placebo-controlled study.

Kava: A Natural Alternative To Anxiety Medication?

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Kava (Piper Methysticum), also known as awa, ava and yaqona, is a crop native to the South Pacific and is a member of the pepper family. The plant sports relatively large, heart-shaped leaves, which accompany slender flower blossoms that reside at the intersections where the branch and stems meet. However, the kava plant has earned its status due to what resides within its hairy, woody roots.

Photo by Simpler Days.

Kava has been used in traditional, tribal settings on the islands of Fiji, Micronesia and Polynesia for hundreds of years. These cultures use the psychoactive beverage as a social and ceremonial offering in a way that’s often compared to how wine is used and consumed in European countries. Traditionally, after being harvested, the root is then pulverized, ground (often by mouth) and shredded. The herbal preparation is then repetitively strained into a bowl using a cold water extraction method, before being served in, and drunk out of, a half coconut shell. This preparation is enjoyed reverently due to its calming and sedating qualities. Because of these effects, growing evidence is starting to support claims that kava is useful for those suffering from insomnia, high stress, depression and anxiety. Interestingly, kava is proving to be as effective as dissolving anxiety as pharmaceutical drugs that are often prescribed for this condition.

The array of active ingredients responsible for the psychoactive effects of kava are known to science as kavaclones. These chemicals include compounds such as dihydrokavain, methysticum and kawaii, all of which have been thoroughly studied in laboratory settings. As a result, there’s empirical evidence that these compounds promote sleep, decrease convulsions and relax muscles in animals. The chemicals described have also shown to be effective painkillers, which is associated with the temporary numbness of the tongue that kava beverages induce when drunk. A double-blind, randomized, placebo controlled study conducted by The University of Melbourne in Australia found kava to be significantly more effective than a placebo at reducing anxiety in a group of 75 participants, all of whom were diagnosed with GAD (General Anxiety Disorder).

Lead researcher, Dr. Jerome Sarris, believes GAD to be a complex and potentially debilitating disorder that can significantly effect the daily lives of those affected, with existing medications only showing modest clinical results. Sarris was quoted by News Room in reference to the study, stating: “We have recognized that plant based medicines may be a viable treatment for patients with chronic anxiety. In this study we’ve been able to show that kava offers a potential natural alternative for the treatment of chronic clinical anxiety. Unlike some other options it has less risk of dependency and less potential side effects.”

Another study carried out at The School of Veterinary Medicine in Berlin, Germany found kava to have very similar anti-anxiety effects to the drug diazepam (Valium) when it was administered to animals. The authors of the study claim that the data supports the use of kava in treating anxiety disorders. Additionally, researchers at the University of Hertfordshire in the United Kingdom and the University of Zurich in Switzerland set out to explore how kava can affect mood and emotions, measuring the three areas of seriousness, cheeriness and bad mood. After a single dose of kava, an increase in cheerfulness was observed in the volunteers and they even performed better when given certain cognitive tasks. This led the researchers to draw a comparison between kava and conventional prescription drugs used to treat anxiety. Conventional drugs often cause unwanted mental side effects and cognitive impairment, whereas kava has been found to actually promote brain function while providing strong anti-anxiety effects and positive feelings such as exhilaration.

There’s much anecdotal evidence related to kava on the internet, many of which can be found in Erowid’s user experience vaults. One user has detailed kava’s ability to cease their anxiety and depression. Another contributor to Erowid gave details of theirexperience claiming: “The quieting of my conscious mind and the total clarity of thought I was experiencing was nothing short of wonderful.”

Kava has seen a recent surge in popularity in the Western world in the areas of medicine and recreational activity. It can be obtained in many different forms from the dried roots, condensed capsules and more potent tinctures. However, users looking for more of a social and recreational setting may want to pay a visit to the growing number of kava bars erupting across the U.S. — from California, to Florida, to Hawaii and elsewhere. In such establishments, both experienced and novice kava drinkers can enjoy the anxiety-easing yet clarity promoting substance legally in the company of friends, sipping from a half coconut shell surrounded by tiki statues, palm leaves, gentle laughter and easy smiles.

