An alternative therapy for graves' disease: clinical effects and mechanisms of an herbal remedy

Graves' disease, the most common cause of hyperthyroidism, is an autoimmune disorder. Antithyroid drugs have been selected as the first-line treatment of Graves' disease in Korea, Japan, and European countries. However, antithyroid drugs such as methimazole (MMI) and prophylthiouracil (PTU) have limitations in clinical applications because of their side effects. In this study, we performed a clinical trial and in vitro study to investigate the clinical effects and action mechanism of Ahnjeonbaekho-tang (AJBHT), an herbal remedy for Graves' disease. In a clinical study of Graves' disease patients who had side effects from antithyroid drugs, we found that treatment by AJBHT resulted in a reduction of serum triiodothyronine (T3) and free thyroxine (FT4) levels and an increase in thyroid stimulating hormone (TSH) levels (T3: p<0.0001, FT4: p=0.0012, TSH: p=0.0370, respectively). In vitro, AJBHT significantly inhibits FRTL-5 cell proliferation, DNA synthesis, cyclic AMP production, T4 synthesis, and the expression of thyroglobulin (Tg) mRNA in comparison with the control. These results suggest that AJBHT might suppress T(4) synthesis by modulating adenosine 3',5'-cyclic monophosphate (cAMP) and Tg expression, and therefore, AJBHT could be an alternative therapy for Graves' disease patients who have side effects from antithyroid drugs.     

紫杉醇类前药的研究进展

紫杉醇(paclitaxel)及其半合成类似物多西紫杉醇(docetaxel) 是迄今为止发现的最为有效的抗癌药物之一,然而该类药物对正常组织、系统具有严重的毒性,而且水溶性较低以及对多药耐药 (MDR) 细胞几乎无活性等,使其临床应用受到限制。近年来,在提高紫杉醇类前药生物利用度和靶向性以及解决紫杉醇对于多药耐药肿瘤细胞无效等方面的研究和开发取得了很大进展。该文对近十几年来紫杉醇类前药的研究进展进行综述。 关键词：紫杉醇;前药;轭合物;水溶性;靶向性 中图分类号:     

Emerging drug therapies in Huntington's disease

Huntington's disease (HD) is a relentless neurodegenerative disease that results in profound disability through a triad of motor, cognitive and neuropsychiatric symptoms. At present, there are very few therapeutic interventions available with the exception of a limited number of drugs that offer mild symptomatic relief. Although the genetic basis of the disease has been identified, the mechanisms behind the cellular pathogenesis are still not clear and as a result no candidate drugs with the potential for disease modification have been found clinically until now. One of the major limitations in assessing the usefulness of drug treatments in HD is the lack of well-designed, double-blind, placebo-controlled clinical trials. Most studies have been open-label, using a small number of patients and tend to concentrate on the motor features of the disease, primarily the chorea. This review discusses the treatments now used for HD before evaluating the newer drugs at present being explored in both the clinic and in the laboratory in mouse models of the disease.     

芳香开窍化合物对MDCK-MDR1单层细胞透过性的影响(英文)

在中医理论体系中,芳香开窍类药物对于调节脑部的药物摄取具有重要的作用。对于此作用的分子机制研究目前仍然有限。MDCK-MDR1细胞是研究药物透过血脑屏障机制的一个理想体外模型,本文用稳定转染的方法建立了MDCK-MDR1细胞系并研究了几种重要的芳香药物对BBB透过性的作用。研究结果表明:我们发现芳香开窍化合物可以在MDCK-MDR1模型上增加FD4的透过性并减少Rho123的外排,说明这些化合物一方面可以打开细胞间的紧密联接,另一方面可以抑制P-gp的作用,从而影响药物吸收。此研究为阐明芳香化合物的作用机制提供了新的见解。     

Vitamin B2: A promising adjuvant in cisplatin based chemoradiotherapy by cellular redox management

