nights and a persistent efficacy after three months.

Efficacy of brief motivational intervention in reducing binge drinking in young men: A randomized controlled trial.

Background: Brief motivational intervention (BMI) is one of the few effective strategies targeting alcohol consumption, but has not been tested in young men in the community. We evaluated the efficacy of BMI in reducing alcohol use and related problems among binge drinkers and in maintaining low-risk drinking among non-bingers. Methods: A random sample of a census of men included during army conscription (which is mandatory for 20-year-old males in Switzerland) was randomized to receive a single face-to-face BMI session (N = 199) or no intervention (N = 219). A six-month follow-up rate was obtained for 88.7% of the subjects. Results: Among binge drinkers, there was 20% less drinking in the BMI group versus the control group (incidence rate ratio = 0.80, confidence interval 0.66-0.98, p = 0.03): the BMI group showed a weekly reduction of 1.5 drinks compared to an increase of 0.8 drinks weekly in the control group. Among subjects who experienced one or more alcohol-related consequences over the last 12 months, there was 19% less drinking in the BMI group compared to the control group (incidence rate ratio = 0.81; confidence interval 0.67-0.97, p = 0.04). Among non-bingers, BMI did not contribute to the maintenance of low-risk drinking. Conclusion: BMI reduced the alcohol use of binge drinkers, particularly among those who experienced certain alcohol-related adverse consequences. No preventive effect of BMI was observed among non-bingers. BMI is a plausible secondary preventive option for young binge drinkers. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study.

This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence. One hundred eighteen patients were randomly assigned to either placebo or acamprosate, and both groups were stratified for concomitant voluntary use of disulfiram. Treatment lasted for 360 days, with an additional 360-day follow-up period. The primary efficacy parameters evaluated were: relapse rate and cumulative abstinence duration (CAD). Results were analyzed according to Intention-To-Treat principles using chi2, t, and multiple regression analyses where appropriate. After 30 days on study medication, 40 of 55 (73%) acamprosate-treated patients were abstinent, compared with 26 of 55 (43%) placebo-treated patients (p = 0.019). The treatment advantage remained throughout the study medication period and was statistically significant until day 270 (p = 0.028). Twenty-seven percent of patients on acamprosate and 53% of patients on placebo had a first drink within the first 30 days of the study. The mean CAD was 137 days (40% abstinent days) for the patients treated with acamprosate and 75 days (21% abstinent days) for the placebo group (p = 0.013). No adverse interaction between acamprosate and disulfiram occurred, and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication. Acamprosate was well tolerated. Diarrhea was the only significant treatment-induced effect. It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism. Concomitant administration of disulfiram improved the effectiveness of acamprosate.

The efficacy of a protective cream in a real-world apprentice hairdresser environment.

The object of this study was to compare the protective action of a new barrier cream (Excipial Protect, Spirig Pharma AG, Egerkingen, Switzerland) to its vehicle in the context of hand irritation of apprentice hairdressers caused by repeated shampooing and exposure to hair-care products. This was a double-blind cross-over comparing Excipial Protect (containing aluminium chlorohydrate 5% as active ingredient) against its vehicle alone. The efficacy of the creams was evaluated taking into account: (1) clinical scores by researchers, (2) biometric measurements, (3) subjective opinions of the subjects. An analysis of variance was performed considering order of application, degree of atopy, and reported number of shampoos. We observed very little difference in efficacy between the protective cream and its vehicle. The presence, however, of aluminium chlorhydrate in the protective cream was shown to have a positive effect against work-related irritation. The cosmetic qualities of the creams seemed, to the participants, to be as important as their real protective and hydrating properties, an important factor in compliance issues.

Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

Genetic polymorphisms and drug interactions modulating CYP2D6 and CYP3A activities have a major effect on oxycodone analgesic efficacy and safety

Background and purpose: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. Experimental approach: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg·kg−1) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. Key results: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone Cmax was correlated with SPT assessment (ρS= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. Conclusions and implications: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

Efficacy of levofloxacin in the treatment of experimental endocarditis caused by viridans group streptococci.