Much like practically every medicinal and recreational substance, kava does not come without its fair share of controversy. There are some safety concerns that link kava usage to possible liver damage, which has led to some governments, such as Poland‘s, to ban and control it. However, Dr. Sarris, a professional who has studied kava in-depth points out: “When extracted in the appropriate way, kava may pose less or no potential liver problems. I hope the results will encourage governments to reconsider the ban.”

Also, many Erowid users speak of using kava extensively for many years without any detrimental side effects, such as this user who has been a frequent drinker for three consecutive years. The author takes a liver test every three months and has reported perfectly safe medical results.

Ultimately, kava is another example of an effective plant medicine that could potentially offer individuals a natural and safer alternative to often dangerous and addictive conventional treatments.

Gabapentin Treatment for Alcohol Dependence.

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A Randomized Clinical Trial

Importance  Approved medications for alcohol dependence are prescribed for less than 9% of US alcoholics.

Objective  To determine if gabapentin, a widely prescribed generic calcium channel/γ-aminobutyric acid–modulating medication, increases rates of sustained abstinence and no heavy drinking and decreases alcohol-related insomnia, dysphoria, and craving, in a dose-dependent manner.

Design, Participants and Setting  A 12-week, double-blind, placebo-controlled, randomized dose-ranging trial of 150 men and women older than 18 years with current alcohol dependence, conducted from 2004 through 2010 at a single-site, outpatient clinical research facility adjoining a general medical hospital.

Interventions  Oral gabapentin (dosages of 0 [placebo], 900 mg, or 1800 mg/d) and concomitant manual-guided counseling.

Main Outcomes and Measures  Rates of complete abstinence and no heavy drinking (coprimary) and changes in mood, sleep, and craving (secondary) over the 12-week study.

Results  Gabapentin significantly improved the rates of abstinence and no heavy drinking. The abstinence rate was 4.1% (95% CI, 1.1%-13.7%) in the placebo group, 11.1% (95% CI, 5.2%-22.2%) in the 900-mg group, and 17.0% (95% CI, 8.9%-30.1%) in the 1800-mg group (P = .04 for linear dose effect; number needed to treat [NNT] = 8 for 1800 mg). The no heavy drinking rate was 22.5% (95% CI, 13.6%-37.2%) in the placebo group, 29.6% (95% CI, 19.1%-42.8%) in the 900-mg group, and 44.7% (95% CI, 31.4%-58.8%) in the 1800-mg group (P = .02 for linear dose effect; NNT = 5 for 1800 mg). Similar linear dose effects were obtained with measures of mood (F2 = 7.37; P = .001), sleep (F2 = 136; P < .001), and craving (F2 = 3.56; P = .03). There were no serious drug-related adverse events, and terminations owing to adverse events (9 of 150 participants), time in the study (mean [SD], 9.1 [3.8] weeks), and rate of study completion (85 of 150 participants) did not differ among groups.

Conclusions and Relevance  Gabapentin (particularly the 1800-mg dosage) was effective in treating alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving, with a favorable safety profile. Increased implementation of pharmacological treatment of alcohol dependence in primary care may be a major benefit of gabapentin as a treatment option for alcohol dependence.

Soure: JAMA

A Phase 3 Trial of Semagacestat for Treatment of Alzheimer’s Disease.

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BACKGROUND

Alzheimer’s disease is characterized by the presence of cortical amyloid-beta (Aβ) protein plaques, which result from the sequential action of β-secretase and γ-secretase on amyloid precursor protein. Semagacestat is a small-molecule γ-secretase inhibitor that was developed as a potential treatment for Alzheimer’s disease.

METHODS

We conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer’s disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer’s Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.