Cancer has been a big challenge in the clinical research arena for many years. All the major anticancer drugs are either not effective or induce serious side effects. Cisplatin (CP) is one of the most valued anticancer drugs against various forms of cancer but it exerts many side effects often resulting in withdrawal of clinical usage during long-term chemotherapy. Thus, increasing the efficacy of the drugs and minimizing deleterious side effects is needed. Vitamins like riboflavin (RF) are promising under photodynamic therapy in this aspect because of its potential as an efficient adjuvant confirmed in many cancer cell lines and animal-based studies. It has been found to alleviate CP-induced side effects significantly under photoillumination in mice. As CP exerts most of its toxic effects by oxidative and nitrosative stress; clubbing ribophototherapy with chemotherapy involving CP can shift the redox status favoring better cancer treatment. This strategy can not only increase the average life span of the cancer patients but also improve their quality of life significantly. However, cancer is still considered as a disease of genetic and metabolic disorders; hence, attacking both aspects of the disease can give better results as compared to contemporary treatment modalities.     

新型小分子免疫抑制剂研究进展

目前临床上应用的免疫抑制剂大多来源于微生物的次生代谢产物,如环孢素、他克莫司等,它们在器官移植和自身免疫系统疾病方面疗效显著,但其不良反应限制了其广泛应用。近年来研究发现了许多高活性、低不良反应的新型小分子免疫抑制剂。本文以新型小分子免疫抑制剂的作用靶点为分类依据,分别综述了鞘氨醇-1-磷酸(S1P)受体激动剂、二氢乳清酸脱氢酶(DHODH)抑制剂、蛋白激酶C(PKC)抑制剂和Janus激酶3(JAK3)抑制剂等4类免疫抑制剂的作用机制、研究现状及不良反应等。     

铂类抗肿瘤配合物的研究进展

铂类药物因抗癌谱广、疗效显著而在临床中被广泛使用。自1978年顺铂应用于临床以来,卡铂、奥沙利铂相继被美国FDA批准,乐铂、奈达铂和依铂分别在中国、日本以及韩国上市。然而,铂类药物的毒副作用和耐药性大大限制了其应用和开发。为提高铂类药物的疗效以及克服其缺陷,大量的新型铂类配合物被设计合成,并在不同阶段开展疗效试验。除与顺铂类似的铂(Ⅱ)配合物之外,近年来作为前药的铂(Ⅳ)配合物也被广泛研究。从铂(Ⅱ)配合物和铂(Ⅳ)配合物2个方面,总结近年来铂类抗肿瘤配合物取得的研究进展,并对配体的选择与配合物设计、作用机制、抗肿瘤效果以及临床应用前景进行概述,以期对今后的新药开发和临床应用有所裨益。     

Therapeutic vaccination against chronic hepatitis C virus infection

Approximately 170 million people worldwide are chronic carriers of Hepatitis C virus (HCV). To date, there is no prophylactic vaccine available against HCV. The standard-of-care therapy for HCV infection involves a combination of pegylated interferon-α and ribavirin. This therapy, which is commonly associated with side effects, has a curative rate varying from 43% (HCV genotype 1) to 80% (HCV genotype 2). In 2011, two direct-acting antiviral agents, telaprevir and boceprevir, were approved by the US Food and drug Administration and are now being used in combination with standard-of-care therapy in selected patients infected with HCV genotype 1. Although both drugs are promising, resulting in a shortening of therapy, these drugs also induce additional side effects and have reduced efficacy in patients who did not respond to standard-of-care previously. An alternative approach would be to treat HCV by stimulating the immune system with a therapeutic vaccine ideally aimed at (i) the eradication of HCV-infected cells and (ii) neutralization of infectious HCV particles. The challenge is to develop therapeutic vaccination strategies that are either at least as effective as antiviral drugs but with lower side effects, or vaccines that, when combined with antiviral drugs, can circumvent long-term use of these drugs thereby reducing their side effects. In this review, we summarize and discuss recent preclinical developments in the area of therapeutic vaccination against chronic HCV infection. Although neutralizing antibodies have been described to exert protective immunity, clinical studies on the induction of neutralizing antibodies in therapeutic settings are limited. Therefore, we will primarily discuss therapeutic vaccines which aim to induce effective cellular immune response against HCV.     