Levofloxacin was investigated against viridans group streptococci in vitro and in rats with experimental aortic endocarditis. The MIC(90)s of levofloxacin and ciprofloxacin for 20 independent isolates of such bacteria were 1 and 8 mg/L, respectively. Rats were infected with two types of organism: either fully susceptible to levofloxacin MIC < or = 0.5 mg/L) or borderline susceptible (MIC 1-2 mg/L). Fully levofloxacin-susceptible bacteria comprised one penicillin-susceptible (MIC 0.004 mg/L) Streptococcus gordonii, and one penicillin-tolerant as well as one intermediate penicillin-resistant (MIC 0.125 mg/L) isogenic strains. Borderline levofloxacin-susceptible bacteria comprised one penicillin-susceptible Streptococcus sanguis and one highly penicillin-resistant Streptococcus mitis (MIC 2 mg/L). Rats were treated for 5 days with drug dosages simulating the following treatments in humans: (i) levofloxacin 500 mg orally once a day (q24 h), (ii) levofloxacin 500 mg orally twice a day (q12 h), (iii) levofloxacin 1 g orally q24 h, (iv) ciprofloxacin 750 mg orally q12 h, and (v) ceftriaxone 2 g iv q24 h. Levofloxacin was equivalent or superior to ceftriaxone, and was successful in treating experimental endocarditis irrespective of penicillin resistance. Nevertheless, standard levofloxacin treatment equivalent to 500 mg q24 h in human was less effective than twice daily 500 mg or once daily 1 g doses against borderline-susceptible organisms. Ciprofloxacin, used as a negative control, was ineffective and selected for resistant isolates. This underlines the importance of MIC determinations when treating severe streptococcal infection with quinolones. In the case of borderline-susceptible pathogens, total daily doses of 1 g of levofloxacin should be considered.

Efficacy of enzyme replacement therapy in Fabry disease.

Enzyme replacement therapy has recently been introduced to treat Fabry disease, a rare X-linked lysosomal storage disorder. The disease occurs due to deficient activity of alpha-galactosidase A, leading to progressive accumulation of globotriaosylceramide in multiple organs and tissues. Renal, cardiac and cerebrovascular manifestations of the disease result in premature death in both hemizygous males and heterozygous females. This paper outlines the clinical signs, symptoms and diagnosis of Fabry disease, and the development of the two available enzyme replacement therapies -- agalsidase alfa and agalsidase beta. Agalsidase alfa and agalsidase beta are produced in a human cell line and in Chinese hamster ovary cells, respectively, resulting in products with the same amino acid sequence as the native human enzyme, but with different patterns of glycosylation. Correct post-translational glycosylation is important in terms of the pharmacokinetics, biodistribution, clinical efficacy and tolerability of genetically engineered protein therapeutics. Differences in glycosylation, which may affect immunogenicity and mannose-6-phosphate receptor-mediated cellular internalisation of administered enzyme, possibly account for the differences in dosing, clinical effects and safety profiles reported for agalsidase alfa and agalsidase beta.

The efficacy of pharmacotherapy for decreasing the expansion rate of abdominal aortic aneurysms: a systematic review and meta-analysis.

BACKGROUND: Pharmacotherapy may represent a potential means to limit the expansion rate of abdominal aortic aneurysms (AAAs). Studies evaluating the efficacy of different pharmacological agents to slow down human AAA-expansion rates have been performed, but they have never been systematically reviewed or summarized. METHODS AND FINDINGS: Two independent reviewers identified studies and selected randomized trials and prospective cohort studies comparing the growth rate of AAA in patients with pharmacotherapy vs. no pharmacotherapy. We extracted information on study interventions, baseline characteristics, methodological quality, and AAA growth rate differences (in mm/year). Fourteen prospective studies met eligibility criteria. Five cohort studies raised the possibility of benefit of beta-blockers [pooled growth rate difference: -0.62 mm/year, (95%CI, -1.00 to -0.24)], but this was not confirmed in three beta-blocker RCTs [pooled RCT growth rate difference: -0.05 mm/year (-0.16 to 0.05)]. Statins have been evaluated in two cohort studies that yield a pooled growth rate difference of -2.97 (-5.83 to -0.11). Doxycycline and roxithromycin have been evaluated in two RCTs that suggest possible benefit [pooled RCT growth rate difference: -1.32 mm/year (-2.89 to 0.25)]. Studies assessing NSAIDs, diuretics, calcium channel blockers and ACE inhibitors, meanwhile, did not find statistically significant differences. CONCLUSIONS: Beta-blockers do not appear to significantly reduce the growth rate of AAAs. Statins and other anti-inflammatory agents appear to hold promise for decreasing the expansion rate of AAA, but need further evaluation before definitive recommendations can be made.