RESULTS

The trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, −9.0 points in the placebo group, −10.5 points in the 100-mg group, and −12.6 points in the 140-mg group; P=0.14 and P<0.001, respectively, for the comparison with placebo). Patients treated with semagacestat lost more weight and had more skin cancers and infections, treatment discontinuations due to adverse events, and serious adverse events (P<0.001 for all comparisons with placebo). Laboratory abnormalities included reduced levels of lymphocytes, T cells, immunoglobulins, albumin, total protein, and uric acid and elevated levels of eosinophils, monocytes, and cholesterol; the urine pH was also elevated.

CONCLUSIONS

As compared with placebo, semagacestat did not improve cognitive status, and patients receiving the higher dose had significant worsening of functional ability. Semagacestat was associated with more adverse events, including skin cancers and infections.

Source: NEJM

Oral Antimycobacterial Therapy in Chronic Cutaneous.

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ABSTRACT

Importance  Sarcoidosis is a chronic granulomatous disease for which there are limited therapeutic options. This is the first randomized, placebo-controlled study to demonstrate that antimycobacterial therapy reduces lesion diameter and disease severity among patients with chronic cutaneous sarcoidosis.

Objective  To evaluate the safety and efficacy of once-daily antimycobacterial therapy on the resolution of chronic cutaneous sarcoidosis lesions.

Design and Participants  A randomized, placebo-controlled, single-masked trial on 30 patients with symptomatic chronic cutaneous sarcoidosis lesions deemed to require therapeutic intervention.

Setting  A tertiary referral dermatology center in Nashville, Tennessee.

Interventions  Participants were randomized to receive either the oral concomitant levofloxacin, ethambutol, azithromycin, and rifampin (CLEAR) regimen or a comparative placebo regimen for 8 weeks with a 180-day follow-up.

Main Outcomes and Measures  Participants were monitored for absolute change in lesion diameter and decrease in granuloma burden, if present, on completion of therapy.

Observations  In the intention-to-treat analysis, the CLEAR-treated group had a mean (SD) decrease in lesion diameter of –8.4 (14.0) mm compared with an increase of 0.07 (3.2) mm in the placebo-treated group (P = .05). The CLEAR group had a significant reduction in granuloma burden and experienced a mean (SD) decline of –2.9 (2.5) mm in lesion severity compared with a decline of –0.6 (2.1) mm in the placebo group (P = .02).

Conclusions and Relevance  Antimycobacterial therapy may result in significant reductions in chronic cutaneous sarcoidosis lesion diameter compared with placebo. These observed reductions, associated with a clinically significant improvement in symptoms, were present at the 180-day follow-up period. Transcriptome analysis of sarcoidosis CD4+ T cells revealed reversal of pathways associated with disease severity and enhanced T-cell function following T-cell receptor stimulation

Source: JAMA

Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism.

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Dabigatran, which is administered in a fixed dose and does not require laboratory monitoring, may be suitable for extended treatment of venous thromboembolism. Methods In two double-blind, randomized trials, we compared dabigatran at a dose of 150 mg twice daily with warfarin (active-control study) or with placebo (placebo-control study) in patients with venous thromboembolism who had completed at least 3 initial months of therapy. Results In the active-control study, recurrent venous thromboembolism occurred in 26 of 1430 patients in the dabigatran group (1.8%) and 18 of 1426 patients in the warfarin group (1.3%) (hazard ratio with dabigatran, 1.44; 95% confidence interval [CI], 0.78 to 2.64; P=0.01 for noninferiority). Major bleeding occurred in 13 patients in the dabigatran group (0.9%) and 25 patients in the warfarin group (1.8%) (hazard ratio, 0.52; 95% CI, 0.27 to 1.02). Major or clinically relevant bleeding was less frequent with dabigatran (hazard ratio, 0.54; 95% CI, 0.41 to 0.71). Acute coronary syndromes occurred in 13 patients in the dabigatran group (0.9%) and 3 patients in the warfarin group (0.2%) (P=0.02). In the placebo-control study, recurrent venous thromboembolism occurred in 3 of 681 patients in the dabigatran group (0.4%) and 37 of 662 patients in the placebo group (5.6%) (hazard ratio, 0.08; 95% CI, 0.02 to 0.25; P<0.001). Major bleeding occurred in 2 patients in the dabigatran group (0.3%) and 0 patients in the placebo group. Major or clinically relevant bleeding occurred in 36 patients in the dabigatran group (5.3%) and 12 patients in the placebo group (1.8%) (hazard ratio, 2.92; 95% CI, 1.52 to 5.60). Acute coronary syndromes occurred in 1 patient each in the dabigatran and placebo groups. Conclusions Dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.