An update on the novel and approved drugs for Alzheimer disease

IntroductionGiven the severity of the condition and the increasing number of patients, developing effective therapies for Alzheimer's disease has become a significant necessity. Aggregation of Amyloid-Beta (Aβ) plaques and Tau Protein Tangles in the brain's nerve tissue are two of the most histopathological/pathophysiological symptoms. Another important element involved in the etiology of Alzheimer's disease is the reduction in acetylcholine (ACh) levels in the brain. Currently available medications for Alzheimer's disease treatment, such as cholinesterase inhibitors and an antagonist of the N-methyl-d-aspartate receptor, can temporarily reduce dementia symptoms but not stop or reverse disease development. In addition, several medicinal plants have been shown to diminish the degenerative characteristics associated with Alzheimer's disease, either in its crude form or as isolated chemicals.AimThis review summarises the results from previous studies that reflect an array of novel therapies underway in various phases of clinical trials. Many are discontinued due to non-adherence to the designed endpoints or the surfacing of unavoidable side effects. The present piece of article focuses on the approved drugs for the treatment of Alzheimer's disease and their related mode of action as well as the promising therapies for the treatment of the said disease. Special attention has been placed on the researched herbal drugs, with the pipeline of novel therapies underway in various phases of clinical trials.ResultThe current article includes a list of approved pharmaceuticals for treating Alzheimer's disease, prospective therapies for the illness's treatment, and a pipeline of novel therapies in various stages of clinical trials.ConclusionThe results suggest that the drugs under clinical trials may open new pathways for the effective treatment of patients with Alzheimer's disease while improving their quality of life.     

Advancing pharmacotherapy for treating Huntington’s disease: a review of the existing literature

Introduction: Huntington’s disease (HD) is an incurable chronic neurodegenerative disorder that typically presents in mid-life with a range of motor, cognitive and affective problems. Patients are currently managed using a combination of drug treatments and non-pharmacological therapies but at present there is no “gold standard” treatment for any aspect of the disease.

Areas covered: In this review the empirical evidence supporting the use of drugs commonly used to treat HD was discussed. In particular, we focus on therapeutics that have either reached phase 3 clinical trials or are already in clinical use.

Expert opinion: The results confirmed that there is a striking lack of evidence to support the efficacy of the drugs currently used in the management of HD. In fact, many drugs are prescribed on the basis of case reports, open label studies, small double blind placebo control trials of limited duration, or personal clinical experience. However of late, the establishment of large international databases, capturing all patients and their clinical details regardless of stage or geographical location has led to an increase in the number of clinical trials conducted on new therapies. Unfortunately, the same is not true for the existing therapies which look set to remain untested for the foreseeable future.     

Herbal Insomnia Medications that Target GABAergic Systems: A Review of the Psychopharmacological Evidence

Insomnia is a common sleep disorder which is prevalent in women and the elderly. Current insomnia drugs mainly target the γ-aminobutyric acid (GABA) receptor, melatonin receptor, histamine receptor, orexin, and serotonin receptor. GABA_A receptor modulators are ordinarily used to manage insomnia, but they are known to affect sleep maintenance, including residual effects, tolerance, and dependence. In an effort to discover new drugs that relieve insomnia symptoms while avoiding side effects, numerous studies focusing on the neurotransmitter GABA and herbal medicines have been conducted. Traditional herbal medicines, such as Piper methysticum and the seed of Zizyphus jujuba Mill var. spinosa, have been widely reported to improve sleep and other mental disorders. These herbal medicines have been applied for many years in folk medicine, and extracts of these medicines have been used to study their pharmacological actions and mechanisms. Although effective and relatively safe, natural plant products have some side effects, such as hepatotoxicity and skin reactions effects of Piper methysticum. In addition, there are insufficient evidences to certify the safety of most traditional herbal medicine. In this review, we provide an overview of the current state of knowledge regarding a variety of natural plant products that are commonly used to treat insomnia to facilitate future studies.     

