Chinese herbal medicine for insomnia : evidence and experience

Insomnia, a condition with significant medical consequences, is becoming more and more prevalent worldwide. Hypnotic drugs are associated with dependence, adverse reactions and long-term risks. Psychotherapy is time- and resource-consuming and largely unavailable. As such, many people who present with insomnia also look for alternative treatments. Recent studies show that Chinese herbal medicine (CHM), a traditional herbal medicine based on holistic theories, could be a potential alternative. The aims of this doctoral research were to explore the potential benefits of CHM for the treatment of insomnia and provide guidance in the treatment of insomnia with CHM. For practical reasons, the empirical aspect of the investigation focuses on one specific CHM product, which is Zao Ren An Shen (ZRAS). The research questions include: (1) Is ZRAS a safe and effective treatment for insomnia disorder? (2) How do Chinese medicine clinicians diagnose and treat insomnia with CHM? This doctoral research consists of a narrative review and three major studies: one systematic review, one randomised, placebo-controlled trial and one clinical experience synthesis. In the systematic review, clinical trial that assessed the efficacy and/or safety of ZRAS for insomnia were systematically searched and screened. In the clinical trial, after one week of placebo run-in, 85 participants with insomnia disorder were randomly allocated to either take ZRAS capsule or placebo for four weeks. Insomnia severity, psychological status, fatigue levels, quality of life, subjective sleep parameters, objective sleep parameters, and adverse events were assessed through the intervention period and at a four-weeks follow-up. Both the investigator and the participants were blind to the treatment allocation. In the clinical experience synthesis (CES), clinical experience reports published in the literature, which described treatment of insomnia with CHM, were systematically reviewed and screened. The systematic review shows that ZRAS is safe and effective for insomnia. The randomised trial support ZRAS capsule as a safe and acceptable treatment, yet failed to improve significantly insomnia severity in insomnia patients. These differences may be explained by the poor quality of the studies included in the systematic review. The studies included in the systematic review and the randomised trial both used a standardised intervention approach. However, Chinese medicine clinician recommend an individualised approach, which may contribute to improved outcomes across a broader range of measures

The influence of traditional herbal formulas on cytokine activity

Many of the botanical “immunomodulators”, a class of herbal medicines widely recognized in traditional medical systems such as Chinese Medicine (TCM) and Ayurvedic Medicine, alter immune function and may offer clinically relevant therapeutics or leads to therapeutics. Many of these traditional remedies are prepared from combinations of medicinal plants which may influence numerous molecular pathways. These effects may differ from the sum of effects from the individual plants and therefore, research demonstrating the effects of the formula is crucial for insights into the effects of traditional remedies. In this review we surveyed the primary literature for research that focused on combinations of medicinal plants and effects on cytokine activity. The results demonstrate that many extracts of herb mixtures have effects on at least one cytokine. The most commonly studies cytokines were IL-4, IL-6, IL-10, TNF and IFN-?. The majority of the formulas researched derived from TCM. The following formulas had activity on at least three cytokines; Chizukit N, CKBM, Daeganghwal-tang, Food Allergy Formula, Gamcho-Sasim-Tang, Hachimi-jio-gan, Herbkines, Hochuekki, Immune System Formula, Jeo-Dang-Tang, Juzen-taiho-to, Kakkon-to, Kan jang, Mao-Bushi-Saishin-to, MSSM-002, Ninjin-youei-to, PG201, Protec, Qing-huo-bai-du-yin, Qingfu Guanjieshu, Sambucol Active Defense, Seng-fu-tang, Shin-Xiao-Xiang, Tien Hsien, Thuja formula, Unkei-to, Vigconic, Wheeze-relief-formula, Xia-Bai-San, Yangyuk-Sanhwa-Tang, Yi-fey Ruenn-hou, and Yuldahansotang. Of the western based combinations, formulas with Echinacea spp. were common and showed multiple activities. Numerous formulas demonstrated activity on both gene and protein expression. The research demonstrates that the reviewed botanical formulas modulate cytokine activity, although the bulk of the research is in vitro. Therapeutic success using these formulas may be partially due to their effects on cytokines. Further study of phytotherapy on cytokine related diseases/syndromes is necessary