Source:NEJM

Acadesine Does Not Improve Outcomes of CABG.

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In a randomized trial, an adenosine-regulating agent had no apparent cardioprotective effect.

Despite advances in surgical technology, ischemia/reperfusion injury associated with coronary artery bypass grafting (CABG) remains an important cause of morbidity and mortality. To evaluate the protective effect of acadesine, an adenosine-regulating agent, investigators at 300 sites in 7 countries conducted a manufacturer-sponsored, randomized, double-blind, placebo-controlled trial involving intermediate- or high-risk patients undergoing nonemergent, on-pump CABG during 2009–2010. The primary composite endpoint was all-cause mortality, nonfatal stroke, or mechanical support for severe left ventricular dysfunction during CABG or 4 weeks of follow-up.

The trial was stopped for futility after enrollment of 30% of the projected study population. The final cohort included 2986 patients (median age, 66), most of whom were white men with hyperlipidemia, diabetes, and family history of cardiovascular disease. The primary-endpoint rate was 5.0% overall and did not differ significantly between the placebo and acadesine groups (5.0% and 5.1%, respectively), as demonstrated by a Kaplan-Meier curve. No between-group difference in the rate of any secondary endpoint reached or approached statistical significance, nor was any significant difference found among groups stratified by Society of Thoracic Surgeons risk quintile.

Comment: Although previous studies yielded promising findings, this well-designed trial failed to show any benefit of acadesine on outcomes in intermediate- or high-risk patients undergoing coronary artery bypass grafting. The rate of the primary endpoint, although lower than the 10% expected with placebo in this population, underscores the need for continued efforts to prevent ischemia/reperfusion injury during and after CABG.

Source: Journal Watch Cardiology

Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study.

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Oral mucositis (OM) is a debilitating toxicity of chemoradiotherapy for head and neck cancer (HNC). This randomized, placebo-controlled, double-blind study evaluated the efficacy and safety of palifermin to reduce OM associated with definitive chemoradiotherapy for locally advanced HNC. PATIENTS AND METHODS Patients receiving conventionally fractionated radiotherapy (2.0 Gy/d, 5 days/wk to 70 Gy) with cisplatin (100 mg/m(2) on days 1, 22, and 43) received palifermin (180 mug/kg) or placebo before starting chemoradiotherapy and then once weekly for 7 weeks. The primary end point was the incidence of severe, observable, and functional OM (WHO grade 3 to 4). Results The palifermin (n = 94) and placebo (n = 94) arms were well balanced. The incidence of severe OM was significantly lower for palifermin than for placebo (54% v 69%; P = .041). In the palifermin arm, median time to severe OM was delayed (47 v 35 days), median duration of severe OM was shortened (5 v 26 days), and the incidence of xerostomia grade >/= 2 was lower (67% v 80%), favoring palifermin; however, the differences were not significant after multiplicity adjustment. Opioid analgesic use, average mouth and throat soreness scores, and chemoradiotherapy compliance were not significantly different between treatment arms. Adverse events were similar between arms (98%, palifermin; 93%, placebo). The most common study drug-related adverse events were rash, flushing, and dysgeusia. After median follow-up of 25.8 months, overall survival and progression-free survival were similar between treatment arms. CONCLUSION Although palifermin reduced severe functional OM, its role in the management of locally advanced HNC during chemoradiotherapy remains to be elucidated.

source: JCO