SR 57746A/xaliproden,a non-peptide neurotrophic compound: prospects and constraints for the treatment of nervous system diseases

Neurodegenerative disorders such as Alzheimer's disease or amyotrophic lateral sclerosis as well as peripheral neuropathies are difficult to treat due to a limited range of effective drugs. Neurotrophic growth factors promote neuronal survival and differentiation and could hence be interesting tools to treat these diseases. Their therapeutic use is limited due their short half-life, their inability to cross the BBB and potential side effects including tumor promotion. SR 57746A is a non-peptide, orally active compound that exhibits neuroprotective effects in various model systems in vitro and in vivo. SR 57746A shows – amongst other activities – agonistic activity on 5-HT_1A receptors. Several clinical trials examined SR 57746A in patients with Alzheimer's disease, amyotrophic lateral sclerosis or chemotherapy-induced peripheral sensory neuropathy. This article reviews the preclinical and clinical data on SR 57746A and points out potential future applications of this compound. However, due to disapointing results in phase III trials, Sanofi-Aventis recently decided to discontinue the development of this drug.     

多靶点抗肿瘤天然产物研究进展

天然产物及其衍生物是抗肿瘤药物的重要组成部分.目前在临床上应用的天然产物来源的抗肿瘤药物以传统细胞毒类药物或靶向某一特定靶点的分子靶向药物为主,其应用受限于药物相关不良反应和肿瘤耐药.近年的研究表明,抗肿瘤活性天然产物往往能够靶向肿瘤细胞的多个靶点,影响肿瘤发生发展中的多个过程.由于肿瘤是一种多因素诱发的系统性疾病,多...     

烯二炔类抗肿瘤抗生素及其靶向药物研究近况

烯二炔类抗生素是一种结构新颖、作用机制独烯二炔结构是其活性中心。该类抗生素具有极强的抗肿瘤活性却因毒性较大难以直接用于临床。近年来,研究人员展开了烯二炔类抗生素靶向药物的研发工作,以提高其肿瘤靶向性并减少药物毒副作用。归纳总结了已报道的天然来源的烯二炔类抗肿瘤抗生素及其活性代谢物,并重点介绍烯二炔类抗生素相关靶向药物的研究进展,旨在为其深度开发提供参考。     

Importance of metabolic activation study to the safe use of Chinese herbal medicines

The number of new drugs approved for clinical use per year is falling in the last decade. One approach to reduce the high rate of attrition during early drug development is to systematically determine the toxic metabolites on the mechanism basis. Traditional Chinese herbal medicines (CHM) have been used extensively for disease treatment and health care. Recently, they have also been used as raw materials for preparation of herbal dietary supplements and nutraceuticals worldwide. However, problems arise due to the adverse effects caused by CHM and their derived products. Similar to synthetic drugs, among the diverse mechanisms the metabolism-induced adverse effect/toxicity is an important safety issue of CHM. For safe use of CHM and herbal products, it is also necessary to study herbinduced toxicities using the mechanism-based approach. CHM consist of multi-ingredients, which makes the study of toxic metabolites more difficult and challenging than that of synthetic drug-induced toxicity. In this mini-review, using hepatotoxicity and nephrotoxicity induced respectively by metabolic activation of pyrrolizidine alkaloids and aristolochic acid present in CHM as examples, we address the significance of metabolic study of CHM and how it contributes to the delineation of the toxic mechanisms, development of mechanismbased biomarkers for the diagnosis and assessment of adverse effect/toxicity of CHM, prediction of toxic dosage, and reduction and prevention of toxicity of CHM.     