Synergistic behaviour of Salvia and Notoginseng species in vascular diseases

As the mainstay and principal form of traditional Chinese medicine (TCM), Chinese herbal medicine (CHM) has been the subject of growing interest and popular use worldwide. However, its unique philosophy, diagnosis and prescription are completely different from Western Medicine (WM), which has brought great challenges for the quality standardisation, safety control, and efficacy evaluation confronting its development in a modernised scientific manner. This PhD project aims to address challenges that revolve around the efficacy research of CHM. Based on CHM theory, the key mechanism of the efficacy of CHM is the synergistic interactions among multiple herbal ingredients in a formula to reach an optimised therapeutic effect, multi-target mode of actions and reduced potential side effects. Several rigorous analytical methods such as combination index (CI), isobolographic analysis and systems biology are designed for the quantitative evaluations of synergistic effects in pharmaceutical combination therapy, and have also been utilised for the study of CHM. Among them, CI and isobologram models are applied for studying the interactions of a small number of active components or herbal extracts on the same target or receptor in which their chemical and pharmacological properties are well defined. A systems biology model may also be used to analyse multi-component, multi-target actions in combinational therapy. However, following a systematic review, it is apparent that the current literature on synergistic study of CHM is still at an early stage. Based on previous studies, we hypothesised that a platform to systematically analyse synergistic interactions of herbal compounds can be established by modern bioassays and scientific models (e.g., CI and isobologram approaches). Herb-pairs are the basic unit for the Chinese herbal formulae. Salvia Miltiorrhiza Radix et Rhizoma and Notoginseng Radix et Rhizome (known as Danshen [DS] and Sanqi [SQ] in TCM) has been one of the most frequently prescribed herb pairs in TCM clinics for cardiovascular disease management for over 30 years in Asian countries. However, very limited mechanistic studies on the combinational benefits on the complex pathological mechanisms of vascular diseases are available, despite the fact that the bioactivities for a single extract have been well studied. Therefore, the DS-SQ herb-pair was selected as a case study to address the issue of synergistic activities in CHM

Evaluation of the efficacy, safety and tolerability of herbal medicine for management of the behavioural and psychological symptoms of dementia

