A Placebo‐Controlled Double‐Blinded Randomized Pilot Study of Combination Phytotherapy in Biochemically Recurrent Prostate Cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136500/1/pros23317_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136500/2/pros23317.pd

Bioavailability of Echinacea Constituents: Caco-2 Monolayers and Pharmacokinetics and the Alkylamides and Caffeic Acid Conjugates

Many studies have been done over the years to assess the effectiveness of Echinacea as an immunomodulator. We have assessed the potential bioavailability of alkylamides and caffeic acid conjugates using Caco-2 monolayers and compared it to their actualbioavailability in a Phase I clinical trial. The caffeic acid conjugates permeated poorly through the Caco-2 monolayers. Alkylamides were found to diffuse rapidly through Caco-2 monolayers. Differences in diffusion rates for each alkylamide correlated to structural variations, with saturation and N-terminal methylation contributing to decreases in diffusion rates. Alkylamide diffusion is not affected by the presence of other constituents and the results for a synthetic alkylamide were in line with those for alkylamides found in an ethanolic Echinacea preparation. We examined plasma from healthy volunteers for 12 hours after ingestion of Echinacea tablets manufactured from an ethanolic liquid extract. Caffeic acid conjugates could not be identified in any plasma sample at any time after tablet ingestion. Alkylamides were detected in plasma 20 minutes after tablet ingestion and for each alkylamide, pharmacokinetic profiles were devised. The data are consistent with the dosing regimen of one tablet three times daily and supports their usage as the primary markers for quality Echinacea preparations

Modulation of macrophage immune responses by Echinacea

Echinacea preparations are widely used herbal medicines for the prevention of colds and minor infections. There is little evidence for the individual components in Echinacea that contribute to immune regulatory activity. Activity of an ethanolic Echinacea extract and several constituents, including cichoric acid, have been examined using three ‘in vitro’ measures of macrophage immune function – NF -KB, TNF-α and nitric oxide (NO). In cultured macrophages, all components except the monoene alkylamide (AA1) decreased lipopolysaccharide (LPS) stimulated NF-KB levels. 0.2 fraction (EPL AA) were found to significantly decrease TNF-α production under LPS stimulated conditions in macrophages. In macrophages, only the alkylamide mixture isolated from the ethanolic Echinacea extract liquid extract did not respond in the same manner in the assays as the individual alkylamides investigated. While cichoric acid has been shown to affect NF -KB, TNF-α and NO levels, it is unlikely to be relevant in the Echinacea alterations of the immune response ‘in vivo’ due to its non-bioavailability – i.e. no demonstrated absorption across the intestinal barrier and no detectable levels in plasma. These results demonstrate that Echinacea is an effective modulator of macrophage immune responses ‘in vitro’

Are we drawing the right conclusions from randomised placebo-controlled trials? A post-hoc analysis of data from a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Assumptions underlying placebo controlled trials include that the placebo effect impacts on all study arms equally, and that treatment effects are additional to the placebo effect. However, these assumptions have recently been challenged, and different mechanisms may potentially be operating in the placebo and treatment arms. The objective of the current study was to explore the nature of placebo versus pharmacological effects by comparing predictors of the placebo response with predictors of the treatment response in a randomised, placebo-controlled trial of a phytotherapeutic combination for the treatment of menopausal symptoms. A substantial placebo response was observed but no significant difference in efficacy between the two arms.</p> <p>Methods</p> <p>A <it>post hoc </it>analysis was conducted on data from 93 participants who completed this previously published study. Variables at baseline were investigated as potential predictors of the response on any of the endpoints of flushing, overall menopausal symptoms and depression. Focused tests were conducted using hierarchical linear regression analyses. Based on these findings, analyses were conducted for both groups separately. These findings are discussed in relation to existing literature on placebo effects.</p> <p>Results</p> <p>Distinct differences in predictors were observed between the placebo and active groups. A significant difference was found for study entry anxiety, and Greene Climacteric Scale (GCS) scores, on all three endpoints. Attitude to menopause was found to differ significantly between the two groups for GCS scores. Examination of the individual arms found anxiety at study entry to predict placebo response on all three outcome measures individually. In contrast, <it>low </it>anxiety was significantly associated with improvement in the active treatment group. None of the variables found to predict the placebo response was relevant to the treatment arm.</p> <p>Conclusion</p> <p>This study was a <it>post hoc </it>analysis of predictors of the placebo versus treatment response. Whilst this study does not explore neurobiological mechanisms, these observations are consistent with the hypotheses that 'drug' effects and placebo effects are not necessarily additive, and that mutually exclusive mechanisms may be operating in the two arms. The need for more research in the area of mechanisms and mediators of placebo versus active responses is supported.</p> <p>Trial Registration</p> <p>International Clinical Trials Registry ISRCTN98972974.</p

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Potential interaction of 'Ginkgo biloba' leaf with antiplatelet or anticoagulant drugs: What is the evidence?