非甾体类雄激素受体的靶向药物研究进展

雄激素受体在前列腺癌的发生和发展中作用明确。临床上用于治疗前列腺癌的药物为雄激素受体配体结合域的竞争性抑制剂。然而,这类药物的疗效因患者表现出现抵抗而受到限制,导致疾病发展为去势抵抗性前列腺癌。近年来靶向雄激素受体N-端结合域或DNA结合域的药物被报道,这些药物能够克服当前药物治疗的缺点,目前正在临床研究中。对不同靶向的非甾体类雄激素受体的研究进展进行综述。     

Risks and benefits of commonly used herbal medicines in Mexico

In Mexico, local empirical knowledge about medicinal properties of plants is the basis for their use as home remedies. It is generally accepted by many people in Mexico and elsewhere in the world that beneficial medicinal effects can be obtained by ingesting plant products. In this review, we focus on the potential pharmacologic bases for herbal plant efficacy, but we also raise concerns about the safety of these agents, which have not been fully assessed. Although numerous randomized clinical trials of herbal medicines have been published and systematic reviews and meta-analyses of these studies are available, generalizations about the efficacy and safety of herbal medicines are clearly not possible. Recent publications have also highlighted the unintended consequences of herbal product use, including morbidity and mortality. It has been found that many phytochemicals have pharmacokinetic or pharmacodynamic interactions with drugs. The present review is limited to some herbal medicines that are native or cultivated in Mexico and that have significant use. We discuss the cultural uses, phytochemistry, pharmacological, and toxicological properties of the following plant species: nopal (Opuntia ficus), peppermint (Mentha piperita), chaparral (Larrea divaricata), dandlion (Taraxacum officinale), mullein (Verbascum densiflorum), chamomile (Matricaria recutita), nettle or stinging nettle (Urtica dioica), passionflower (Passiflora incarnata), linden flower (Tilia europea), and aloe (Aloe vera). We conclude that our knowledge of the therapeutic benefits and risks of some herbal medicines used in Mexico is still limited and efforts to elucidate them should be intensified.     

Pharmacological activity of cardiovascular agents from herbal medicine

Some of the active phytochemicals in herbal medicine are finding therapeutic use. For example, patients with heart disease are reported to benefit from treatment with herbal medicine with fewer side effects. Previous studies showed the inhibitory effects of tetramethylpyrazine, an active component of medicinal herb, on phosphodiesterase that is associated with heart disease and the cardio-protective effects of other herbal medicine that was used to protect ischemia-reperfusion injury of rat hearts. Individual herbal medicines show antipyretic, analgesic and anti-inflammatory and anti-cancer effects. In addition to sharing many therapeutic activities, the active components of herbal medicine are also used in nutrient supplement for cardiovascular disease. Numerous in vitro studies of herbal medicine on different cell lines and in vivo study of herbal medicine have been reported. However, the mechanism of actions remains unclear. The present review aims to give an overview of the recent development of herbal medicine in treatment of cardiovascular disease, and covers the possible mechanism of action of some of active principles. The study will provide insights into drug action and demonstrate the therapeutic benefits of herbal medicine for the treatment of cardiovascular disease.     

Pharmacology and toxicology of Bupleurum root-containing Kampo medicines in clinical use

Kampo (Japanese traditional herbal) medicines have been produced by combining multiple crude drugs, almost all of plant origin but with some of animal or mineral origin, and contain a great many substances. Their effect is a combination of the various interactions of the constituent substances, whether they are enhancing, synergistic or suppressive. Kampo medicine has an overall effect that is different from the combined effects of individual crude drugs, and several side effects such as anorexia, slight fever and nausea have been reported in the treatment of certain disorders and disease states with Kampo medicines. Among 210 medical formulations used in Japan, some relevant information on the clinical uses, pharmacology and toxicology of six manufactured Kampo medical formulations, Shosaikoto, Daisaikoto, Saikokeishito, Hochuekkito, Saibokuto and Saireito, containing Bupleurum root are reviewed. Studies of some potential interactions between Kampo medicine and western drugs are also considered.