Dementia involves a gradual loss of memory and cognitive skills. Over 50% of people with dementia also suffer from the behavioural and psychological symptoms of dementia (BPSD). BPSD refer to disturbed perception, thought content and mood associated with dementia, and include psychosis, agitation, aggression, irritability, depression, anxiety and abnormal motor activity. BPSD can have a negative impact on the progression of Alzheimer’s disease and related disorders and are associated with a greater level of caregiver distress. Currently recommended pharmacological treatments for dementia, including acetylcholinesterase inhibitors and memantine, focus on relieving cognitive symptoms, while BPSD are managed according to the presenting symptoms. Guidelines recommend non-pharmacological approaches for BPSD but selective serotonin reuptake inhibitors, analgesics and second generation antipsychotics may be used when other approaches fail. Pharmacological treatments for BPSD have limited benefit and safe prescribing is difficult as some may produce severe adverse effects and may worsen cognitive symptoms. Consequently, there is a pressing need for new approaches to BPSD management. Multiple clinical studies have reported that herbal medicines (HMs), such as Ginkgo biloba leaf extract, can alleviate BPSD as well as improve cognition in dementia. The present project aimed to determine the current state of evidence for HMs and propose future directions for the development of plant-based therapeutics for managing BPSD. Both historical use and contemporary clinical trials provide evidence for the use of herbs for management of memory impairment, cognitive symptoms of dementia and BPSD. Based on these findings, there is potential for identifying effective herbal interventions that could be fast-tracked into clinical use for this unmet need. Identification of useful compounds and their possible mechanisms of action may contribute to development of new therapeutic approaches and/or drug discovery. Notably, the acetylcholinesterase inhibitors galantamine and rivastigmine were discovered from plant-derived compounds. The objectives of this project were to assess the current state of evidence and its limitations regarding the efficacy, safety and tolerability of HMs for BPSD by systematically reviewing and analysing the results of clinical trials and the classical Chinese medicine literature on BPSD; identify any HMs that show potential benefit for BPSD; based on the best available evidence, select a herbal intervention suitable for further clinical investigation; and design a rigorous randomised controlled trial (RCT) to test the intervention that addresses the limitations of previous clinical studies. The comprehensive systematic review and meta-analysis included 31 controlled clinical trials testing 19 different HMs. Meta-analysis of well-designed, placebo-controlled studies indicated that the G. biloba leaf extract EGb 761® was safe and well-tolerated. Significant and clinically meaningful improvements in BPSD and cognition were detected at 24 weeks. However, independently funded studies of G. biloba leaf extract are needed to confirm these findings. Meta-analysis of randomised, comparative effectiveness studies of the Japanese multi-herb formula Yokukansan (Chinese: Yi gan san) showed no significant differences on BPSD outcomes when compared to standard pharmacotherapies used in Japan for BPSD management and superiority to no treatment. However, the only placebo-controlled study of Yokukansan for BPSD did not find any difference in BPSD outcomes at the end of four weeks treatment. Important limitations were identified in this trial which could have resulted in a false negative. These included its short duration, relatively small sample size, large improvement in the placebo group, and the use of a simplified outcome measure which could be less likely to detect changes in symptoms. Overall, the clinical evidence for Yokukansan suggested improvements in BPSD, notably in the clinically important symptoms of irritability/lability and agitation/aggression. An issue identified with Yokukansan was the increased risk of liquorice-induced hypokalaemia, which requires monitoring. Lack of replication and methodological issues in the studies testing other HMs precluded any conclusions for these other interventions. The classical Chinese medical literature was evaluated using the Zhong Hua Yi Dian database, using similar methods to a previous study which evaluated the herbs used for treatment of the cognitive symptoms of dementia. No specific term in the literature corresponded with BPSD, although terms for specific symptoms such as anxiety, depression and agitation were frequently mentioned in conjunction with terms for memory impairment. Some of the HMs described in the classical Chinese medical literature for treatment of memory impairments with mood and behavioural symptoms had also been tested in the clinical trial literature, including Glycyrrhiza uralensis, Poria cocos and Angelica species, which are ingredients of Yokukansan, but the most frequently cited herbs in the classical literature were generally not the same as the frequently tested HMs in clinical trials. The in vitro and in vivo literature showed evidence of relevance to treatment of BPSD for G. biloba, Yokukansan and their constituent compounds. For both these HMs, animal studies have reported anti-aggression-like, antidepressant-like, anxiolytic-like effects as well as benefits on abnormal motor activities and reduction in cognitive impairments and mental stress. Important activities of G. biloba leaf and Yokukansan of relevance to BPSD include modulation of neurotransmission, neuroendocrine regulation and antioxidant effects. The issue of wide variation in placebo effect sizes in BPSD studies was explored through meta-analysis of placebo data. Results showed that placebo effect sizes for BPSD have increased over time. Proposed new studies may therefore require larger sample sizes in order to be adequately powered. Based on the available evidence, it appears that EGb 761® provides small improvements in cognitive symptoms and reduces BPSD while Yokukansan can improve BPSD but not cognition, although it does not appear to have any negative effect on cognition. Both HMs are available commercially, are well characterised and are in widespread use but their combination has not been tested in a clinical trial. Notably, most studies of EGb 761® were conducted in Europe or Russia while Yokukansan was tested in Japan. Therefore, it was proposed that the combination of EGb 761® and Yokukansan at conservative dosages should be tested through an adequately powered, randomised, placebo-controlled clinical trial. A clinical trial protocol was designed which utilised validated diagnostic criteria and assessments relevant to an older population with BPSD, including assessments of caregiver distress associated with BPSD. Issues relating to informed consent from participants and their caregivers were addressed. Safety was an important consideration and was addressed through inclusion and exclusion criteria, careful monitoring of adverse events and strategies to reduce the risk of liquorice-induced hypokalaemia. The results of the RCT would provide useful data on the safety, tolerability and efficacy of this combined intervention in an Australian population with BPSD. The results would assist with clinical decision-making in the management of BPSD