Some writers hold the view that the combination of 'Ginkgo biloba' with anticoagulant or antiplatelet drugs represents a serious health risk. Such concerns are largely based on the assumption that Ginkgo has clinically relevant antiplatelet activity, as well as accounts of bleeding episodes associated with Ginkgo consumption. To investigate whether these bleeding episodes have a pharmacodynamic, idiosyncratic or coincidental basis, a review of controlled clinical studies and case reports was undertaken. Results from controlled studies consistently indicate that Ginkgo does not significantly impact haemostasis nor adversely affect the safety of coadministered aspirin or warfarin. Most of these studies were undertaken using EGb 761, a well-defined extract of 'Ginkgo biloba'. In contrast, EGb 761 has not generally been implicated in the case reports. In general, the quality of these case reports is low. Nevertheless, the possibility of an idiosyncratic bleeding event due to Ginkgo use cannot be excluded on the basis of the available information. However, there is scant information from case reports or controlled trials to support the suggestion that Ginkgo potentiates the effects of anticoagulant or antiplatelet drugs. Such high-level safety concerns for this herb are deemed to be unsupported by the currently available evidence

Safety considerations during pregnancy and lactation

Background and Perspective: The following risks could potentially be associated with the use of a herbs during pregnancy: • Toxicity to the mother, which may also indirectly impair the health or development of the ,child; • Toxicity to the child (i. e., foetotoxidty); • Developmental malformations (i.e. teratogeneis); • Increased risk of miscarriage; and health defects on the child, both short term and long term (e.g., increased risk of chronic health problems later in life, such as cancer). There is currently no consensus regarding the safety considerations surrounding the use of herbs during pregnancy. On one hand, some regulatory authorities appear to be adopting the policy that if there is no clear evidence of safety from a controlled clinical trial then a herb should not be recommended during pregnancy. This is well illustrated by deliberations of the Complimentary Medicines Evaluation Committee (CMEC) of the Australian Therapeutic Goods Administration (TGA). CMEC assessed the safe use of over- the -counter (OTC) products containing kava (Piper Methysticum) and came to the conclusion, despite the lack of evidence for harm from kava during pregnancy (and well before the link between kava and hepatotoxicit y was suggested), that kava products should carry the following warning : 'Not for prolonged use, If symptoms persist seek advice from a health care practitioner. Those who are pregnant or nursing are not recommended to use Kava.' The American Herbal Products Association suggests that professional advice should be sought before using Kava during pregnancy

Evaluating, Designing, and Accessing Herbal Medicine Research

An ongoing debate among herbalists and natural therapists involves what role, if any, science must play in the future of herbal medicine. Some feel that the traditional basis of herbal medicine provides a completely adequate therapy and that the scientific investigation of herbs or herbal therapy has little to offer. They caution that the wholesale incorporation of scientific methods into the practice of herbal medicine will result in adverse changes - changes that will make herbal medicine less than what it is today. They fear that herbal medicine will lose its traditional basis, its insight, and its soul. Perhaps it will become a sick hybrid that is neither scientifically sound nor valid as a therapy; possibly, herbal medicine will become totally reductionist, with herbs, similar to many modern drugs, used only for superficial symptom control. Among some herbalists, science is seen as a technique for information gathering that is inferior to the knowledge derived from insight, inspiration, and intuition

The Ultimate Herbal Compendium: A desktop guide for herbal prescribers

For some time now I have felt the need in my practice for an up-to-date, accurate and reliable ready reference. In a busy practice the time between taking a case and arriving at a final prescription can be relatively short. Decisions have to be made quickly, comprehensively and accurately, drawing on the best available information. Relying on memory is not always the best option and the currently available texts do not fully meet all the clinical requirements. I felt there was a role for a book that contained easily found information on a wide range of herbs and conditions, including doses for herbs in tablet form as well as liquids. This Compendium has been developed with these requirements in mind. I have carefully researched, compiled and cross-referenced the available herbal information. But above all I was guided and informed by my clinical experience. As such, this compendium represents the distillation of more than 23 years of clinical practice