Oral Chinese herbal medicine for psoriasis vulgaris

Background: Psoriasis vulgaris is a common chronic immunological inflammatory skin disease without cure. Psoriasis is associated with increased risk of serious co-morbidities such as cardiovascular disease and diabetes. Current conventional therapies can be expensive and commonly have adverse effects. Hence further effective and safe therapies are needed. Chinese herbal medicine (CHM) has been utilised for centuries for the management of psoriasis. This thesis reviewed its current clinical and experimental psoriasis evidence and aimed to develop and test an evidence based CHM formulation. Methods: Firstly, two systematic reviews and meta-analyses were conducted using the Cochrane Library Systematic Review Method to examine published CHM research for psoriasis. 1) Randomised controlled trials (RCTs) of oral CHM for psoriasis vulgaris compared with placebo. 2) RCTs combining oral CHM with conventional therapy for psoriasis vulgaris. Secondly, in vitro and in vivo data for commonly used CHM phytochemicals were reviewed to evaluate their potential biological psoriatic mechanisms. Lastly based on the review findings and available treatment guidelines an optimised oral CHM formulation (PSORI-CM01) was developed for psoriasis vulgaris and then clinically evaluated via a rigorous designed pilot placebo double-blind RCT. Results: Literature review indicated mild–moderate psoriasis is undertreated, and topical treatments have limited efficacy. Systematic review found oral CHM has benefit compared with placebo; however, the effect size is relatively small. Further systematic review of CHM combined with conventional therapy indicated it increases effects and reduces adverse events. Subsequent in vitro and in vivo review recognised Paeonia. lactiflora Pallas and Paeonia veitchii Lynch constituents and those of other CHM act on pathways similar to conventional psoriasis drugs. The pilot RCT investigates PSORI-CM01 in a mild to moderate psoriasis vulgaris (psoriasis area severity index (PASI) 7–12) population. Thirty participants undergo a two-week run-in phase then receive 12-weeks of PSORI-CM01 plus calcipotriol or placebo plus calcipotriol. The pilot study is to determine the feasibility for an adequately powered RCT. Primary outcome is PASI change (%) and secondary measures include: PASI 75 rate, QoL change (dermatology life quality index (DLQI) and Skindex 29), acceptability of treatment, change to psoriasis-related cytokines (such as TNF-α and IL-23) and adverse events. Blood plasma specimens are collected at weeks –2, 12 and 24 then concentrations of inflammatory cytokines measured via multi-assay technique (Bio-Plex® Multiplex System). The pilot RCT is ongoing, interim results indicated baseline analysis (n=11) mean PASI score 9.0±2.4, and DLQI score 10±7.6. Conclusion: Oral CHM has promising efficacy for psoriasis and combined with conventional treatments enhances effects. Evidence suggests combined treatment is safe; however, long-term follow-up data are limited. Efficacy of CHM is related to the mechanistic actions of contained constituents, some of which coincide with conventional drug treatment targets. PSORI-CM01 has in vitro and in vivo evidence indicating its therapeutic benefit is via modulation of known psoriatic biological pathways. The current pilot will provide data on the feasibility of a larger-scale study and provide preliminary data for PSORI-CM01 efficacy and safety

Endometriosis

Endometriosis is a common and serious disease that is estimated to cost the world economy $9.7 billion a year. Most of these costs come from lost productivity at work. As such, it is important to help women receive earlier diagnosis and more effective treatment. This book presents a comprehensive overview of endometriosis, including information on molecular diagnostics and imaging methods for early detection as well as new, less-invasive treatments that preserve women’s fertility

Diets, Foods and Food Components Effect on Dyslipidemia

Dyslipidemia, and particularly hypercholesterolemia, remains a main cardiovascular disease risk factor, partly reversible with the improvement of life-style, including dietary, habits. Even when a pharmacological treatment is begun, dietary support to lipid-lowering is always desired. This book will provide a selection of new evidence on the possible lipid-lowering effects of some dietary and medicinal plant components, reporting some interesting reviews, experimental data and results from clinical trials. The book is adapted for experts in nutrition but also for all scientists involved in cardiovascular disease prevention

Research Topics in Medicines and How Our Board Members Are Engaged in Them

With the development of analytical instruments, the academic system has become more complicated, producing new journals one after another. Therefore, it became much important to clarify what is original of “Medicines”. As the name Medicines indicates, it includes science and practice of caring for a patient and managing the diagnosis, prognosis, prevention, treatment or palliation of their injury or disease. Therefore, Medicines differs from other journals with similar title in that it covers a wide range of fields, from traditional medicine to rapidly developing molecular-targeted drugs, focusing on their pharmacological effects, structure–activity relationships, metabolic pathways, gene expression, using cultured cells, animals, and clinical trials. Most parts of this Special Issue were written by our editorial board members, who described the research topics and how they are engaged in their field of research. All of these articles are their life-long story. We collected a total number of 22 original works by basic researchers and clinical doctors. We hope that readers can get a chance to know the current status of diverse fields of medicines, and what your most important research themes are after reading these articles